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What was the dosage of drug 'FILGRASTIM'?
|
Filgrastim associations with CAR T-cell therapy.
Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T-cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post-CAR T-cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T-cell therapy may lead to an increase in severity of CRS without decreasing infection rates.
Abbreviations
ANCabsolute neutrophil count
ASTCTAmerican Society of Transplantation and Cellular Therapy
CARchimeric antigen receptor
CTCAECommon Terminology Criteria for Adverse Events
DLBCLdiffuse large B‐cell lymphoma
G‐CSFgranulocyte colony‐stimulating factor
GM‐CSFgranulocyte‐macrophage colony‐stimulating factor
ICANSimmune effector cell‐associated neurotoxicity syndrome
IFNinterferon
ILinterleukin
IQRinterquartile range
RICErituximab/ifosfamide/carboplatin/etoposide
1 INTRODUCTION
While chimeric antigen receptor (CAR) T‐cell therapy is an exciting advancement in the treatment of patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), its application is limited by associated toxicities, including cytokine release syndrome (CRS), neurotoxicity and severe cytopenias, with 78% of patients developing Grade 3 or higher neutropenia in the ZUMA‐1 trial.
1
Recombinant granulocyte colony‐stimulating factor (G‐CSF) has been widely used to shorten the duration of neutropenia and risk of infection in other settings, such as neutropenic complications after conditioning for hematopoietic cell transplant.
2
However, in CAR T‐cell therapy, myeloid growth factors have the potential to increase the incidence and/or severity of CRS and immune effector cell‐associated neurotoxicity syndrome (ICANS) by promotion of proinflammatory cytokine secretion from monocytes and macrophages.
3
,
4
,
5
Preclinically, monocytes and macrophages are the main source of interleukin (IL)‐1 and IL‐6 during CRS.
4
,
5
Surprisingly, CRS severity is mediated not by CAR T‐cell‐derived cytokines, but by those of monocytes and macrophages.
4
,
5
Therefore, we sought to determine if a relationship exists between filgrastim administration, which stimulates myelopoiesis and enhances granulocyte function, and CRS. There is currently a lack of evidence to guide clinicians on the benefits and risks of recombinant myeloid growth factor use in CAR T‐cell treatment.
2 MATERIALS AND METHODS
Between March 2018 and May 2019, we reviewed 22 patients with DLBCL treated with axicabtagene ciloleucel with or without concurrent use of filgrastim. Prior to CAR T‐cell infusion, all patients received standard lymphodepleting therapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day on days −5 through −3, except for one patient that received reduced doses for chronic kidney disease Stage IV (fludarabine 15 mg/m2/day and cyclophosphamide 375 mg/m2/day). Prophylactic tocilizumab 8 mg/kg was given to all patients at 36 hours after CAR T‐cell infusion, with additional doses of tocilizumab and/or steroids given for evidence of CRS/ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system.
6
Filgrastim was administered at physician discretion after CAR T‐cell infusion at a weight‐based dose of either 300 or 480 mcg, and cumulative filgrastim dose was recorded within the first 30 days. Toxicity after CAR T‐cell therapy was also assessed up to 30 days postinfusion. Any patient with neutropenic fever was treated with broad‐spectrum antibiotics; no prophylactic antibiotics were given. Documented infections were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
7
Antibiotics were also administered for any confirmed infections. Chi‐squared test or Cochran‐Armitage test were performed to examine association between cohort characteristics and the study variable of administration with or without filgrastim.
3 RESULTS
Baseline patient characteristics are displayed in Table 1. The median age at the time of CAR T‐cell therapy was 65.0 years (interquartile range [IQR], 57.0‐68.8). The majority (14 patients, 63.6%) had high‐grade DLBCL, while 5 patients had DLBCL not otherwise specified, 2 patients had transformed follicular lymphoma and 1 patient had Richter's transformation. Seven patients (31.8%) had refractory DLBCL, while 15 patients (68.2%) had relapsed DLBCL with a median number of relapses prior to CAR T‐cell therapy of 1.0 (IQR, 0.0‐2.0). Thirteen patients (59.1%) had received greater than or equal to three prior therapies. Only one patient (4.6%) had received autologous hematopoietic cell transplant prior to CAR T‐cell therapy. Ten patients (45.5%) received bridging therapy for high disease burden before CAR T‐cell therapy, which included rituximab/gemcitabine‐oxaliplatin (7 patients), cytarabine/thiotepa (1 patient), rituximab/dexamethasone/cytarabine/cisplatin (1 patient), rituximab/ifosfamide/carboplatin/etoposide (RICE, 1 patient) and rituximab/cyclophosphamide/dexamethasone (1 patient). The number of cycles of bridging therapy ranged from 1 to 3 with a median of 2.
TABLE 1 Baseline patient and disease characteristics
All patients (N = 22)
Age at time of CAR T‐cell therapy (median, IQR) 65.0 (57.0, 68.8)
≥65 12 (54.6%)
<65 10 (45.5%)
Gender
Male 12 (54.6%)
Female 10 (45.5%)
Ethnicity
Caucasian 12 (54.6%)
Hispanic 7 (31.8%)
Asian 0 (0%)
African American 1 (4.6%)
Other 2 (9.1%)
Disease type
DLBCL NOS 5 (22.7%)
Transformed follicular 2 (9.1%)
Richter's transformation 1 (4.6%)
High‐grade DLBCL 14 (63.6%)
Cell of origin
GCB 10 (45.5%)
Non‐GCB 10 (45.5%)
Unspecified 2 (9.1%)
Relapse or Refractory
Relapse 15 (68.2%)
Refractory 7 (31.8%)
Number of prior therapies
<3 9 (40.9%)
≥3 13 (59.1%)
ASCT prior to CAR T‐cell therapy 1 (4.6%)
ECOG at time of CAR T‐cell therapy
0‐1 21 (95.5%)
2‐4 1 (4.6%)
Bridging therapy given before CAR T‐cell therapy
Yes 10 (45.5%)
No 12 (54.6%)
Abbreviations: ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; DLBCL, diffuse large B‐cell lymphoma; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B‐cell; NOS, not otherwise specified.
Seven of the 22 patients (31.8%) received filgrastim by physician discretion at a target dose of 5 mcg/kg/day with 3 patients receiving 300 mcg/day and 4 patients receiving 480 mcg/day. The median start day of filgrastim was 2 days post‐CAR T‐cell therapy (range Day −2 to Day +7), and the median number of filgrastim doses was 6 (range, 3‐18). The median duration of neutropenia after CAR T‐cell therapy was 5 days (IQR, 4.5‐8.5) for patients who received filgrastim compared to 15 days (IQR, 8.0‐30.0) for patients who did not receive filgrastim (P = .016; Table 2). Fourteen patients (63.6%) developed neutropenic fever after CAR T‐cell therapy, 6 of whom received filgrastim and 8 of whom had not (P = .193; Table 2). Five patients (22.7%) developed an infection in the 30 days post‐CAR T‐cell therapy including Clostridium difficile colitis (one patient, Grade 3), Enterococcus faecalis bacteremia (one patient, Grade 4), pneumonia (one patient, Grade 3) and Herpes simplex virus (two patients, Grades 1 and 2). Among the seven patients that received filgrastim, three patients (42.9%) developed an infection and two patients (28.6%) developed a Grade 3 or greater infection. Among the 15 patients that did not receive filgrastim, 2 patients (13.2%) developed an infection and 1 patient (6.7%) developed a Grade 3 or greater infection. There was no difference in the incidence and severity of infection between patients who received filgrastim and those that did not (P = .274, P = .138; Table 2; Figure 1).
TABLE 2 CAR T‐cell associated toxicity
All patients (N = 22) G‐CSF administered (N = 7) G‐CSF not administered (N = 15)
P value
Median duration of neutropenia (days) (IQR) 10 (6.0, 25.8) 5 (4.5, 8.5) 15 (8.0, 30.0) .016
Febrile neutropenia
No 8 (36.4%) 1 (14.3%) 7 (46.7%) .193
Yes 14 (63.6%) 6 (85.7%) 8 (53.5%)
New infection .274
None 17 (77.3%) 4 (57.1%) 13 (86.7%)
Any grade 5 (22.7%) 3 (42.9%) 2 (13.2%)
CRS .193
None 8 (36.4%) 1 (14.3%) 7 (46.7%)
Any grade 14 (63.6%) 6 (85.7%) 8 (53.3%)
ICANS .647
None 11 (50.0%) 3 (42.9%) 8 (53.3%)
Any grade 11 (50.0%) 4 (57.1%) 7 (46.7%)
Steroids given .648
No 9 (40.9%) 2 (28.6%) 7 (46.7%)
Yes 13 (59.1%) 5 (71.4%) 8 (53.3%)
More than one dose of tocilizumab given .074
No 10 (45.5%) 1 (14.3%) 9 (60.0%)
Yes 12 (54.6%) 6 (85.7%) 6 (40.0%)
Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; G‐CSF, granulocyte colony‐stimulating factor; ICANS, immune effector cell‐associated neurotoxicity syndrome.
FIGURE 1 Severity of chimeric antigen receptor (CAR) T‐cell associated toxicities based on granulocyte colony‐stimulating factor (G‐CSF) use. ICANS, immune effector cell‐associated neurotoxicity syndrome [Color figure can be viewed at wileyonlinelibrary.com]
CRS was noted in 14 patients overall (63.6%), and 4 patients (18.2%) had Grade 3 or higher CRS. Among the seven patients that received filgrastim, six patients (85.7%) had evidence of CRS and three patients (42.9%) had Grade 3 or higher CRS. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) had evidence of CRS and 1 patient (6.7%) had evidence of Grade 3 or higher CRS. ICANS was noted in 11 patients overall (50.0%), and 9 patients (40.9%) had Grade 3 or higher ICANS. Among the seven patients that received filgrastim, four patients (57.1%) had evidence of ICANS and three patients (42.9%) had evidence of Grade 3 or higher ICANS. Among the 15 patients that did not receive filgrastim, 7 patients (46.7%) had evidence of ICANS and 6 patients (40.0%) had Grade 3 or higher ICANS. There was no significant difference in the incidence of developing CRS (any grade) or ICANS (any grade) between the group of patients that received filgrastim and those that did not (P = .193, P = .647; Table 2). There was, however, a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042), but no increase in the severity of ICANS based on filgrastim use (P = .660; Figure 1).
Thirteen patients (59.1%) received corticosteroids after CAR T‐cell treatment at a median cumulative dosage of 666.7 mg prednisone equivalents (IQR, 445.0‐933.3), with the majority (9 patients, 69.2%) receiving steroids in the first 5 days post‐CAR T‐cell infusion. Half of the patient cohort (12 patients, 54.6%) required at least one dose of tocilizumab in addition to the scheduled prophylactic dose. Among the seven patients that received filgrastim, 5 patients (71.4%) received corticosteroids and 6 patients (85.7%) received more than one dose of tocilizumab. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) received corticosteroids and 6 patients (40.0%) received more than one dose of tocilizumab. There was no association between filgrastim use and steroid use or administration of additional doses of tocilizumab (P = .648, P = .074).
4 DISCUSSION
At our institution, filgrastim was administered after CAR T‐cell therapy at physician discretion with less than half of our patient cohort receiving filgrastim (seven patients, 31.8%). Importantly, although the median duration of neutropenia was significantly lower for patients who received filgrastim, there was no difference in the development or severity of infections (P = .274, P = .138). Instead, while patients given filgrastim were not more likely to develop CRS (P = .193), the severity of CRS was higher in those that received filgrastim (P = .042), as has been suggested by preclinical data modeling myeloid growth factors in combination with CAR T‐cells.
4
,
5
The development of CRS is related to activation of in vivo T‐cell expansion and the production of T‐cell effector cytokines, including IL‐6, IL‐10 and interferon (IFN)‐γ,
8
which are also downstream products of myeloid cells stimulated by filgrastim. One preclinical study showed that higher levels of murine G‐CSF correlated strongly with CRS severity and survival.
5
Elevated systemic levels of IL‐6 in particular have been associated with severe CRS, and IL‐6 receptor blockade with the monoclonal antibody tocilizumab is an important agent used to reduce CRS toxicity.
9
,
10
Of all the cytokines analyzed in the ZUMA‐2 study, only peak levels of granzyme B and granulocyte‐macrophage colony stimulating factor (GM‐CSF, a closely related protein to G‐CSF) were associated with severe CRS and severe ICANS.
11
CAR T‐cell associated neurotoxicity has been associated with elevations in similar inflammatory markers to CRS (IL‐6, IL‐10, IFNγ), in addition to higher serum levels of G‐CSF and GM‐CSF.
12
,
13
Mouse models of CRS and ICANS have suggested that the main driver of CAR T‐cell neurotoxicity is actually IL‐1 secretion from activated macrophages.
4
,
5
Unlike its efficacy in CRS, tocilizumab did not protect mice from lethal neurotoxicity, a finding analogous in humans; however the IL‐1 receptor antagonist anakinra abolished both CRS and neurotoxicity.
4
,
12
Interestingly, in addition to its stimulatory effects on granulocytes, filgrastim has immunomodulatory effects on other immune cells and can inhibit inflammatory cytokine production within monocytes or macrophages.
14
This may account for why we found no association with filgrastim and the development or severity of neurotoxicity (P = .647, P = .660). GM‐CSF, which induces both granulocytes and macrophages, may be more closely tied to neurotoxic effects and, in fact, GM‐CSF inhibition has been shown to reduce neuroinflammation and prevent CRS.
15
The guidelines on use of filgrastim and other growth factors with CAR T‐cell therapy are not standardized. While some recommend administration of myeloid growth factors once absolute neutrophil count (ANC) decreases to <500/μL and to continue until ANC increases to ≥1500/μL,
16
others recommend administration of filgrastim only if patients develop Grade 1 CRS at the same time as neutropenia or in the setting of neutropenic fever.
17
The use of myeloid growth factors across institutions employing CAR T‐cell therapy is also mixed. In an electronic survey on the current administrative, logistic and toxicity management practices of CAR T‐cell therapy across the United States by the ASTCT, out of 28 respondents, 46% used growth factor if allowed by product labeling, 29% never administered growth factor, 14% determined the use of growth factor on a patient‐specific basis and 11% administered growth factor to all patients.
18
Although our study is limited by its small sample size and retrospective nature, we suggest that myeloid growth factor administration be used with caution in patients undergoing CAR T‐cell therapy. We found an association between filgrastim use and CRS severity, suggesting that increasing the number of patients in the study would strengthen the association. However, the effect size of the association was small. Further studies are required to determine the safety of myeloid growth factors after CAR T‐cell therapy.
CONFLICT OF INTEREST
The authors declared no potential conflicts of interest.
ETHICS STATEMENT
This study was approved by the University of California Los Angeles Institutional Review Board. Informed consent was not required for this study.
ACKNOWLEDGMENT
This work was supported by National Institutes of Health Grant Number 1K08CA245483‐01. Myung Shin Sim was supported by NIH National Center for Advancing Translational Sciences (Grant 5UL1TR001881‐05).
DATA AVAILABILITY STATEMENT
Data are available on request from the authors.
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5 MICROGRAM/KILOGRAM, QD
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DrugDosageText
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CC BY-NC
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33091961
| 18,449,659
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2021-03-01
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What was the dosage of drug 'FLUDARABINE PHOSPHATE'?
|
Filgrastim associations with CAR T-cell therapy.
Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T-cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post-CAR T-cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T-cell therapy may lead to an increase in severity of CRS without decreasing infection rates.
Abbreviations
ANCabsolute neutrophil count
ASTCTAmerican Society of Transplantation and Cellular Therapy
CARchimeric antigen receptor
CTCAECommon Terminology Criteria for Adverse Events
DLBCLdiffuse large B‐cell lymphoma
G‐CSFgranulocyte colony‐stimulating factor
GM‐CSFgranulocyte‐macrophage colony‐stimulating factor
ICANSimmune effector cell‐associated neurotoxicity syndrome
IFNinterferon
ILinterleukin
IQRinterquartile range
RICErituximab/ifosfamide/carboplatin/etoposide
1 INTRODUCTION
While chimeric antigen receptor (CAR) T‐cell therapy is an exciting advancement in the treatment of patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), its application is limited by associated toxicities, including cytokine release syndrome (CRS), neurotoxicity and severe cytopenias, with 78% of patients developing Grade 3 or higher neutropenia in the ZUMA‐1 trial.
1
Recombinant granulocyte colony‐stimulating factor (G‐CSF) has been widely used to shorten the duration of neutropenia and risk of infection in other settings, such as neutropenic complications after conditioning for hematopoietic cell transplant.
2
However, in CAR T‐cell therapy, myeloid growth factors have the potential to increase the incidence and/or severity of CRS and immune effector cell‐associated neurotoxicity syndrome (ICANS) by promotion of proinflammatory cytokine secretion from monocytes and macrophages.
3
,
4
,
5
Preclinically, monocytes and macrophages are the main source of interleukin (IL)‐1 and IL‐6 during CRS.
4
,
5
Surprisingly, CRS severity is mediated not by CAR T‐cell‐derived cytokines, but by those of monocytes and macrophages.
4
,
5
Therefore, we sought to determine if a relationship exists between filgrastim administration, which stimulates myelopoiesis and enhances granulocyte function, and CRS. There is currently a lack of evidence to guide clinicians on the benefits and risks of recombinant myeloid growth factor use in CAR T‐cell treatment.
2 MATERIALS AND METHODS
Between March 2018 and May 2019, we reviewed 22 patients with DLBCL treated with axicabtagene ciloleucel with or without concurrent use of filgrastim. Prior to CAR T‐cell infusion, all patients received standard lymphodepleting therapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day on days −5 through −3, except for one patient that received reduced doses for chronic kidney disease Stage IV (fludarabine 15 mg/m2/day and cyclophosphamide 375 mg/m2/day). Prophylactic tocilizumab 8 mg/kg was given to all patients at 36 hours after CAR T‐cell infusion, with additional doses of tocilizumab and/or steroids given for evidence of CRS/ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system.
6
Filgrastim was administered at physician discretion after CAR T‐cell infusion at a weight‐based dose of either 300 or 480 mcg, and cumulative filgrastim dose was recorded within the first 30 days. Toxicity after CAR T‐cell therapy was also assessed up to 30 days postinfusion. Any patient with neutropenic fever was treated with broad‐spectrum antibiotics; no prophylactic antibiotics were given. Documented infections were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
7
Antibiotics were also administered for any confirmed infections. Chi‐squared test or Cochran‐Armitage test were performed to examine association between cohort characteristics and the study variable of administration with or without filgrastim.
3 RESULTS
Baseline patient characteristics are displayed in Table 1. The median age at the time of CAR T‐cell therapy was 65.0 years (interquartile range [IQR], 57.0‐68.8). The majority (14 patients, 63.6%) had high‐grade DLBCL, while 5 patients had DLBCL not otherwise specified, 2 patients had transformed follicular lymphoma and 1 patient had Richter's transformation. Seven patients (31.8%) had refractory DLBCL, while 15 patients (68.2%) had relapsed DLBCL with a median number of relapses prior to CAR T‐cell therapy of 1.0 (IQR, 0.0‐2.0). Thirteen patients (59.1%) had received greater than or equal to three prior therapies. Only one patient (4.6%) had received autologous hematopoietic cell transplant prior to CAR T‐cell therapy. Ten patients (45.5%) received bridging therapy for high disease burden before CAR T‐cell therapy, which included rituximab/gemcitabine‐oxaliplatin (7 patients), cytarabine/thiotepa (1 patient), rituximab/dexamethasone/cytarabine/cisplatin (1 patient), rituximab/ifosfamide/carboplatin/etoposide (RICE, 1 patient) and rituximab/cyclophosphamide/dexamethasone (1 patient). The number of cycles of bridging therapy ranged from 1 to 3 with a median of 2.
TABLE 1 Baseline patient and disease characteristics
All patients (N = 22)
Age at time of CAR T‐cell therapy (median, IQR) 65.0 (57.0, 68.8)
≥65 12 (54.6%)
<65 10 (45.5%)
Gender
Male 12 (54.6%)
Female 10 (45.5%)
Ethnicity
Caucasian 12 (54.6%)
Hispanic 7 (31.8%)
Asian 0 (0%)
African American 1 (4.6%)
Other 2 (9.1%)
Disease type
DLBCL NOS 5 (22.7%)
Transformed follicular 2 (9.1%)
Richter's transformation 1 (4.6%)
High‐grade DLBCL 14 (63.6%)
Cell of origin
GCB 10 (45.5%)
Non‐GCB 10 (45.5%)
Unspecified 2 (9.1%)
Relapse or Refractory
Relapse 15 (68.2%)
Refractory 7 (31.8%)
Number of prior therapies
<3 9 (40.9%)
≥3 13 (59.1%)
ASCT prior to CAR T‐cell therapy 1 (4.6%)
ECOG at time of CAR T‐cell therapy
0‐1 21 (95.5%)
2‐4 1 (4.6%)
Bridging therapy given before CAR T‐cell therapy
Yes 10 (45.5%)
No 12 (54.6%)
Abbreviations: ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; DLBCL, diffuse large B‐cell lymphoma; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B‐cell; NOS, not otherwise specified.
Seven of the 22 patients (31.8%) received filgrastim by physician discretion at a target dose of 5 mcg/kg/day with 3 patients receiving 300 mcg/day and 4 patients receiving 480 mcg/day. The median start day of filgrastim was 2 days post‐CAR T‐cell therapy (range Day −2 to Day +7), and the median number of filgrastim doses was 6 (range, 3‐18). The median duration of neutropenia after CAR T‐cell therapy was 5 days (IQR, 4.5‐8.5) for patients who received filgrastim compared to 15 days (IQR, 8.0‐30.0) for patients who did not receive filgrastim (P = .016; Table 2). Fourteen patients (63.6%) developed neutropenic fever after CAR T‐cell therapy, 6 of whom received filgrastim and 8 of whom had not (P = .193; Table 2). Five patients (22.7%) developed an infection in the 30 days post‐CAR T‐cell therapy including Clostridium difficile colitis (one patient, Grade 3), Enterococcus faecalis bacteremia (one patient, Grade 4), pneumonia (one patient, Grade 3) and Herpes simplex virus (two patients, Grades 1 and 2). Among the seven patients that received filgrastim, three patients (42.9%) developed an infection and two patients (28.6%) developed a Grade 3 or greater infection. Among the 15 patients that did not receive filgrastim, 2 patients (13.2%) developed an infection and 1 patient (6.7%) developed a Grade 3 or greater infection. There was no difference in the incidence and severity of infection between patients who received filgrastim and those that did not (P = .274, P = .138; Table 2; Figure 1).
TABLE 2 CAR T‐cell associated toxicity
All patients (N = 22) G‐CSF administered (N = 7) G‐CSF not administered (N = 15)
P value
Median duration of neutropenia (days) (IQR) 10 (6.0, 25.8) 5 (4.5, 8.5) 15 (8.0, 30.0) .016
Febrile neutropenia
No 8 (36.4%) 1 (14.3%) 7 (46.7%) .193
Yes 14 (63.6%) 6 (85.7%) 8 (53.5%)
New infection .274
None 17 (77.3%) 4 (57.1%) 13 (86.7%)
Any grade 5 (22.7%) 3 (42.9%) 2 (13.2%)
CRS .193
None 8 (36.4%) 1 (14.3%) 7 (46.7%)
Any grade 14 (63.6%) 6 (85.7%) 8 (53.3%)
ICANS .647
None 11 (50.0%) 3 (42.9%) 8 (53.3%)
Any grade 11 (50.0%) 4 (57.1%) 7 (46.7%)
Steroids given .648
No 9 (40.9%) 2 (28.6%) 7 (46.7%)
Yes 13 (59.1%) 5 (71.4%) 8 (53.3%)
More than one dose of tocilizumab given .074
No 10 (45.5%) 1 (14.3%) 9 (60.0%)
Yes 12 (54.6%) 6 (85.7%) 6 (40.0%)
Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; G‐CSF, granulocyte colony‐stimulating factor; ICANS, immune effector cell‐associated neurotoxicity syndrome.
FIGURE 1 Severity of chimeric antigen receptor (CAR) T‐cell associated toxicities based on granulocyte colony‐stimulating factor (G‐CSF) use. ICANS, immune effector cell‐associated neurotoxicity syndrome [Color figure can be viewed at wileyonlinelibrary.com]
CRS was noted in 14 patients overall (63.6%), and 4 patients (18.2%) had Grade 3 or higher CRS. Among the seven patients that received filgrastim, six patients (85.7%) had evidence of CRS and three patients (42.9%) had Grade 3 or higher CRS. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) had evidence of CRS and 1 patient (6.7%) had evidence of Grade 3 or higher CRS. ICANS was noted in 11 patients overall (50.0%), and 9 patients (40.9%) had Grade 3 or higher ICANS. Among the seven patients that received filgrastim, four patients (57.1%) had evidence of ICANS and three patients (42.9%) had evidence of Grade 3 or higher ICANS. Among the 15 patients that did not receive filgrastim, 7 patients (46.7%) had evidence of ICANS and 6 patients (40.0%) had Grade 3 or higher ICANS. There was no significant difference in the incidence of developing CRS (any grade) or ICANS (any grade) between the group of patients that received filgrastim and those that did not (P = .193, P = .647; Table 2). There was, however, a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042), but no increase in the severity of ICANS based on filgrastim use (P = .660; Figure 1).
Thirteen patients (59.1%) received corticosteroids after CAR T‐cell treatment at a median cumulative dosage of 666.7 mg prednisone equivalents (IQR, 445.0‐933.3), with the majority (9 patients, 69.2%) receiving steroids in the first 5 days post‐CAR T‐cell infusion. Half of the patient cohort (12 patients, 54.6%) required at least one dose of tocilizumab in addition to the scheduled prophylactic dose. Among the seven patients that received filgrastim, 5 patients (71.4%) received corticosteroids and 6 patients (85.7%) received more than one dose of tocilizumab. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) received corticosteroids and 6 patients (40.0%) received more than one dose of tocilizumab. There was no association between filgrastim use and steroid use or administration of additional doses of tocilizumab (P = .648, P = .074).
4 DISCUSSION
At our institution, filgrastim was administered after CAR T‐cell therapy at physician discretion with less than half of our patient cohort receiving filgrastim (seven patients, 31.8%). Importantly, although the median duration of neutropenia was significantly lower for patients who received filgrastim, there was no difference in the development or severity of infections (P = .274, P = .138). Instead, while patients given filgrastim were not more likely to develop CRS (P = .193), the severity of CRS was higher in those that received filgrastim (P = .042), as has been suggested by preclinical data modeling myeloid growth factors in combination with CAR T‐cells.
4
,
5
The development of CRS is related to activation of in vivo T‐cell expansion and the production of T‐cell effector cytokines, including IL‐6, IL‐10 and interferon (IFN)‐γ,
8
which are also downstream products of myeloid cells stimulated by filgrastim. One preclinical study showed that higher levels of murine G‐CSF correlated strongly with CRS severity and survival.
5
Elevated systemic levels of IL‐6 in particular have been associated with severe CRS, and IL‐6 receptor blockade with the monoclonal antibody tocilizumab is an important agent used to reduce CRS toxicity.
9
,
10
Of all the cytokines analyzed in the ZUMA‐2 study, only peak levels of granzyme B and granulocyte‐macrophage colony stimulating factor (GM‐CSF, a closely related protein to G‐CSF) were associated with severe CRS and severe ICANS.
11
CAR T‐cell associated neurotoxicity has been associated with elevations in similar inflammatory markers to CRS (IL‐6, IL‐10, IFNγ), in addition to higher serum levels of G‐CSF and GM‐CSF.
12
,
13
Mouse models of CRS and ICANS have suggested that the main driver of CAR T‐cell neurotoxicity is actually IL‐1 secretion from activated macrophages.
4
,
5
Unlike its efficacy in CRS, tocilizumab did not protect mice from lethal neurotoxicity, a finding analogous in humans; however the IL‐1 receptor antagonist anakinra abolished both CRS and neurotoxicity.
4
,
12
Interestingly, in addition to its stimulatory effects on granulocytes, filgrastim has immunomodulatory effects on other immune cells and can inhibit inflammatory cytokine production within monocytes or macrophages.
14
This may account for why we found no association with filgrastim and the development or severity of neurotoxicity (P = .647, P = .660). GM‐CSF, which induces both granulocytes and macrophages, may be more closely tied to neurotoxic effects and, in fact, GM‐CSF inhibition has been shown to reduce neuroinflammation and prevent CRS.
15
The guidelines on use of filgrastim and other growth factors with CAR T‐cell therapy are not standardized. While some recommend administration of myeloid growth factors once absolute neutrophil count (ANC) decreases to <500/μL and to continue until ANC increases to ≥1500/μL,
16
others recommend administration of filgrastim only if patients develop Grade 1 CRS at the same time as neutropenia or in the setting of neutropenic fever.
17
The use of myeloid growth factors across institutions employing CAR T‐cell therapy is also mixed. In an electronic survey on the current administrative, logistic and toxicity management practices of CAR T‐cell therapy across the United States by the ASTCT, out of 28 respondents, 46% used growth factor if allowed by product labeling, 29% never administered growth factor, 14% determined the use of growth factor on a patient‐specific basis and 11% administered growth factor to all patients.
18
Although our study is limited by its small sample size and retrospective nature, we suggest that myeloid growth factor administration be used with caution in patients undergoing CAR T‐cell therapy. We found an association between filgrastim use and CRS severity, suggesting that increasing the number of patients in the study would strengthen the association. However, the effect size of the association was small. Further studies are required to determine the safety of myeloid growth factors after CAR T‐cell therapy.
CONFLICT OF INTEREST
The authors declared no potential conflicts of interest.
ETHICS STATEMENT
This study was approved by the University of California Los Angeles Institutional Review Board. Informed consent was not required for this study.
ACKNOWLEDGMENT
This work was supported by National Institutes of Health Grant Number 1K08CA245483‐01. Myung Shin Sim was supported by NIH National Center for Advancing Translational Sciences (Grant 5UL1TR001881‐05).
DATA AVAILABILITY STATEMENT
Data are available on request from the authors.
|
30 MILLIGRAM/SQ. METER, QD
|
DrugDosageText
|
CC BY-NC
|
33091961
| 18,449,659
|
2021-03-01
|
What was the dosage of drug 'TOCILIZUMAB'?
|
Filgrastim associations with CAR T-cell therapy.
Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T-cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post-CAR T-cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T-cell therapy may lead to an increase in severity of CRS without decreasing infection rates.
Abbreviations
ANCabsolute neutrophil count
ASTCTAmerican Society of Transplantation and Cellular Therapy
CARchimeric antigen receptor
CTCAECommon Terminology Criteria for Adverse Events
DLBCLdiffuse large B‐cell lymphoma
G‐CSFgranulocyte colony‐stimulating factor
GM‐CSFgranulocyte‐macrophage colony‐stimulating factor
ICANSimmune effector cell‐associated neurotoxicity syndrome
IFNinterferon
ILinterleukin
IQRinterquartile range
RICErituximab/ifosfamide/carboplatin/etoposide
1 INTRODUCTION
While chimeric antigen receptor (CAR) T‐cell therapy is an exciting advancement in the treatment of patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), its application is limited by associated toxicities, including cytokine release syndrome (CRS), neurotoxicity and severe cytopenias, with 78% of patients developing Grade 3 or higher neutropenia in the ZUMA‐1 trial.
1
Recombinant granulocyte colony‐stimulating factor (G‐CSF) has been widely used to shorten the duration of neutropenia and risk of infection in other settings, such as neutropenic complications after conditioning for hematopoietic cell transplant.
2
However, in CAR T‐cell therapy, myeloid growth factors have the potential to increase the incidence and/or severity of CRS and immune effector cell‐associated neurotoxicity syndrome (ICANS) by promotion of proinflammatory cytokine secretion from monocytes and macrophages.
3
,
4
,
5
Preclinically, monocytes and macrophages are the main source of interleukin (IL)‐1 and IL‐6 during CRS.
4
,
5
Surprisingly, CRS severity is mediated not by CAR T‐cell‐derived cytokines, but by those of monocytes and macrophages.
4
,
5
Therefore, we sought to determine if a relationship exists between filgrastim administration, which stimulates myelopoiesis and enhances granulocyte function, and CRS. There is currently a lack of evidence to guide clinicians on the benefits and risks of recombinant myeloid growth factor use in CAR T‐cell treatment.
2 MATERIALS AND METHODS
Between March 2018 and May 2019, we reviewed 22 patients with DLBCL treated with axicabtagene ciloleucel with or without concurrent use of filgrastim. Prior to CAR T‐cell infusion, all patients received standard lymphodepleting therapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day on days −5 through −3, except for one patient that received reduced doses for chronic kidney disease Stage IV (fludarabine 15 mg/m2/day and cyclophosphamide 375 mg/m2/day). Prophylactic tocilizumab 8 mg/kg was given to all patients at 36 hours after CAR T‐cell infusion, with additional doses of tocilizumab and/or steroids given for evidence of CRS/ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system.
6
Filgrastim was administered at physician discretion after CAR T‐cell infusion at a weight‐based dose of either 300 or 480 mcg, and cumulative filgrastim dose was recorded within the first 30 days. Toxicity after CAR T‐cell therapy was also assessed up to 30 days postinfusion. Any patient with neutropenic fever was treated with broad‐spectrum antibiotics; no prophylactic antibiotics were given. Documented infections were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
7
Antibiotics were also administered for any confirmed infections. Chi‐squared test or Cochran‐Armitage test were performed to examine association between cohort characteristics and the study variable of administration with or without filgrastim.
3 RESULTS
Baseline patient characteristics are displayed in Table 1. The median age at the time of CAR T‐cell therapy was 65.0 years (interquartile range [IQR], 57.0‐68.8). The majority (14 patients, 63.6%) had high‐grade DLBCL, while 5 patients had DLBCL not otherwise specified, 2 patients had transformed follicular lymphoma and 1 patient had Richter's transformation. Seven patients (31.8%) had refractory DLBCL, while 15 patients (68.2%) had relapsed DLBCL with a median number of relapses prior to CAR T‐cell therapy of 1.0 (IQR, 0.0‐2.0). Thirteen patients (59.1%) had received greater than or equal to three prior therapies. Only one patient (4.6%) had received autologous hematopoietic cell transplant prior to CAR T‐cell therapy. Ten patients (45.5%) received bridging therapy for high disease burden before CAR T‐cell therapy, which included rituximab/gemcitabine‐oxaliplatin (7 patients), cytarabine/thiotepa (1 patient), rituximab/dexamethasone/cytarabine/cisplatin (1 patient), rituximab/ifosfamide/carboplatin/etoposide (RICE, 1 patient) and rituximab/cyclophosphamide/dexamethasone (1 patient). The number of cycles of bridging therapy ranged from 1 to 3 with a median of 2.
TABLE 1 Baseline patient and disease characteristics
All patients (N = 22)
Age at time of CAR T‐cell therapy (median, IQR) 65.0 (57.0, 68.8)
≥65 12 (54.6%)
<65 10 (45.5%)
Gender
Male 12 (54.6%)
Female 10 (45.5%)
Ethnicity
Caucasian 12 (54.6%)
Hispanic 7 (31.8%)
Asian 0 (0%)
African American 1 (4.6%)
Other 2 (9.1%)
Disease type
DLBCL NOS 5 (22.7%)
Transformed follicular 2 (9.1%)
Richter's transformation 1 (4.6%)
High‐grade DLBCL 14 (63.6%)
Cell of origin
GCB 10 (45.5%)
Non‐GCB 10 (45.5%)
Unspecified 2 (9.1%)
Relapse or Refractory
Relapse 15 (68.2%)
Refractory 7 (31.8%)
Number of prior therapies
<3 9 (40.9%)
≥3 13 (59.1%)
ASCT prior to CAR T‐cell therapy 1 (4.6%)
ECOG at time of CAR T‐cell therapy
0‐1 21 (95.5%)
2‐4 1 (4.6%)
Bridging therapy given before CAR T‐cell therapy
Yes 10 (45.5%)
No 12 (54.6%)
Abbreviations: ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; DLBCL, diffuse large B‐cell lymphoma; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B‐cell; NOS, not otherwise specified.
Seven of the 22 patients (31.8%) received filgrastim by physician discretion at a target dose of 5 mcg/kg/day with 3 patients receiving 300 mcg/day and 4 patients receiving 480 mcg/day. The median start day of filgrastim was 2 days post‐CAR T‐cell therapy (range Day −2 to Day +7), and the median number of filgrastim doses was 6 (range, 3‐18). The median duration of neutropenia after CAR T‐cell therapy was 5 days (IQR, 4.5‐8.5) for patients who received filgrastim compared to 15 days (IQR, 8.0‐30.0) for patients who did not receive filgrastim (P = .016; Table 2). Fourteen patients (63.6%) developed neutropenic fever after CAR T‐cell therapy, 6 of whom received filgrastim and 8 of whom had not (P = .193; Table 2). Five patients (22.7%) developed an infection in the 30 days post‐CAR T‐cell therapy including Clostridium difficile colitis (one patient, Grade 3), Enterococcus faecalis bacteremia (one patient, Grade 4), pneumonia (one patient, Grade 3) and Herpes simplex virus (two patients, Grades 1 and 2). Among the seven patients that received filgrastim, three patients (42.9%) developed an infection and two patients (28.6%) developed a Grade 3 or greater infection. Among the 15 patients that did not receive filgrastim, 2 patients (13.2%) developed an infection and 1 patient (6.7%) developed a Grade 3 or greater infection. There was no difference in the incidence and severity of infection between patients who received filgrastim and those that did not (P = .274, P = .138; Table 2; Figure 1).
TABLE 2 CAR T‐cell associated toxicity
All patients (N = 22) G‐CSF administered (N = 7) G‐CSF not administered (N = 15)
P value
Median duration of neutropenia (days) (IQR) 10 (6.0, 25.8) 5 (4.5, 8.5) 15 (8.0, 30.0) .016
Febrile neutropenia
No 8 (36.4%) 1 (14.3%) 7 (46.7%) .193
Yes 14 (63.6%) 6 (85.7%) 8 (53.5%)
New infection .274
None 17 (77.3%) 4 (57.1%) 13 (86.7%)
Any grade 5 (22.7%) 3 (42.9%) 2 (13.2%)
CRS .193
None 8 (36.4%) 1 (14.3%) 7 (46.7%)
Any grade 14 (63.6%) 6 (85.7%) 8 (53.3%)
ICANS .647
None 11 (50.0%) 3 (42.9%) 8 (53.3%)
Any grade 11 (50.0%) 4 (57.1%) 7 (46.7%)
Steroids given .648
No 9 (40.9%) 2 (28.6%) 7 (46.7%)
Yes 13 (59.1%) 5 (71.4%) 8 (53.3%)
More than one dose of tocilizumab given .074
No 10 (45.5%) 1 (14.3%) 9 (60.0%)
Yes 12 (54.6%) 6 (85.7%) 6 (40.0%)
Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; G‐CSF, granulocyte colony‐stimulating factor; ICANS, immune effector cell‐associated neurotoxicity syndrome.
FIGURE 1 Severity of chimeric antigen receptor (CAR) T‐cell associated toxicities based on granulocyte colony‐stimulating factor (G‐CSF) use. ICANS, immune effector cell‐associated neurotoxicity syndrome [Color figure can be viewed at wileyonlinelibrary.com]
CRS was noted in 14 patients overall (63.6%), and 4 patients (18.2%) had Grade 3 or higher CRS. Among the seven patients that received filgrastim, six patients (85.7%) had evidence of CRS and three patients (42.9%) had Grade 3 or higher CRS. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) had evidence of CRS and 1 patient (6.7%) had evidence of Grade 3 or higher CRS. ICANS was noted in 11 patients overall (50.0%), and 9 patients (40.9%) had Grade 3 or higher ICANS. Among the seven patients that received filgrastim, four patients (57.1%) had evidence of ICANS and three patients (42.9%) had evidence of Grade 3 or higher ICANS. Among the 15 patients that did not receive filgrastim, 7 patients (46.7%) had evidence of ICANS and 6 patients (40.0%) had Grade 3 or higher ICANS. There was no significant difference in the incidence of developing CRS (any grade) or ICANS (any grade) between the group of patients that received filgrastim and those that did not (P = .193, P = .647; Table 2). There was, however, a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042), but no increase in the severity of ICANS based on filgrastim use (P = .660; Figure 1).
Thirteen patients (59.1%) received corticosteroids after CAR T‐cell treatment at a median cumulative dosage of 666.7 mg prednisone equivalents (IQR, 445.0‐933.3), with the majority (9 patients, 69.2%) receiving steroids in the first 5 days post‐CAR T‐cell infusion. Half of the patient cohort (12 patients, 54.6%) required at least one dose of tocilizumab in addition to the scheduled prophylactic dose. Among the seven patients that received filgrastim, 5 patients (71.4%) received corticosteroids and 6 patients (85.7%) received more than one dose of tocilizumab. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) received corticosteroids and 6 patients (40.0%) received more than one dose of tocilizumab. There was no association between filgrastim use and steroid use or administration of additional doses of tocilizumab (P = .648, P = .074).
4 DISCUSSION
At our institution, filgrastim was administered after CAR T‐cell therapy at physician discretion with less than half of our patient cohort receiving filgrastim (seven patients, 31.8%). Importantly, although the median duration of neutropenia was significantly lower for patients who received filgrastim, there was no difference in the development or severity of infections (P = .274, P = .138). Instead, while patients given filgrastim were not more likely to develop CRS (P = .193), the severity of CRS was higher in those that received filgrastim (P = .042), as has been suggested by preclinical data modeling myeloid growth factors in combination with CAR T‐cells.
4
,
5
The development of CRS is related to activation of in vivo T‐cell expansion and the production of T‐cell effector cytokines, including IL‐6, IL‐10 and interferon (IFN)‐γ,
8
which are also downstream products of myeloid cells stimulated by filgrastim. One preclinical study showed that higher levels of murine G‐CSF correlated strongly with CRS severity and survival.
5
Elevated systemic levels of IL‐6 in particular have been associated with severe CRS, and IL‐6 receptor blockade with the monoclonal antibody tocilizumab is an important agent used to reduce CRS toxicity.
9
,
10
Of all the cytokines analyzed in the ZUMA‐2 study, only peak levels of granzyme B and granulocyte‐macrophage colony stimulating factor (GM‐CSF, a closely related protein to G‐CSF) were associated with severe CRS and severe ICANS.
11
CAR T‐cell associated neurotoxicity has been associated with elevations in similar inflammatory markers to CRS (IL‐6, IL‐10, IFNγ), in addition to higher serum levels of G‐CSF and GM‐CSF.
12
,
13
Mouse models of CRS and ICANS have suggested that the main driver of CAR T‐cell neurotoxicity is actually IL‐1 secretion from activated macrophages.
4
,
5
Unlike its efficacy in CRS, tocilizumab did not protect mice from lethal neurotoxicity, a finding analogous in humans; however the IL‐1 receptor antagonist anakinra abolished both CRS and neurotoxicity.
4
,
12
Interestingly, in addition to its stimulatory effects on granulocytes, filgrastim has immunomodulatory effects on other immune cells and can inhibit inflammatory cytokine production within monocytes or macrophages.
14
This may account for why we found no association with filgrastim and the development or severity of neurotoxicity (P = .647, P = .660). GM‐CSF, which induces both granulocytes and macrophages, may be more closely tied to neurotoxic effects and, in fact, GM‐CSF inhibition has been shown to reduce neuroinflammation and prevent CRS.
15
The guidelines on use of filgrastim and other growth factors with CAR T‐cell therapy are not standardized. While some recommend administration of myeloid growth factors once absolute neutrophil count (ANC) decreases to <500/μL and to continue until ANC increases to ≥1500/μL,
16
others recommend administration of filgrastim only if patients develop Grade 1 CRS at the same time as neutropenia or in the setting of neutropenic fever.
17
The use of myeloid growth factors across institutions employing CAR T‐cell therapy is also mixed. In an electronic survey on the current administrative, logistic and toxicity management practices of CAR T‐cell therapy across the United States by the ASTCT, out of 28 respondents, 46% used growth factor if allowed by product labeling, 29% never administered growth factor, 14% determined the use of growth factor on a patient‐specific basis and 11% administered growth factor to all patients.
18
Although our study is limited by its small sample size and retrospective nature, we suggest that myeloid growth factor administration be used with caution in patients undergoing CAR T‐cell therapy. We found an association between filgrastim use and CRS severity, suggesting that increasing the number of patients in the study would strengthen the association. However, the effect size of the association was small. Further studies are required to determine the safety of myeloid growth factors after CAR T‐cell therapy.
CONFLICT OF INTEREST
The authors declared no potential conflicts of interest.
ETHICS STATEMENT
This study was approved by the University of California Los Angeles Institutional Review Board. Informed consent was not required for this study.
ACKNOWLEDGMENT
This work was supported by National Institutes of Health Grant Number 1K08CA245483‐01. Myung Shin Sim was supported by NIH National Center for Advancing Translational Sciences (Grant 5UL1TR001881‐05).
DATA AVAILABILITY STATEMENT
Data are available on request from the authors.
|
8 MILLIGRAM/KILOGRAM
|
DrugDosageText
|
CC BY-NC
|
33091961
| 18,449,659
|
2021-03-01
|
What was the outcome of reaction 'Diffuse large B-cell lymphoma'?
|
Filgrastim associations with CAR T-cell therapy.
Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T-cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post-CAR T-cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T-cell therapy may lead to an increase in severity of CRS without decreasing infection rates.
Abbreviations
ANCabsolute neutrophil count
ASTCTAmerican Society of Transplantation and Cellular Therapy
CARchimeric antigen receptor
CTCAECommon Terminology Criteria for Adverse Events
DLBCLdiffuse large B‐cell lymphoma
G‐CSFgranulocyte colony‐stimulating factor
GM‐CSFgranulocyte‐macrophage colony‐stimulating factor
ICANSimmune effector cell‐associated neurotoxicity syndrome
IFNinterferon
ILinterleukin
IQRinterquartile range
RICErituximab/ifosfamide/carboplatin/etoposide
1 INTRODUCTION
While chimeric antigen receptor (CAR) T‐cell therapy is an exciting advancement in the treatment of patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), its application is limited by associated toxicities, including cytokine release syndrome (CRS), neurotoxicity and severe cytopenias, with 78% of patients developing Grade 3 or higher neutropenia in the ZUMA‐1 trial.
1
Recombinant granulocyte colony‐stimulating factor (G‐CSF) has been widely used to shorten the duration of neutropenia and risk of infection in other settings, such as neutropenic complications after conditioning for hematopoietic cell transplant.
2
However, in CAR T‐cell therapy, myeloid growth factors have the potential to increase the incidence and/or severity of CRS and immune effector cell‐associated neurotoxicity syndrome (ICANS) by promotion of proinflammatory cytokine secretion from monocytes and macrophages.
3
,
4
,
5
Preclinically, monocytes and macrophages are the main source of interleukin (IL)‐1 and IL‐6 during CRS.
4
,
5
Surprisingly, CRS severity is mediated not by CAR T‐cell‐derived cytokines, but by those of monocytes and macrophages.
4
,
5
Therefore, we sought to determine if a relationship exists between filgrastim administration, which stimulates myelopoiesis and enhances granulocyte function, and CRS. There is currently a lack of evidence to guide clinicians on the benefits and risks of recombinant myeloid growth factor use in CAR T‐cell treatment.
2 MATERIALS AND METHODS
Between March 2018 and May 2019, we reviewed 22 patients with DLBCL treated with axicabtagene ciloleucel with or without concurrent use of filgrastim. Prior to CAR T‐cell infusion, all patients received standard lymphodepleting therapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day on days −5 through −3, except for one patient that received reduced doses for chronic kidney disease Stage IV (fludarabine 15 mg/m2/day and cyclophosphamide 375 mg/m2/day). Prophylactic tocilizumab 8 mg/kg was given to all patients at 36 hours after CAR T‐cell infusion, with additional doses of tocilizumab and/or steroids given for evidence of CRS/ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system.
6
Filgrastim was administered at physician discretion after CAR T‐cell infusion at a weight‐based dose of either 300 or 480 mcg, and cumulative filgrastim dose was recorded within the first 30 days. Toxicity after CAR T‐cell therapy was also assessed up to 30 days postinfusion. Any patient with neutropenic fever was treated with broad‐spectrum antibiotics; no prophylactic antibiotics were given. Documented infections were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
7
Antibiotics were also administered for any confirmed infections. Chi‐squared test or Cochran‐Armitage test were performed to examine association between cohort characteristics and the study variable of administration with or without filgrastim.
3 RESULTS
Baseline patient characteristics are displayed in Table 1. The median age at the time of CAR T‐cell therapy was 65.0 years (interquartile range [IQR], 57.0‐68.8). The majority (14 patients, 63.6%) had high‐grade DLBCL, while 5 patients had DLBCL not otherwise specified, 2 patients had transformed follicular lymphoma and 1 patient had Richter's transformation. Seven patients (31.8%) had refractory DLBCL, while 15 patients (68.2%) had relapsed DLBCL with a median number of relapses prior to CAR T‐cell therapy of 1.0 (IQR, 0.0‐2.0). Thirteen patients (59.1%) had received greater than or equal to three prior therapies. Only one patient (4.6%) had received autologous hematopoietic cell transplant prior to CAR T‐cell therapy. Ten patients (45.5%) received bridging therapy for high disease burden before CAR T‐cell therapy, which included rituximab/gemcitabine‐oxaliplatin (7 patients), cytarabine/thiotepa (1 patient), rituximab/dexamethasone/cytarabine/cisplatin (1 patient), rituximab/ifosfamide/carboplatin/etoposide (RICE, 1 patient) and rituximab/cyclophosphamide/dexamethasone (1 patient). The number of cycles of bridging therapy ranged from 1 to 3 with a median of 2.
TABLE 1 Baseline patient and disease characteristics
All patients (N = 22)
Age at time of CAR T‐cell therapy (median, IQR) 65.0 (57.0, 68.8)
≥65 12 (54.6%)
<65 10 (45.5%)
Gender
Male 12 (54.6%)
Female 10 (45.5%)
Ethnicity
Caucasian 12 (54.6%)
Hispanic 7 (31.8%)
Asian 0 (0%)
African American 1 (4.6%)
Other 2 (9.1%)
Disease type
DLBCL NOS 5 (22.7%)
Transformed follicular 2 (9.1%)
Richter's transformation 1 (4.6%)
High‐grade DLBCL 14 (63.6%)
Cell of origin
GCB 10 (45.5%)
Non‐GCB 10 (45.5%)
Unspecified 2 (9.1%)
Relapse or Refractory
Relapse 15 (68.2%)
Refractory 7 (31.8%)
Number of prior therapies
<3 9 (40.9%)
≥3 13 (59.1%)
ASCT prior to CAR T‐cell therapy 1 (4.6%)
ECOG at time of CAR T‐cell therapy
0‐1 21 (95.5%)
2‐4 1 (4.6%)
Bridging therapy given before CAR T‐cell therapy
Yes 10 (45.5%)
No 12 (54.6%)
Abbreviations: ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; DLBCL, diffuse large B‐cell lymphoma; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B‐cell; NOS, not otherwise specified.
Seven of the 22 patients (31.8%) received filgrastim by physician discretion at a target dose of 5 mcg/kg/day with 3 patients receiving 300 mcg/day and 4 patients receiving 480 mcg/day. The median start day of filgrastim was 2 days post‐CAR T‐cell therapy (range Day −2 to Day +7), and the median number of filgrastim doses was 6 (range, 3‐18). The median duration of neutropenia after CAR T‐cell therapy was 5 days (IQR, 4.5‐8.5) for patients who received filgrastim compared to 15 days (IQR, 8.0‐30.0) for patients who did not receive filgrastim (P = .016; Table 2). Fourteen patients (63.6%) developed neutropenic fever after CAR T‐cell therapy, 6 of whom received filgrastim and 8 of whom had not (P = .193; Table 2). Five patients (22.7%) developed an infection in the 30 days post‐CAR T‐cell therapy including Clostridium difficile colitis (one patient, Grade 3), Enterococcus faecalis bacteremia (one patient, Grade 4), pneumonia (one patient, Grade 3) and Herpes simplex virus (two patients, Grades 1 and 2). Among the seven patients that received filgrastim, three patients (42.9%) developed an infection and two patients (28.6%) developed a Grade 3 or greater infection. Among the 15 patients that did not receive filgrastim, 2 patients (13.2%) developed an infection and 1 patient (6.7%) developed a Grade 3 or greater infection. There was no difference in the incidence and severity of infection between patients who received filgrastim and those that did not (P = .274, P = .138; Table 2; Figure 1).
TABLE 2 CAR T‐cell associated toxicity
All patients (N = 22) G‐CSF administered (N = 7) G‐CSF not administered (N = 15)
P value
Median duration of neutropenia (days) (IQR) 10 (6.0, 25.8) 5 (4.5, 8.5) 15 (8.0, 30.0) .016
Febrile neutropenia
No 8 (36.4%) 1 (14.3%) 7 (46.7%) .193
Yes 14 (63.6%) 6 (85.7%) 8 (53.5%)
New infection .274
None 17 (77.3%) 4 (57.1%) 13 (86.7%)
Any grade 5 (22.7%) 3 (42.9%) 2 (13.2%)
CRS .193
None 8 (36.4%) 1 (14.3%) 7 (46.7%)
Any grade 14 (63.6%) 6 (85.7%) 8 (53.3%)
ICANS .647
None 11 (50.0%) 3 (42.9%) 8 (53.3%)
Any grade 11 (50.0%) 4 (57.1%) 7 (46.7%)
Steroids given .648
No 9 (40.9%) 2 (28.6%) 7 (46.7%)
Yes 13 (59.1%) 5 (71.4%) 8 (53.3%)
More than one dose of tocilizumab given .074
No 10 (45.5%) 1 (14.3%) 9 (60.0%)
Yes 12 (54.6%) 6 (85.7%) 6 (40.0%)
Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; G‐CSF, granulocyte colony‐stimulating factor; ICANS, immune effector cell‐associated neurotoxicity syndrome.
FIGURE 1 Severity of chimeric antigen receptor (CAR) T‐cell associated toxicities based on granulocyte colony‐stimulating factor (G‐CSF) use. ICANS, immune effector cell‐associated neurotoxicity syndrome [Color figure can be viewed at wileyonlinelibrary.com]
CRS was noted in 14 patients overall (63.6%), and 4 patients (18.2%) had Grade 3 or higher CRS. Among the seven patients that received filgrastim, six patients (85.7%) had evidence of CRS and three patients (42.9%) had Grade 3 or higher CRS. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) had evidence of CRS and 1 patient (6.7%) had evidence of Grade 3 or higher CRS. ICANS was noted in 11 patients overall (50.0%), and 9 patients (40.9%) had Grade 3 or higher ICANS. Among the seven patients that received filgrastim, four patients (57.1%) had evidence of ICANS and three patients (42.9%) had evidence of Grade 3 or higher ICANS. Among the 15 patients that did not receive filgrastim, 7 patients (46.7%) had evidence of ICANS and 6 patients (40.0%) had Grade 3 or higher ICANS. There was no significant difference in the incidence of developing CRS (any grade) or ICANS (any grade) between the group of patients that received filgrastim and those that did not (P = .193, P = .647; Table 2). There was, however, a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042), but no increase in the severity of ICANS based on filgrastim use (P = .660; Figure 1).
Thirteen patients (59.1%) received corticosteroids after CAR T‐cell treatment at a median cumulative dosage of 666.7 mg prednisone equivalents (IQR, 445.0‐933.3), with the majority (9 patients, 69.2%) receiving steroids in the first 5 days post‐CAR T‐cell infusion. Half of the patient cohort (12 patients, 54.6%) required at least one dose of tocilizumab in addition to the scheduled prophylactic dose. Among the seven patients that received filgrastim, 5 patients (71.4%) received corticosteroids and 6 patients (85.7%) received more than one dose of tocilizumab. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) received corticosteroids and 6 patients (40.0%) received more than one dose of tocilizumab. There was no association between filgrastim use and steroid use or administration of additional doses of tocilizumab (P = .648, P = .074).
4 DISCUSSION
At our institution, filgrastim was administered after CAR T‐cell therapy at physician discretion with less than half of our patient cohort receiving filgrastim (seven patients, 31.8%). Importantly, although the median duration of neutropenia was significantly lower for patients who received filgrastim, there was no difference in the development or severity of infections (P = .274, P = .138). Instead, while patients given filgrastim were not more likely to develop CRS (P = .193), the severity of CRS was higher in those that received filgrastim (P = .042), as has been suggested by preclinical data modeling myeloid growth factors in combination with CAR T‐cells.
4
,
5
The development of CRS is related to activation of in vivo T‐cell expansion and the production of T‐cell effector cytokines, including IL‐6, IL‐10 and interferon (IFN)‐γ,
8
which are also downstream products of myeloid cells stimulated by filgrastim. One preclinical study showed that higher levels of murine G‐CSF correlated strongly with CRS severity and survival.
5
Elevated systemic levels of IL‐6 in particular have been associated with severe CRS, and IL‐6 receptor blockade with the monoclonal antibody tocilizumab is an important agent used to reduce CRS toxicity.
9
,
10
Of all the cytokines analyzed in the ZUMA‐2 study, only peak levels of granzyme B and granulocyte‐macrophage colony stimulating factor (GM‐CSF, a closely related protein to G‐CSF) were associated with severe CRS and severe ICANS.
11
CAR T‐cell associated neurotoxicity has been associated with elevations in similar inflammatory markers to CRS (IL‐6, IL‐10, IFNγ), in addition to higher serum levels of G‐CSF and GM‐CSF.
12
,
13
Mouse models of CRS and ICANS have suggested that the main driver of CAR T‐cell neurotoxicity is actually IL‐1 secretion from activated macrophages.
4
,
5
Unlike its efficacy in CRS, tocilizumab did not protect mice from lethal neurotoxicity, a finding analogous in humans; however the IL‐1 receptor antagonist anakinra abolished both CRS and neurotoxicity.
4
,
12
Interestingly, in addition to its stimulatory effects on granulocytes, filgrastim has immunomodulatory effects on other immune cells and can inhibit inflammatory cytokine production within monocytes or macrophages.
14
This may account for why we found no association with filgrastim and the development or severity of neurotoxicity (P = .647, P = .660). GM‐CSF, which induces both granulocytes and macrophages, may be more closely tied to neurotoxic effects and, in fact, GM‐CSF inhibition has been shown to reduce neuroinflammation and prevent CRS.
15
The guidelines on use of filgrastim and other growth factors with CAR T‐cell therapy are not standardized. While some recommend administration of myeloid growth factors once absolute neutrophil count (ANC) decreases to <500/μL and to continue until ANC increases to ≥1500/μL,
16
others recommend administration of filgrastim only if patients develop Grade 1 CRS at the same time as neutropenia or in the setting of neutropenic fever.
17
The use of myeloid growth factors across institutions employing CAR T‐cell therapy is also mixed. In an electronic survey on the current administrative, logistic and toxicity management practices of CAR T‐cell therapy across the United States by the ASTCT, out of 28 respondents, 46% used growth factor if allowed by product labeling, 29% never administered growth factor, 14% determined the use of growth factor on a patient‐specific basis and 11% administered growth factor to all patients.
18
Although our study is limited by its small sample size and retrospective nature, we suggest that myeloid growth factor administration be used with caution in patients undergoing CAR T‐cell therapy. We found an association between filgrastim use and CRS severity, suggesting that increasing the number of patients in the study would strengthen the association. However, the effect size of the association was small. Further studies are required to determine the safety of myeloid growth factors after CAR T‐cell therapy.
CONFLICT OF INTEREST
The authors declared no potential conflicts of interest.
ETHICS STATEMENT
This study was approved by the University of California Los Angeles Institutional Review Board. Informed consent was not required for this study.
ACKNOWLEDGMENT
This work was supported by National Institutes of Health Grant Number 1K08CA245483‐01. Myung Shin Sim was supported by NIH National Center for Advancing Translational Sciences (Grant 5UL1TR001881‐05).
DATA AVAILABILITY STATEMENT
Data are available on request from the authors.
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Fatal
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ReactionOutcome
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CC BY-NC
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2021-03-01
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse event'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
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Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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RISPERIDONE
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DrugsGivenReaction
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CC BY-NC
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33098548
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2021-06
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dizziness'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dystonia'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'High density lipoprotein decreased'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Psychotic disorder'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sedation'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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What was the dosage of drug 'RISPERIDONE'?
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Long-Term Assessment of Lurasidone in Schizophrenia: Post Hoc Analysis of a 12-Month, Double Blind, Active-Controlled Trial and 6-Month Open-Label Extension Study.
BACKGROUND
A post hoc analysis of a double-blind (DB) active control trial and an open-label extension (OLE) study was conducted to evaluate the long-term effects of lurasidone in patients with schizophrenia.
METHODS
In the DB trial, patients were randomised to receive lurasidone or risperidone for 12 months. In OLE, all patients received lurasidone for an additional 6 months. Treatment-emergent adverse events (TEAEs) were evaluated. Efficacy assessments included relapse rate (DB trial only), and Positive and Negative Syndrome Scale, Clinical Global Impression-Severity scale, and Montgomery-Åsberg Depression Rating Scale.
RESULTS
In the DB trial, patients with schizophrenia were randomised to lurasidone (n = 399) and risperidone (n = 190), of whom 129 and 84 continued into OLE, respectively. During the DB trial, incidence of TEAEs was similar for lurasidone (84.1%) and risperidone (84.2%). Lurasidone was associated with minimal changes in metabolic variables and prolactin levels, whereas risperidone was associated with clinically significant increases in prolactin and fasting glucose levels. The proportion of patients with metabolic syndrome was significantly lower in patients treated with lurasidone versus risperidone at the end of the DB trial (25.5% vs 40.4%; p = 0.0177). During OLE, patients switching from risperidone to lurasidone experienced a reduction in weight and prolactin levels; those continuing treatment with lurasidone experienced minimal changes in metabolic variables and prolactin. At the end of OLE, the proportion of patients with metabolic syndrome was no longer significantly different between groups (23.5% vs 31.5%; p = not significant). Efficacy outcomes were generally similar between groups during the DB trial, and were maintained during OLE.
CONCLUSIONS
Lurasidone was generally well tolerated and effective in clinically stable schizophrenia patients over the long term. Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients switching from risperidone. Patients switching from risperidone experienced improvements in metabolic parameters and prolactin levels. These findings confirm lurasidone's long-term effectiveness and favourable metabolic profile in patients with schizophrenia.
BACKGROUND
ClinicalTrials.gov identifier NCT00641745.
Key Summary Points
People with schizophrenia are at higher risk than the general population of cardiometabolic diseases, the risk of which is further increased by some antipsychotics.
This analysis evaluated the long-term effects of lurasidone in patients with schizophrenia, who received lurasidone during a double-blind trial and its open-label extension study, or who received risperidone during the double-blind trial but then switched to lurasidone during the open-label study.
Lurasidone demonstrated sustained long-term efficacy and was associated with minimal changes in metabolic variables and prolactin levels.
Patients switching from risperidone to lurasidone experienced improvements in metabolic parameters and prolactin levels.
These findings confirm lurasidone’s long-term efficacy and favourable metabolic safety profile in patients with schizophrenia.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13084943.
Introduction
Schizophrenia is a severe and chronic mental illness that affects approximately 20 million people worldwide [1]. People with schizophrenia are 2–3 times as likely to die early as the general population, resulting in a reduced life expectancy of 10–20 years [2, 3]. This reduction in life expectancy largely results from an increased likelihood of cardiovascular disease, diabetes mellitus, and other physical conditions, exacerbated by insufficient prevention of modifiable risk factors [3, 4]. Cardiovascular disease is the leading cause of death in schizophrenia, individuals with the disorder having significantly higher risks of metabolic syndrome, abdominal obesity, dyslipidaemia, and hypertension than the general population [5–8]. Moreover, metabolic disturbances in those with schizophrenia increase with disease duration and age [5]. Although cardiometabolic disturbances appear to be an intrinsic part of schizophrenia itself, the risk of such disturbances is frequently increased by antipsychotic treatment, particularly treatment with atypical antipsychotics [3, 5]. With the exception of clozapine, the efficacy of atypical antipsychotics is largely similar, but the agents vary greatly in terms of safety profiles, most notably with regard to cardiometabolic risk [9, 10].
Lurasidone is a once-daily second-generation antipsychotic that is widely approved for the treatment of schizophrenia, including in Europe and the USA [11, 12]. Similar to most other atypical antipsychotics, lurasidone has high binding affinity for dopamine D2 and serotonin 5-HT2A receptors and moderate affinity for D3 and 5-HT1A receptors, but it differs from other atypical agents in being an antagonist with high affinity for 5-HT7 receptors and having negligible affinity for histamine H1 and muscarinic M1 receptors [11, 13]. Lurasidone has a relatively benign cardiometabolic profile when compared with most other atypical antipsychotics, being associated with minimal weight gain and no clinically meaningful alterations in lipid, glucose, and prolactin levels or the electrocardiogram (ECG) QT interval [9, 10, 14].
The long-term safety, tolerability, and efficacy of lurasidone were assessed in a 12-month, international, double-blind (DB), active-controlled trial [Study 237], in which patients were randomised to receive treatment with either lurasidone or risperidone [15]. This was followed by a 6-month open-label extension (OLE) study (Study 237-EXT), in which all patients received treatment with lurasidone (those having received risperidone during the initial DB trial switching to lurasidone) [16]. These studies included patients with a primary diagnosis of schizophrenia or schizoaffective disorder, as established by a structured diagnostic interview and application of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria [6]. Patients with schizoaffective disorder experience the psychotic symptoms of schizophrenia (e.g. delusions, hallucinations, disorganised thinking, flat affect), along with symptoms of a mood disorder, such as depression and/or mania [17], but tend to have more favourable outcomes than those with schizophrenia [18]. There are currently no specific treatment guidelines for schizoaffective disorder, due to a lack of evidence in patients with the disorder [19], and there may be differences in sensitivity to antipsychotics in term of efficacy and safety between patients with schizophrenia and schizoaffective disorder.
Given the differences in diagnostic criteria and outcomes for schizophrenia and schizoaffective disorder, post hoc analyses of Studies 237 and 237-EXT were conducted in order to assess the safety, tolerability, and efficacy of lurasidone versus risperidone over 12 months, specifically in patients with schizophrenia, and to further assess the long-term safety, tolerability, and efficacy of lurasidone over an additional 6 months in patients with schizophrenia treated with lurasidone in Study 237 and in those who switched from risperidone to lurasidone at the start of Study 237-EXT.
Methods
The methodologies of Studies 237 (DB trial) and 237-EXT (OLE study) were published previously, and the studies are registered on ClinicalTrials.gov (NCT00641745) [15, 16]. Both were conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an independent ethics committee or institutional review board at each study centre, and all patients provided written informed consent prior to participation [15, 16].
Study Population
Key inclusion criteria for schizophrenia patients in the initial DB trial were: age 18–75 years; primary diagnosis of schizophrenia (DSM-IV criteria) of at least 1-year duration; ‘clinically stable’ (non-acute phase of illness) for ≥ 8 weeks before baseline; no change in antipsychotic medications for ≥ 6 weeks before screening; no hospitalisation for psychiatric illness for ≥ 8 weeks before screening; and moderate or lower (≤ 4) severity rating on the Positive and Negative Syndrome Scale (PANSS) items of delusions, conceptual disorganisation, hallucinations, and unusual thought content. Key exclusion criteria included: current clinically significant somatic disorders or abnormal laboratory testing; clinically significant suicidal ideation, suicidal behaviour, or violent behaviour in the past 6 months; a history of a poor/inadequate response or intolerability to risperidone; and body mass index (BMI) < 18.5 or > 40 kg/m2 [15]. Patients who completed the initial DB trial were eligible to continue into the OLE study [16].
Study Design
In the initial DB trial, patients were randomised in a 2:1 ratio to receive lurasidone (flexibly dosed, 37–111 mg/day) or risperidone (flexibly dosed, 2–6 mg/day) for 12 months [15]. In the OLE study, all patients were treated with lurasidone. To maintain the DB in the initial trial, all patients entering the OLE study received 3 days of single-blind placebo washout followed by 7 days of lurasidone 80 mg/day, after which lurasidone dosing could be adjusted, based on the judgment of the investigator, within a dose range of 37–111 mg/day over a treatment period of 6 months [16].
Study Assessments
In the DB trial, patients were monitored for safety, tolerability, and efficacy every 1–3 weeks for the first 12 weeks and monthly thereafter [15]. In the OLE study, assessments were conducted at OLE baseline and monthly thereafter [16]. Assessments were the same during the DB trial and OLE study, with the exception of relapse rate, which was only measured during the DB trial [15, 16].
Safety was assessed by evaluation of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, extrapyramidal symptom (EPS)-related TEAEs, and metabolic-related TEAEs, and by monitoring of metabolic variables (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, glucose, glycated haemoglobin [HbA1c], and insulin), prolactin, weight, BMI, waist circumference, and ECG parameters. TEAEs presented for the OLE study were those recorded during the period from the baseline of the OLE study to the end of the OLE study. EPS-related and metabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial. EPS-related TEAEs comprised bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus. Metabolic-related TEAEs included increased blood glucose, increased blood triglycerides, diabetes mellitus, increased HbA1c, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase. The proportion of patients with metabolic syndrome was assessed at baseline, month 6, and month 12. Patients were classified as having metabolic syndrome based on the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria [20] when any three of the following five criteria were met: large waist circumference (≥ 102 cm for men; ≥ 88 cm for women [US criteria]), elevated triglycerides (≥ 150 mg/dL), low HDL cholesterol (< 40 mg/dL in men; < 50 mg/dL in women), elevated blood pressure (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg), or elevated fasting glucose (≥ 100 mg/dL). In the current analysis, an NCEP ATP III criterion was not considered to be met if a patient had normal values for triglycerides, blood pressure, HDL cholesterol, and/or glucose while receiving drug treatment for one or more of these parameters. Movement disorders were evaluated using the Barnes Akathisia Scale (BAS) [21], Simpson-Angus Scale (SAS) [22], and Abnormal Involuntary Movement Scale (AIMS) [23].
Efficacy assessments included relapse rate (DB trial only), PANSS [24], Clinical Global Impression–Severity scale (CGI-S) [23], and Montgomery–Åsberg Depression Rating Scale (MADRS) [25]. Relapse was defined as the earliest occurrence of: worsening of the PANSS total score by 30% from baseline and CGI-S > 3; rehospitalisation for worsening of psychosis; or emergence of suicidal ideation, homicidal ideation, and/or risk of harm to self or others [15].
Statistical Analysis
Full details of the statistical methodologies employed have been published previously [15, 16]. The safety population was defined as all randomised patients who received at least one dose of study medication, and the intent-to-treat (ITT) population was defined as all randomised patients who received at least one dose of study medication and had a baseline and at least one post-baseline efficacy assessment for PANSS or CGI-S.
In the DB trial, the changes in continuous variables from baseline were evaluated and compared between treatment groups using a non-parametric rank analysis of covariance at month-12 last observation carried forward (LOCF) endpoint. For some variables, shifts from baseline to LOCF endpoint were additionally assessed as the percentage of patients with values below, within, and above the normal range. Categorical safety outcomes were further evaluated using the number needed to harm (NNH). The 95% confidence interval (CI) for NNH was calculated based on the Wald method [26, 27]. Time to relapse was analysed using the Kaplan–Meier method and Cox progression hazards model. PANSS, CGI-S, and MADRS scores were analysed using a mixed model for repeated measurement [15].
In the OLE study, changes from baseline were calculated from DB baseline to OLE LOCF endpoint, and from OLE baseline to OLE LOCF endpoint, comparing the groups of patients who initially received lurasidone in the DB trial (‘lurasidone–lurasidone’ group) with those who initially received risperidone and switched to lurasidone at the start of the OLE study (‘risperidone–lurasidone’ group). Observed cases and LOCF analyses were performed [16].
Results
Patient Disposition
The randomised population of the initial DB trial included 629 patients [15], of whom 589 had schizophrenia and 40 had schizoaffective disorder. Of the 589 patients with schizophrenia who were included in the current study, 399 and 190 were randomised to receive treatment with lurasidone and risperidone, respectively (Fig. 1). Overall, 139/399 (34.8%) patients treated with lurasidone and 86/190 (45.3%) patients treated with risperidone completed the 1-year DB trial. The most common reasons for discontinuation (lurasidone vs risperidone) were withdrawal of consent (17.0% vs 14.7%), adverse events (16.5% vs 10.0%), loss to follow-up (11.3% vs 8.9%), and insufficient clinical response (7.5% vs 6.3%). A total of 129 patients treated with lurasidone and 84 patients treated with risperidone continued into the OLE study, of whom 103/129 (79.8%) and 62/84 (73.8%) completed the OLE study, respectively (Fig. 1). The most common reason for discontinuation during the OLE study (lurasidone vs risperidone) was loss to follow-up/withdrawal of consent (9.3% vs 10.7%).Fig. 1 Disposition of patients with schizophrenia. *Due to a lack of drug supply at study centres in Argentina and Brazil, patients who had not completed the DB trial had the option of enrolling in the OLE study or discontinuing the study. DB double-blind, OLE open-label extension
Patient Characteristics
Demographic and clinical characteristics were generally well balanced between treatment groups at baseline in both the DB trial and the OLE study (Table 1). The mean (standard deviation [SD]) age in the lurasidone versus risperidone groups was 41.9 (11.3) versus 41.1 (11.3) years at baseline in the DB trial, and 44.2 (10.8) versus 42.5 (10.8) years at baseline in the OLE study. A slightly higher proportion of lurasidone versus risperidone patients were male (74.2% vs 63.7% at DB baseline; 75.2% vs 66.7% at OLE baseline). The PANSS total, CGI-S total, and MADRS total scores were similar between treatment groups at baseline in both the DB trial and OLE study.Table 1 Demographic and baseline characteristics in (A) the DB trial and (B) the OLE study (safety population)
Characteristic (A) DB trial (Study 237) (B) OLE study (Study 237-EXT)
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Gender, n (%)
Male 290 (74.2) 121 (63.7) 97 (75.2) 56 (66.7)
Female 101 (25.8) 69 (36.3) 32 (24.8) 28 (33.3)
Age, years
Mean (SD) 41.9 (11.3) 41.1 (11.3) 44.2 (10.8) 42.5 (10.8)
Median (range) 43.0 (18–73) 43.0 (18–65) 46.0 (19–70) 46.0 (20–62)
Race, n (%)
Black/African American 208 (53.2) 95 (50.0) 64 (49.6) 38 (45.2)
White 136 (34.8) 80 (42.1) 46 (35.7) 38 (45.2)
Asian 17 (4.3) 3 (1.6) 6 (4.7) 1 (1.2)
Other 30 (7.7) 12 (6.3) 13 (10.1) 7 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino 312 (79.8) 148 (77.9) 95 (73.6) 60 (71.4)
Hispanic or Latino 79 (20.2) 42 (22.1) 34 (26.4) 24 (28.6)
Duration of illness, years
Mean (SD) 3.8 (6.2)a,b 3.5 (5.0)a 17.1 (10.8) 17.5 (11.8)
Median (range) 1.0 (0–34)a,b 2.0 (0–34)a 16.0 (1–47) 16.0 (1–42)
Number of prior hospitalisations, n (%)
0 83 (21.2) 37 (19.5) 35 (27.1) 15 (17.9)
1 67 (17.1) 35 (18.4) 24 (18.6) 17 (20.2)
2 57 (14.6) 30 (15.8) 24 (18.6) 17 (20.2)
3 54 (13.8) 21 (11.1) 18 (14.0) 10 (11.9)
≥ 4 130 (33.2) 67 (35.3) 28 (21.7) 25 (29.8)
PANSS total score at DB baseline
Mean (SD) 65.0 (12.5) 65.7 (12.2) 63.8 (13.2) 64.2 (12.7)
Median (range) 65.0 (34–98) 66.0 (34–103) 63.0 (34–95) 65.0 (34–103)
CGI-S total score at DB baseline
Mean (SD) 3.4 (0.6) 3.5 (0.6) 3.4 (0.7) 3.5 (0.6)
Median (range) 3.0 (1.0–5.0) 4.0 (2.0–4.0) 3.0 (1–4) 4.0 (2–4)
MADRS total score at DB baseline
Mean (SD) 7.2 (6.8) 8.1 (7.4) 6.2 (6.3) 7.0 (6.4)
Median (range) 6.0 (0–34) 6.0 (0–34) 5.0 (0–32) 6.0 (0–34)
PANSS total score at OLE baseline
Mean (SD) NA NA 55.1 (13.8) 55.8 (11.2)
Median (range) 56.0 (30–103) 56.5 (30–78)
CGI-S total score at OLE baseline
Mean (SD) NA NA 2.8 (0.8) 2.9 (0.8)
Median (range) 3.0 (1–4) 3.0 (1–5)
MADRS total score at OLE baseline
Mean (SD) NA NA 4.8 (5.4) 4.4 (4.4)
Median (range) 4.0 (0–33) 4.0 (0–29)
aLast acute episode to randomisation
bN = 389
CGI-S Clinical Global Impression–Severity scale, DB double-blind, MADRS Montgomery–Åsberg Depression Rating Scale, NA not applicable, OLE open-label extension, PANSS Positive and Negative Syndrome Scale, SD standard deviation
Antipsychotic Treatment
The majority of patients had been treated with antipsychotic medication before enrolment (lurasidone, 96.2%; risperidone, 96.3%), and the mean (SD) duration of prior exposure was 198.7 (147.4) days in the lurasidone group (median, 196.0; range 1–391) and 225.9 (154.0) days in the risperidone group (median, 321.0; range, 1–397). The mean (SD) daily doses at DB baseline were 78.6 (20.2) mg/day for lurasidone (median, 74.0; range 37.6–110.4) and 4.3 (1.0) mg/day for risperidone (median, 4.0; range, 2.0–6.0). The modal daily doses were 37 (13.3%), 74 (60.1%), and 111 (26.6%) mg/day for lurasidone, and 2 (10.5%), 4 (61.1%), and 6 (28.4%) mg/day for risperidone.
During the OLE study, mean (SD) exposure to lurasidone was 168.5 (49.3) days in the lurasidone–lurasidone group (median, 186.0; range, 1–215) and 158.9 (55.6) days in the risperidone–lurasidone group (median, 182.5; range, 4–208). The mean (SD) dose of lurasidone during the OLE study was 74.4 (11.7) mg/day in the lurasidone–lurasidone group (median, 74.0; range, 39–105) and 77.3 (13.1) mg/day in the risperidone–lurasidone group (median, 74.0; range, 39–108). Modal daily doses were 37 (6.2%), 74 (86.8%), and 111 (7.0%) in the lurasidone–lurasidone group, and 37 (3.6%), 74 (81.0%), and 111 (15.5%) in the risperidone–lurasidone group. The total exposure to lurasidone was 60 patient-years for the lurasidone–lurasidone group and 37 patient-years for the risperidone–lurasidone group.
Safety and Tolerability
Study 237
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone and risperidone groups (84.1% vs 84.2%) (Table 2a). The incidence of serious TEAEs was 10.7% in the lurasidone group and 8.9% in the risperidone group. The most frequently reported serious TEAEs (≥ 2% of patients) in the lurasidone versus risperidone groups were psychotic disorder (2.6% vs 4.2%) and schizophrenia (2.0% vs 1.1%). Suicidal ideation was reported as a serious TEAE in two patients (0.5%) treated with lurasidone and two patients (1.1%) treated with risperidone. A greater proportion of patients treated with lurasidone versus risperidone discontinued due to TEAEs (21.0% vs 14.2%), with an NNH of 15 (95% CI, 8–276). The rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%, and most TEAEs led to discontinuation in < 1% of patients in either group.Table 2 Summary of TEAEs during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
TEAE category Number of patients (%) NNH (95% CI)a
Lurasidone
N = 391 Risperidone
N = 190
Any TEAE 329 (84.1) 160 (84.2)
Most frequently reported TEAEsb
Insomnia 60 (15.3) 24 (12.6) 37 (NS)
Nausea 60 (15.3) 20 (10.5) 21 (NS)
Sedation 54 (13.8) 27 (14.2) −251 (NS)
Akathisia 53 (13.6) 14 (7.4) 17 (9, 87)
Somnolence 53 (13.6) 33 (17.4) −27 (NS)
Headache 38 (9.7) 28 (14.7) −20 (NS)
Weight increase 38 (9.7) 38 (20.0) −10 (−26, −6)
Vomiting 37 (9.5) 7 (3.7) 18 (11, 55)
Anxiety 35 (9.0) 16 (8.4) 189 (NS)
Weight decrease 29 (7.4) 9 (4.7) 38 (NS)
Dizziness 24 (6.1) 6 (3.2) 34 (NS)
Nasopharyngitis 21 (5.4) 12 (6.3) −106 (NS)
Psychotic disorder 19 (4.9) 13 (6.8) −51 (NS)
Parkinsonism 17 (4.3) 10 (5.3) −110 (NS)
Dystonia 13 (3.3) 12 (6.3) −34 (NS)
Constipation 7 (1.8) 11 (5.8) −26 (−234, −14)
Any EPS-related TEAEc 48 (12.3) 36 (18.9) −15 (−457, −8)
Any metabolic-related TEAEd 52 (13.3) 43 (22.6) −11 (−41, −7)
Any serious TEAE 42 (10.7) 17 (8.9) 56 (NS)
Most frequently reported serious TEAEse
Psychotic disorder 10 (2.6) 8 (4.2) −61 (NS)
Schizophrenia 8 (2.0) 2 (1.1) 101 (NS)
Suicidal ideation 2 (0.5) 2 (1.1) −185 (NS)
Any TEAE leading to discontinuation 82 (21.0) 27 (14.2) 15 (8, 276)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 13 (3.3) 8 (4.2) −113 (NS)
Schizophrenia 12 (3.1) 4 (2.1) 104 (NS)
Suicidal ideation 4 (1.0) 2 (1.1) −3377 (NS)
Akathisia 4 (1.0) 2 (1.1) −3377 (NS)
Hallucination, auditory 4 (1.0) 0 98 (50, 3906)
Vomiting 4 (1.0) 0 98 (50, 3906)
Electrocardiogram QT prolonged 0 2 (1.1) −96 (NS)
(B) OLE study (Study 237-EXT)
TEAE category Number of patients (%)
Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Any TEAE 76 (58.9) 49 (58.3)
Most frequently reported TEAEsb
Headache 6 (4.7) 7 (8.3)
Psychotic disorder 6 (4.7) 6 (7.1)
Parkinsonism 5 (3.9) 5 (6.0)
Insomnia 3 (2.3) 5 (6.0)
Anxiety 2 (1.6) 6 (7.1)
Any EPS-related TEAEc 11 (8.5) 6 (7.1)
Any metabolic-related TEAEd 4 (3.1) 5 (6.0)
Any serious TEAE 7 (5.4) 3 (3.6)
Types of serious TEAE
Psychotic disorder 2 (1.6) 1 (1.2)
Schizophrenia 1 (0.8) 1 (1.2)
Completed suicide 1 (0.8) 0
Ankle fracture 1 (0.8) 0
Non-small cell lung cancer 1 (0.8) 0
Convulsion 1 (0.8) 0
Carbon monoxide poisoning 0 1 (1.2)
Any TEAE leading to discontinuation 7 (5.4) 6 (7.1)
Most frequently reported TEAEs leading to discontinuatione
Psychotic disorder 1 (0.8) 2 (2.4)
Nausea 0 1 (1.2)
Hepatitis C 0 1 (1.2)
Anxiety 0 1 (1.2)
Schizophrenia 0 1 (1.2)
aLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
b ≥ 5% of patients in either group
cEPS-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: bradykinesia, cogwheel rigidity, drooling, dystonia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, torticollis, tremor, and trismus
dMetabolic-related TEAEs were determined by medical review of preferred terms prior to unblinding in the DB trial and comprised: increased blood glucose, increased blood triglycerides, diabetes mellitus, increased glycosylated haemoglobin, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia, metabolic syndrome, overweight, type 2 diabetes mellitus, and weight increase
e ≥ 1% of patients in either group
CI confidence interval, EPS extrapyramidal symptoms, NNH number needed to harm, NS not significant (the 95% CI contains infinity), TEAE treatment-emergent adverse event
EPS-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (12.3% vs 18.9%), with an NNH of −15 (95% CI, −457 to −8). The most frequently reported EPS-related TEAEs (≥ 3% of patients in either group) were parkinsonism (lurasidone, 4.3%; risperidone, 5.3%), dystonia (3.3% vs 6.3%), and tremor (3.1% vs 3.2%).
Metabolic-related TEAEs were reported less frequently in patients treated with lurasidone versus risperidone (13.3% vs 22.6%), with an NNH of −11 (95% CI, −41 to −7). This difference was driven primarily by the lower incidence of increased weight with lurasidone versus risperidone (9.7% vs 20.0%), and this was the only metabolic-related TEAE reported by > 1% of patients in either group.
The most frequently reported TEAEs (≥ 15% of patients in either group) were insomnia (lurasidone, 15.3%; risperidone, 12.6%), nausea (15.3% vs 10.5%), somnolence (13.6% vs 17.4%), and increased weight (9.7% vs 20.0%). A higher proportion of lurasidone versus risperidone patients experienced akathisia (13.6% vs 7.4%; NNH, 17 [95% CI, 9–87]) and vomiting (9.5% vs 3.7%; NNH, 18 (95% CI, 11–55), whereas a lower proportion of lurasidone versus risperidone patients experienced increased weight (9.7% vs 20.0%; NNH, −10 [95% CI, −26 to −6]) and constipation (1.8% vs 5.8%; NNH, −26 [95% CI, −234 to −14]).
There were nine reports of suicidal ideation, six (1.5%) in the lurasidone group and three (1.6%) in the risperidone group.
Laboratory Parameters
Table 3 summarises changes from baseline to LOCF endpoint and the proportion of patients shifting from low or normal values to high or abnormal values for metabolic variables and for prolactin levels. The median fasting level of HDL cholesterol remained stable in patients treated with lurasidone but decreased in patients treated with risperidone (median change, 0 vs −2.0 mg/dL; p = 0.042). The proportion of patients whose HDL cholesterol level shifted from high/normal to low was 8.4% for lurasidone versus 17.3% for risperidone (NNH, −12 [−67 to −7]). Median fasting levels of glucose remained stable in patients treated with lurasidone but increased in patients treated with risperidone (median change, 0 vs 2.0 mg/dL; p = 0.034), and the proportion of patients whose glucose level shifted from low/normal to high was 21.9% for lurasidone versus 33.3% for risperidone (NNH, −9 [−131 to −5]). Median fasting levels of insulin decreased slightly with lurasidone but increased with risperidone (median change, −0.3 vs 1.0 mU/L; p = 0.007), although the proportion of patients whose insulin level shifted from low/normal to high was similar between groups (8.6% for lurasidone vs 11.7% for risperidone; NNH, −32 [95% CI, not significant; contains infinity]). The greatest difference between groups was observed for prolactin levels, which increased substantially in male and female patients treated with risperidone, but only marginally in patients treated with lurasidone (Table 3; Fig. 2). This was also reflected in the proportion of patients who shifted from low/normal to high prolactin levels, which was substantially lower for lurasidone than for risperidone in both male patients (14.2% vs 40.9%; NNH, −4 [−7 to −3]) and female patients (13.6% vs 58.0%; NNH, −3 [−4 to −2]).Table 3 Summary of changes in metabolic variables and prolactin during (A) the DB trial and (B) the OLE study (safety population)
(A) DB trial (Study 237)
Variable Median change; mean change (SD); n p value Proportion shift low/normal to higha NNH (95% CI)b
Lurasidone
N = 391 Risperidone
N = 190 Lurasidone
N = 391 Risperidone
N = 190
Total cholesterol, mg/dL −2.0; −3.1 (29.0); 295 −5.0; −2.7 (36.7); 143 NS 29/181 (16.0%) 10/82 (12.2%) 27 (NSc)
HDL cholesterol, mg/dL 0; −0.3 (8.7); 295 −2.0; −2.0 (9.4); 143 0.042 22/261 (8.4%) 22/127 (17.3%) −12 (−67, −7)
LDL cholesterol, mg/dL −1.0; −1.1 (25.2); 295 −3.0; −3.3 (27.5); 143 NS 30/209 (14.4%)d 8/100 (8.0%)d 16 (NSc)
Triglycerides, mg/dL −4.0; −7.3 (75.2); 295 −4.0; 9.7 (106.2); 143 NS 17/255 (6.7%) 9/123 (7.3%) −154 (NSc)
Glucose, mg/dL 0; 2.1 (24.5); 293 2.0; 4.4 (19.0); 144 0.034 44/201 (21.9%) 35/105 (33.3%) −9 (−131, −5)
HbA1c, % 0; 0.0 (0.3); 329 0; 0.1 (0.3); 158 NS 17/265 (6.4%) 5/137 (3.6%) 37 (NSc)
Insulin, mU/L −0.3; 0.7 (26.6); 322 1.0; 6.0 (27.4); 151 0.007 25/292 (8.6%) 17/145 (11.7%) −32 (NSc)
Prolactin—male, ng/mL 0; 2.4 (13.5); 258 7.3; 9.4 (14.3); 107 < 0.001 33/232 (14.2%) 38/93 (40.9%) −4 (−7, −3)
Prolactin—female, ng/mL 0.5; 4.2 (35.2); 95 25.7; 34.1 (55.4); 59 < 0.001 11/81 (13.6%) 29/50 (58.0%) −3 (−4, −2)
Weight, kg −0.3; −1.0 (5.1); 384 1.1; 1.5 (5.1); 185 < 0.001
≥ 7% increase 29/384 (7.6%) 26/185 (14.1%) −16 (−120, −9)
≥ 7% decrease 50/384 (13.0%) 11/185 (5.9%) 15 (9, 44)
Body mass index, kg/m2 −0.1; −0.3 (1.7); 384 0.4; 0.6 (1.8); 185 < 0.001 18/384 (4.7%)e 17/185 (9.1%)e −23 (NSc)
Waist circumference, cm 0; −0.5 (6.0); 288 1.0; 1.7 (6.0); 148 < 0.001 – – –
(B) OLE study (Study 237-EXT)
Variable Lurasidone–lurasidone
N = 129 Risperidone–lurasidone
N = 84
Total cholesterol, mg/dL
n 118 75
DB baseline, mean (SD)
Median change from DB baseline to OLE LOCF endpoint
198.2 (46.6)
−11.0
187.3 (49.5)
−3.0
Median change from OLE baseline to OLE LOCF endpoint −4.0 4.0
HDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 47.6 (13.9) 46.8 (13.3)
Median change from DB baseline to OLE LOCF endpoint 0 −1.0
Median change from OLE baseline to OLE LOCF endpoint 0 3.0
LDL cholesterol, mg/dL
n 118 75
DB baseline, mean (SD) 120.7 (36.9) 111.0 (37.5)
Median change from DB baseline to OLE LOCF endpoint −6.5 1.0
Median change from OLE baseline to OLE LOCF endpoint −2.5 8.0
Triglycerides, mg/dL
n 118 75
DB baseline, mean (SD) 129.2 (64.5) 135.3 (91.5)
Median change from DB baseline to OLE LOCF endpoint −11.0 −11.0
Median change from OLE baseline to OLE LOCF endpoint −3.5 −4.0
Glucose, mg/dL
n 118 75
DB baseline, mean (SD) 95.3 (13.7) 93.8 (12.0)
Median change from DB baseline to OLE LOCF endpoint −1.0 2.0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
HbA1c, %
n 121 75
DB baseline, mean (SD) 5.7 (0.4) 5.6 (0.4)
Median change from DB baseline to OLE LOCF endpoint 0 0.1
Median change from OLE baseline to OLE LOCF endpoint 0 0
Insulin, mU/L
n 124 79
DB baseline, mean (SD) 13.2 (19.4) 11.5 (15.4)
Median change from DB baseline to OLE LOCF endpoint −0.9 −0.2
Median change from OLE baseline to OLE LOCF endpoint 0.1 −0.6
Prolactin—male, ng/mL
n 95 54
DB baseline, mean (SD) 8.0 (6.9) 10.6 (9.8)
Median change from DB baseline to OLE LOCF endpoint 0.1 −1.1
Median change from OLE baseline to OLE LOCF endpoint 0.1 −10.5
Prolactin—female, ng/mL
n 31 27
DB baseline, mean (SD) 21.4 (25.4) 16.4 (39.8)
Median change from DB baseline to OLE LOCF endpoint −2.9 4.1
Median change from OLE baseline to OLE LOCF endpoint 0 −29.7
Weight, kg
n 127 81
DB baseline, mean (SD) 79.4 (18.3) 81.7 (18.3)
Median change from DB baseline to OLE LOCF endpoint −0.6 0.6
Median change from OLE baseline to OLE LOCF endpoint −0.5 −1.5
Body mass index, kg/m2
n 127 81
DB baseline, mean (SD) 27.2 (5.3) 28.1 (5.6)
Median change from DB baseline to OLE LOCF endpoint −0.2 0.2
Median change from OLE baseline to OLE LOCF endpoint −0.1 −0.5
Waist circumference, cm
n 108 66
DB baseline, mean (SD) 93.4 (13.9) 96.3 (14.7)
Median change from DB baseline to OLE LOCF endpoint −0.5 0
Median change from OLE baseline to OLE LOCF endpoint 0 −1.0
All variables measured under fasting conditions except HbA1c and prolactin
aNormal ranges: HDL cholesterol, > 35 mg/dL; glucose, 59–99 mg/dL; insulin, 3–28 mU/L; prolactin, 2.1–17.7 ng/mL (men) and 2.8–29.2 ng/mL (women)
bLurasidone versus risperidone. NNH is provided only for comparisons in which the 95% CI did not include infinity, denoting statistical significance at the p ≤ 0.05 threshold. NNH = 1/(rate with lurasidone − rate with risperidone) and rounded up. A negative NNH denotes an advantage for lurasidone relative to risperidone and can be expressed as a positive number if the comparison is risperidone vs lurasidone instead of lurasidone vs risperidone
c95% CI contains infinity
dFor HDL cholesterol, the shift measured was from high/normal to low
eFor body mass index, the shift measured was any upward shift (i.e. from underweight to normal or higher, normal to overweight or obese, and overweight to obese)
CI confidence interval, DB double-blind, HbA1c glycosylated haemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, LOCF last observation carried forward, NNH number needed to harm, NS not significant, OLE open-label extension, SD standard deviation
Fig. 2 Change in prolactin over time from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial, for (a) males and (b) females. DB double-blind, LOCF last observation carried forward, OLE open-label extension
During the DB trial, the proportion of patients with metabolic syndrome decreased slightly following treatment with lurasidone (from 28.9% at baseline to 25.5% at month 12), but increased following treatment with risperidone (from 28.3% at baseline to 40.4% at month 12), the between-group difference being significant at month 12 (p = 0.0177; Fig. 3a).Fig. 3 Change in percentage of patients with metabolic syndrome (a) from DB baseline to month 12 and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (safety population). DB double-blind, LOCF last observation carried forward, NS not significant, OLE open-label extension
Electrocardiography
There were no clinically relevant ECG changes from baseline to LOCF endpoint in either treatment group, and no patients had a Fridericia’s corrected QT interval of > 500 ms or an increase of ≥ 60 ms at any time during the study.
Weight, BMI, and Waist Circumference
Changes from baseline in weight, BMI, and waist circumference differed significantly between groups (Table 3; Fig. 4a). The median change in weight during the DB trial was −0.3 kg for lurasidone versus +1.1 kg for risperidone (p < 0.001). The proportion of patients experiencing ≥ 7% increase in weight was lower for lurasidone than for risperidone (7.6% vs 14.1%; NNH, −16 [−120 to −9]), and the proportion of patients who experienced ≥ 7% decrease in weight was significantly higher for lurasidone than for risperidone (13.0% vs 5.9%; NNH, 15 [9–44]). The median change in BMI during the DB trial was −0.1 kg/m2 for lurasidone versus +0.4 kg/m2 for risperidone (p < 0.001). The proportion of patients who experienced an upward shift in BMI category (i.e. from underweight to normal or higher, normal to overweight or obese, or overweight to obese) was lower with lurasidone than with risperidone, although this difference was not significant (4.7% vs 9.1%; NNH, −23 [95% CI, not significant; contains infinity]). Median and mean increases in waist circumference were experienced by patients treated with risperidone (median, 1 cm; mean, 17 cm) but not by those treated with lurasidone (mean, 0 cm; median, −0.5 cm) (p < 0.001).Fig. 4 Change in weight over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in DB trial. DB double-blind, LOCF last observation carried forward, OLE open-label extension
Movement Rating Scales
The mean (SD) baseline BAS total scores were 0.3 (0.9) and 0.2 (0.7) in the lurasidone and risperidone groups, respectively. There was a small but statistically significant increase from baseline to LOCF endpoint in the mean (standard error [SE]) BAS total score in patients treated with lurasidone (0.14 [0.04]; p = 0.002), but there was no significant change in the risperidone group (−0.10 [0.06]; p = 0.110). The between-group treatment difference at LOCF endpoint was 0.2 (SE, 0.07; p = 0.001). Mean (SD) baseline AIMS total scores were 0.6 (1.6) and 0.5 (1.4) in the lurasidone and risperidone groups, respectively. These scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant. Mean (SD) baseline SAS 10-item scores were 0.1 (0.2) and 0.1 (0.3) in the lurasidone and risperidone groups, respectively. As with AIMS, these scores did not change significantly from baseline to the LOCF endpoint, and the between-group treatment difference was non-significant.
Study 237-EXT
TEAEs
The proportion of patients with TEAEs was similar between the lurasidone–lurasidone and risperidone–lurasidone groups (58.9% vs 58.3%), as were the proportions of patients with EPS-related TEAEs (8.5% vs 7.1%) and serious TEAEs (5.4% vs 3.6%) (Table 2b). The most frequently reported TEAEs (≥ 5% of patients in the overall population) were headache (lurasidone–lurasidone, 4.7%; risperidone–lurasidone, 8.3%) and psychotic disorder (4.7% vs 7.1%).
The most frequently reported EPS-related TEAEs were parkinsonism (lurasidone–lurasidone, 3.9%; risperidone–lurasidone, 6.0%) and dystonia (1.6% vs 1.2%). All other EPS-related TEAEs occurred in no more than one patient in both groups combined. Akathisia was reported as a TEAE for 3.1% of patients in the lurasidone–lurasidone group and 2.4% of patients in the risperidone–lurasidone group.
The most frequently reported metabolic-related TEAEs were weight increase (lurasidone–lurasidone, 0.8%; risperidone–lurasidone, 2.4%) and increased blood triglycerides (1.6% vs 0%). All other metabolic-related TEAEs occurred in no more than one patient in both groups combined.
Serious TEAEs occurred in 10 patients (4.7%) overall. Serious TEAEs occurring in more than one patient were psychotic disorder (lurasidone–lurasidone, 1.6%; risperidone–lurasidone, 1.2%) and schizophrenia (0.8% vs 1.2%). There was one completed suicide in the lurasidone–lurasidone group, and suicidal depression was reported for one patient in the risperidone–lurasidone group. TEAEs leading to discontinuation occurred in 5.4% and 7.1% of patients in the lurasidone–lurasidone and risperidone–lurasidone groups, respectively. The only TEAE that led to discontinuation of more than one patient was psychotic disorder (lurasidone–lurasidone, n = 1 [0.8%]; risperidone–lurasidone, n = 2 [2.4%]).
Laboratory Parameters
In the lurasidone–lurasidone group, there was a slight decrease from OLE baseline to OLE LOCF endpoint in median total cholesterol and triglyceride levels, with minimal or no changes in other metabolic variables (Table 3b). In the risperidone–lurasidone group, there was an increases from OLE baseline to OLE LOCF endpoint in LDL cholesterol, HDL cholesterol, and total cholesterol levels, and a decrease in triglyceride and insulin levels, with minimal or no changes in other metabolic variables. Prolactin levels remained stable in male and female patients in the lurasidone–lurasidone group, but there was a marked reduction in prolactin levels in male and female patients in the risperidone–lurasidone group (Table 3b; Fig. 2).
At OLE baseline, the proportion of patients with metabolic syndrome was significantly lower in the lurasidone–lurasidone group than the risperidone–lurasidone group (24.8% vs 41.7%; p = 0.0098) (Fig. 3b). The proportion of patients with metabolic syndrome decreased in both groups during the OLE, but to a greater extent in the risperidone–lurasidone group than the lurasidone–lurasidone group, and the between-group difference for lurasidone–lurasidone versus risperidone–lurasidone was no longer significantly different at month 6 (21.8% vs 33.9%) or LOCF endpoint (23.5% vs 31.5%).
Electrocardiography
There were no clinically meaningful changes in mean ECG parameters during the OLE study.
Weight, BMI, and Waist Circumference
There was a slight decrease in mean weight in the lurasidone–lurasidone group from OLE baseline to OLE LOCF endpoint, with minimal changes in median BMI and waist circumference (Table 3b; Fig. 4b). In the risperidone–lurasidone group, mean weight decreased by approximately 2.5 kg from OLE baseline to OLE LOCF endpoint, resulting in a slight decrease in mean weight from DB baseline (Fig. 4b), and a slight decrease was also observed in median BMI and waist circumference (Table 3b). At OLE LOCF endpoint, the proportion of patients who experienced ≥ 7% increase in weight from OLE baseline was 3.1% in the lurasidone–lurasidone group and 2.5% in the risperidone–lurasidone group, and the proportion of patients who experienced ≥ 7% decrease in weight was 6.3% and 16.0%, respectively.
Movement Rating Scales
In the lurasidone–lurasidone and risperidone–lurasidone groups, the mean change in BAS total score from OLE baseline to OLE LOCF endpoint was 0.0 in both groups (median changes also 0.0), the mean change in SAS was −0.01 and 0.00 (median, 0.0 and 0.0), respectively, and the mean change in AIMS total score was 0.3 and 0.3 (median, 0.0 and 0.0), respectively.
Efficacy
Study 237
Relapse Rates
In total, 79/384 (20.6%) patients treated with lurasidone and 29/186 (15.6%) patients treated with risperidone experienced relapse during the DB trial (ITT population) (Fig. 5). The Kaplan–Meier estimate for probability of relapse ranged from 10.2% at week 6 to 27.0% at month 12 in patients treated with lurasidone, and from 8.9% at week 6 to 20.1% at month 12 in patients treated with risperidone. Since the estimates at month 12 were < 50% for both groups, the median survival times to relapse could not be calculated. The relapse hazard ratio for lurasidone versus risperidone was 1.44 (95% CI, 0.94–2.20; p = 0.096).Fig. 5 Kaplan–Meier estimate of the probability of relapse in the DB trial (Study 237) (ITT population). CI confidence interval, DB double-blind, HR hazard ratio, ITT intent-to treat
Positive and Negative Syndrome Scale
The mean PANSS total score decreased from baseline during the 12-month DB trial in both the lurasidone and risperidone groups (mean [95% CI] change, −4.8 [−6.5, −3.0] and −6.6 [−8.9, −4.4], respectively), with no significant differences between groups at any time point (Fig. 6A).Fig. 6 Change in PANSS total score over time (a) from DB baseline to DB LOCF endpoint and (b) from DB baseline to OLE LOCF endpoint, by treatment assignment in Study 237 (ITT population). DB double-blind, ITT intent-to treat, LOCF last observation carried forward, OLE open-label extension, PANSS Positive and Negative Syndrome Scale
Clinical Global Impression–Severity
The mean CGI-S score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.4 [−0.5, −0.3] and −0.4 [−0.5, −0.2], respectively), with no significant differences between groups at any time point.
Montgomery–Åsberg Depression Rating Scale
The mean MADRS total score decreased from DB baseline to month 12 in both the lurasidone and risperidone groups (mean [95% CI] change, −0.8 [−1.6, 0.0] and −2.3 [−3.2, −1.3], respectively). The difference between groups was statistically significant at month 12 (p = 0.013) but not at earlier time points.
Study 237-EXT
Positive and Negative Syndrome Scale
The improvement in PANSS total score observed during the DB trial was maintained during the OLE study in both the lurasidone–lurasidone and risperidone–lurasidone groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint, 0.6 [−0.9, 2.1] and 1.3 [−0.6, 3.1], respectively) (Fig. 6b).
Clinical Global Impression–Severity
The improvement in CGI-S score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.0 [−0.1, 0.2]; risperidone–lurasidone, 0.0 [−0.1, 0.2]).
Montgomery–Åsberg Depression Rating Scale
The improvement in MADRS total score observed during the DB trial was maintained during the OLE study in both treatment groups (mean [95% CI] change from OLE baseline to OLE LOCF endpoint: lurasidone–lurasidone, 0.1 [−0.7, 0.9]; risperidone–lurasidone, 1.1 [0.1, 2.1]).
Discussion
This post hoc analysis of a 12-month, DB, active-controlled trial and 6-month OLE study demonstrated that lurasidone was generally well tolerated and effective in treating clinically stable patients with schizophrenia over the long term. It also demonstrated that lurasidone was generally well tolerated and maintained effectiveness in patients with schizophrenia who switched to lurasidone having been treated with risperidone for 12 months in the DB trial. These findings are consistent with those of the original DB trial [15] and OLE study [16], which included patients with schizoaffective disorder as well as schizophrenia, but confirm lurasidone’s tolerability and effectiveness specifically in patients with schizophrenia, who have been shown to have less favourable outcomes than those with schizoaffective disorder [18, 28].
During the DB trial, the proportions of patients with TEAEs and serious TEAEs were similar in the lurasidone and risperidone groups. Although a greater proportion of patients in the lurasidone versus risperidone group discontinued due to TEAEs (NNH: 15), the rate of discontinuation due to individual TEAEs did not differ between groups by more than approximately 1%. It is also noteworthy that a key exclusion criterion for participation in the trial was a history of a poor or an inadequate response or intolerability to risperidone, meaning that the population may have been enriched in terms of tolerability and response to risperidone. A higher proportion of patients treated with lurasidone versus risperidone experienced akathisia (NNH: 17), and there was a small but statistically significant increase from baseline in BAS score with lurasidone but not with risperidone. By contrast, EPS-related TEAEs were reported less frequently with lurasidone than with risperidone (NNH: −15). Metabolic-related TEAEs were also reported less frequently with lurasidone versus risperidone (NNH: −11), primarily due to the lower incidence of weight gain with lurasidone in comparison with risperidone (NNH: −10).
Consistent with the findings for metabolic-related TEAEs, lurasidone demonstrated a more benign profile than risperidone in terms of metabolic variables, prolactin, weight, BMI, and waist circumference. The greatest difference between groups was observed for prolactin levels, the proportion of patients shifting from low/normal to high prolactin levels being substantially lower for lurasidone versus risperidone, in both male and female patients (NNH: −4 [male]; −3 [female]). Lurasidone treatment was associated with a negligible impact on fasting glucose levels, whereas risperidone treatment resulted in a median increase of 2.0 mg/dL over the 12 months of the trial [NNH: −9]. The proportion of patients experiencing a clinically significant weight increase (≥ 7% increase) was approximately two-fold higher for risperidone versus lurasidone (NNH: −16), whereas the proportion who experienced a clinically significant weight decrease (≥ 7% decrease) was approximately two-fold higher for lurasidone versus risperidone (NNH: 15). Differences in the metabolic impact of lurasidone and risperidone were also reflected in the proportions of patients with NCEP ATP III-defined metabolic syndrome, which were similar between groups at baseline but significantly higher for risperidone versus lurasidone at the end of the DB trial. Indeed, the proportion of patients with metabolic syndrome decreased slightly following lurasidone treatment.
During the OLE study, the proportions of patients experiencing TEAEs, EPS-related TEAEs, serious TEAEs, and TEAEs leading to discontinuation were generally comparable between patients who received lurasidone throughout the DB trial and OLE study (lurasidone–lurasidone group) and those who switched from risperidone to lurasidone at the start of the OLE study (risperidone–lurasidone group). Psychotic disorder was the only serious TEAE reported by more than one patient in either group (lurasidone–lurasidone, n = 2; risperidone–lurasidone, n = 1) and the only TEAE leading to discontinuation of more than one patient in either group (risperidone–lurasidone, n = 2; lurasidone–lurasidone, n = 1). Changes in movement rating scales (BAS, SAS, and AIMS) were minimal and similar between groups during the OLE study.
The proportion of patients with metabolic-related TEAEs was lower in the lurasidone–lurasidone than in the risperidone–lurasidone group, although the incidence was low in both groups, and most individual metabolic-related TEAEs occurred in no more than one patient in both groups combined. Patients in the lurasidone–lurasidone group experienced a slight decrease in the median levels of total cholesterol (−4.0 mg/dL) and triglycerides (−3.5 mg/dL) from OLE baseline to OLE endpoint, and minimal or no change in other metabolic variables. In the risperidone–lurasidone group, there was an increase from OLE baseline to OLE endpoint in the median levels of LDL cholesterol (+8 mg/dL), HDL cholesterol (+3.0 mg/dL), and total cholesterol (+4.0 mg/dL), and a decrease in the median levels of triglycerides (−4.0 mg/dL) and insulin (−0.6 mU/L), with minimal or no changes in other metabolic variables. As in the DB trial, the greatest change was observed for prolactin levels, which remained stable in the lurasidone–lurasidone group but decreased substantially in both male and female patients in the risperidone–lurasidone group (median changes: −10.5 ng/mL [male] and −29.7 ng/mL [female]). Median body weight decreased during the OLE study in both groups, but the decrease was greater in patients in the risperidone–lurasidone group (−1.5 kg) than in the lurasidone–lurasidone group (−0.5 kg). The mean weight decrease in the risperidone–lurasidone group during the OLE study was approximately 2.5 kg, resulting in a slight decrease in weight from DB baseline. Similar patterns were observed for BMI and waist circumference. During the OLE study, the proportion of patients who experienced clinically significant weight gain was low in both groups. However, the proportion of patients who experienced a clinically significant decrease in weight was substantially higher in the risperidone–lurasidone than in the lurasidone–lurasidone group (16.0% vs 6.3%). The proportion of patients with metabolic syndrome was significantly higher in the risperidone–lurasidone versus lurasidone–lurasidone group at OLE baseline, but decreased in both groups during the OLE study, particularly in the risperidone–lurasidone group, and the between-group difference was no longer significant by the end of the OLE trial.
The safety/tolerability findings observed in the current study are consistent with the known safety profiles of lurasidone [11] and risperidone [29]. The rate of akathisia observed with lurasidone during the DB trial (13.6%) was similar to that reported in short-term placebo-controlled trials (12.9%) [11]. However, the rate of discontinuation due to akathisia in the lurasidone group was low (1.0%), and akathisia was not reported as a common TEAE in the OLE study in either group. Risperidone is commonly associated with prolactin elevation and weight gain [29], as observed in the current study. The findings of this study are also consistent with those from other long-term studies; for example, in a pooled analysis of six studies (including two with the active comparators risperidone and quetiapine XR) which assessed the effect of 12 months of lurasidone treatment on weight in patients with schizophrenia, the mean change in weight from baseline to month 12 was −0.4 kg with lurasidone, versus +2.6 kg with risperidone and +1.2 kg with quetiapine XR [30]. Moreover, several meta-analyses of available evidence for atypical antipsychotics have demonstrated that lurasidone has a relatively benign cardiometabolic profile in comparison with other agents, whereas risperidone is associated with a moderate risk of weight gain and high risk of prolactin elevation [9, 10, 14].
An important finding of the current study was that patients who switched from risperidone to lurasidone at the start of the OLE phase experienced a marked decrease in weight and prolactin levels, which had increased during 12 months of treatment with risperidone in the DB trial. These findings are consistent with previous findings [31–33]. In a 6-month OLE study of a 6-week trial during which patients with acute exacerbation of schizophrenia were treated with lurasidone or olanzapine, patients who had gained weight while being treated with olanzapine experienced decreased weight and improved lipid levels after switching to lurasidone in the OLE study, whereas those treated with lurasidone during the initial trial and OLE study experienced minimal changes in weight and lipid parameters [31]. Similarly, prolactin elevation that occurred during olanzapine treatment in the initial trial decreased following the switch to lurasidone in the OLE study [31]. In another study, in which patients with schizophrenia or schizoaffective disorder were switched to lurasidone after being stable on treatment with a range of antipsychotics (most commonly quetiapine, risperidone, and aripiprazole), improvements in body weight and lipid levels were observed following 6 weeks of treatment with lurasidone [32]. During the subsequent OLE study, in which all patients continued to be treated with lurasidone, there were no clinically relevant adverse changes in body weight, lipids, glucose, insulin, or prolactin [33].
Efficacy was assessed as a secondary objective of the current study. During the DB trial, patients treated with lurasidone and risperidone experienced improvements in PANSS total score, CGI-S score, and MADRS total score. There were no significant differences between treatment groups at any time point, with the exception of the MADRS total score, which was decreased (improved) to a significantly greater extent in the risperidone versus lurasidone group at month 12, but not at earlier time points. A higher proportion of patients in the lurasidone versus risperidone group experienced relapse during the DB trial, the relapse hazard ratio for lurasidone versus risperidone being 1.44 (p = 0.096). Once again, it should be pointed out that patients who previously showed a poor or inadequate response to risperidone were excluded from participation in the trial, which may have enriched the population in terms of response to risperidone. During the OLE study, improvements in PANSS total score, CGI-S score, and MADRS total score observed during the DB trial were maintained in both the lurasidone–lurasidone group and the risperidone–lurasidone group.
There is increasing recognition of the importance of addressing the physical as well as the mental health of patients with conditions such as schizophrenia. Indeed, the Lancet Psychiatry Commission has recently published a ‘blueprint’ outlining strategies for protecting the physical health of people with mental illness, which highlights that protecting the physical health of people receiving treatment for mental illness should be regarded as within the scope of clinical duty of care [34]. Individuals with schizophrenia have a significantly higher risk of cardiometabolic complications than the general population (5–8-fold), which is often exacerbated by the effects of antipsychotic therapy, especially treatment with atypical antipsychotics [3, 5]. Treatment guidelines therefore advocate screening patients for cardiometabolic risk, and intervening where necessary to improve their physical health, not only through lifestyle interventions (such as diet, exercise, and smoking) and by actively treating cardiometabolic conditions (such as hypertension and dyslipidaemia), but also by choosing and adapting antipsychotic treatment in order to minimise the likelihood of long-term adverse physical sequelae [34-37]. Since atypical antipsychotics vary greatly in terms of their safety profiles, particularly with regard to cardiometabolic risk [9, 10], the choice of antipsychotic treatment is particularly relevant, and guidelines highlight the importance of choosing an antipsychotic at the outset of treatment that will minimise the risk of developing or exacerbating cardiometabolic complications, and of switching antipsychotic treatment where necessary in order to reverse or minimise the development and impact of such complications [34-37]. Within this context, the findings of the current study are encouraging, not only in confirming that lurasidone is associated with minimal changes in cardiometabolic parameters over the long term, but also in demonstrating that patients who have developed weight gain, other metabolic disturbances (e.g. raised glucose levels), or prolactin elevation while being treated with risperidone can experience improvements in these parameters after switching to lurasidone.
As previously noted, a limitation of the current study is that it excluded patients with a history of a poor or inadequate response or intolerability to risperidone. This may have introduced bias by enriching the study population for patients who were responsive to risperidone and who had previously demonstrated tolerability to the agent, which could have affected both the safety/tolerability and effectiveness outcomes in favour of risperidone. The study was also limited in that it was a post hoc subgroup analysis, and the OLE phase was limited by its open-label design and the lack of a control arm. Since this study was conducted in patients with clinically stable schizophrenia, its findings cannot be extrapolated to those with acute exacerbation of schizophrenia.
Conclusion
In summary, the findings from this DB trial and OLE study confirm that lurasidone is generally well tolerated and effective in treating patients with clinically stable schizophrenia over the long term (up to 18 months). Lurasidone was also generally well tolerated and maintained effectiveness over 6 months in patients with schizophrenia who switched to lurasidone having previously been treated with risperidone for 12 months. Long-term lurasidone treatment was associated with minimal changes in metabolic variables and prolactin levels, and patients who switched from risperidone to lurasidone experienced improvements in prolactin levels, weight and other metabolic parameters. These findings support the use of lurasidone within the context of addressing the physical as well as mental health of patients with schizophrenia.
Acknowledgements
Funding
The study was funded by Sunovion Pharmaceuticals Europe Ltd. The journal’s Rapid Service Fees were also funded by Sunovion Pharmaceuticals Europe Ltd.
Medical Writing, Editorial, and Other Assistance
Editorial support for the preparation of this manuscript was provided by John Scopes of mXm Medical Communications and funded by Sunovion Pharmaceuticals Europe Ltd.
Authorship
All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Preeya J. Patel, Christian Weidenfeller and Andrew P. Jones are employees of Sunovion Pharmaceuticals Europe Ltd. Jens Nilsson was an employee of Sunovion Pharmaceuticals Europe Ltd at the time of this study but has been a full-time employee of Vifor Pharma Nordiska since September 2020. Jay Hsu is an employee of Sunovion Pharmaceuticals Inc.
Compliance with Ethics Guidelines
Studies 237 and 237-EXT (registered on ClinicalTrials.gov; NCT00641745) were both conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation and with the ethical principles of the Declaration of Helsinki. The studies were reviewed and approved by an Independent Ethics Committee or Institutional Review Board at each study centre and all patients provided written informed consent prior to participation.
Data Availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Long-Term Antithrombotic Treatments Prescribed for Cardiovascular Diseases in Patients with Hemophilia: Results from the French Registry.
Cardiovascular diseases (CVDs) are a major issue in aging patients with hemophilia (PWHs). Antithrombotic agents are widely used in the general population for CVD treatment, but this recommendation is not fully applicable to PWHs. To improve treatment strategies, a prospective case-control study (COCHE) that analyzed CVD management and follow-up (2 years/patient) in PWHs was performed in France from 2011 to 2018. In total, 68 PWHs (median age: 65 years [39-89]; 48 mild, 10 moderate, and 10 severe hemophilia) were included (n = 50 with acute coronary syndrome, n = 17 with atrial fibrillation, n = 1 with both). They were matched with 68 control PWHs without antithrombotic treatment. In our series, bleeding was significantly influenced by (1) hemophilia severity, with a mean annualized bleeding ratio significantly higher in COCHE patients than in controls with basal clotting factor level up to 20%, (2) antihemorrhagic regimen (on-demand vs. prophylaxis) in severe (hazard ratio [HR] = 16.69 [95% confidence interval, CI: 8.2-47.26]; p < 0.0001) and moderate hemophilia (HR = 42.43 [95% CI: 1.86-966.1]; p = 0.0028), (3) type of antithrombotic treatment in mild hemophilia, with a significantly higher risk of bleeding in COCHE patients than in controls for dual-pathway therapy (HR = 15.64 [95% CI: 1.57-115.8]; p = 0.019), anticoagulant drugs alone (HR = 9.91 [95% CI: 1.34-73.47]; p = 0.0248), dual antiplatelet therapy (HR = 5.31 [95% CI: 1.23-22.92]; p = 0.0252), and single antiplatelet therapy (HR = 3.76 [95% CI: 1.13-12.55]; p = 0.0313); and (4) HAS-BLED score ≥3 (odds ratio [OR] = 33 [95% CI: 1.43-761.2]; p = 0.0065). Gastrointestinal bleeding was also significantly higher in COCHE patients than in controls (OR = 15 [95% CI: 1.84-268]; p = 0.0141). The COCHE study confirmed that antithrombotic treatments in PWHs are associated with increased bleeding rates in function of hemophilia-specific factors and also of known factors in the general population.
Introduction
Hemophilia management has significantly improved in the last decades. Since the emergence of clotting factor concentrates in the 1970s,
1
the life expectancy of patients with hemophilia (PWHs) has dramatically increased from less than 30 to over 60 years in high-income countries.
2
3
4
5
6
7
8
Consequently, aging PWHs are increasingly confronted with age-related conditions, such as cardiovascular diseases (CVDs), primarily acute coronary syndrome (ACS) and atrial fibrillation (AF).
Antithrombotic treatments, mainly antiplatelet agents, play a central role in secondary CVD prevention. It is now well established that dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitors, such as clopidogrel, is required after drug-eluting stent (DES) implantation.
9
There are also well-defined guidelines for AF management in function of the patient's CHA
2
D
2
-VASc score. This includes the long-term use of anticoagulant drugs, mainly vitamin K antagonists (VKAs) or direct oral anticoagulants (DOAs).
10
In the case of high ischemic/thrombogenic risk, anticoagulant and antiplatelet drugs can be combined.
11
Although these drug combinations are expected to increase the bleeding risk in PWHs, this effect has not yet been demonstrated by studies with high levels of evidence. Evidence-based guidelines for the optimal management of acute CVD in PWHs or for secondary prevention are limited, as well as the published recommendations on how to handle the higher bleeding risk associated with invasive procedures that require hemostasis-interfering drugs.
12
13
14
15
As properly controlled randomized trials are not feasible in PWHs, we set up a case–control study in France to prospectively collect data on the management of coronary artery disease (CAD)/ACS or AF in PWHs, and on the consequences, particularly of antithrombotic treatments, during the 2-year follow-up.
Methods
The COCHE study is a French prospective, noninterventional, multicenter case–control registry. The study was started in July 2011 and data were collected until December 2017. The COCHE group (i.e., the cases) included PWHs A or B who started an antithrombotic treatment for ACS/CAD or for nonvalvular AF, according to the recommendations for CVD management in the general population. For each included patient, a specially designed case report form was filled at inclusion, and then all treatment changes, new cardiovascular events, and bleeding events were recorded in a follow-up form at month 1 after inclusion, and every 6 months for 2 years. The collected data included demographic features and disease characteristics, cardiovascular risk factors and antecedents, ACS/CAD or AF treatment modalities, major and minor bleeding events, and factor replacement therapy before, during, and after any cardiovascular event. According to the International Society on Thrombosis and Haemostasis recommendations, major bleeds were defined as events that required pro-hemostatic substitutive treatment, hospitalization, transfusion, or surgical/radiological interventions.
16
17
The control group included PWHs followed at the Hemophilia Treatment Centre (HTC) of Rennes, France. Each control patient was matched with one patient of the COCHE group on the basis of age (±5 years), hemophilia type and severity (±5 and ± 2% of clotting factor level for mild and moderate forms, respectively), antifactor inhibitor status, and type (on-demand or prophylaxis) of clotting factor replacement therapy (only for patients with severe hemophilia). Data for the control group were retrospectively collected from February 2016 to January 2018, for the same number of months as for the matched case. These data were extracted from the HTC medical file, HTC comprehensive daily board of hospitalization, and each patient's hemophilia diary. This allowed collecting precise information on each clotting factor infusion, hospitalization, and emergency surgery in the control group.
The mean annualized bleeding rates (ABRs) and annualized cardiovascular event rates (ACvR) during the study follow-up were calculated for both groups. For each patient, the sum of all events was divided by the exact number of months (then transformed in years) of follow-up. The mean ABR and ACvR were compared between groups and also within the COCHE group in function of the used antithrombotic treatment, antihemorrhagic regimen (prophylaxis/on-demand), hemophilia severity, clotting factor levels, and HAS-BLED score for patients with AF. Number and causes of death were recorded.
This study did not affect the normal patient management and did not lead to specific treatments or investigations. The physicians' prescribing freedom was entirely maintained. Prior to inclusion, each patient was informed about the registry procedures and provided a written consent. For the study, only anonymized data were used. This study followed the Declaration of Helsinki and local legislation. In accordance with the European and French regulations, this study was approved by the Comité consultatif sur le traitement de l'information en matière de recherche and the Commission nationale informatique et libertés on April 7, 2011 and February 1, 2012, respectively. The registry was supervised by a scientific committee that included both hematologists and cardiologists.
All statistical analyses were performed with the GraphPad Prism software (version 7.00 for Windows, GraphPad Software, La Jolla, California, United States). Categorical variables were expressed as percentages, and continuous variables as means (with lower/upper 95% confidence intervals, CIs) or medians (with minimum and maximum values). The frequency and distribution of bleeding and cardiovascular events were computed with their 95% CI. The Fischer's exact
t
-test was used for qualitative variables, as appropriate, and odds ratios (ORs) were determined. Hazard ratios (HRs) were used to determine the risk of bleeding from different antithrombotic treatments over time. Significance was set at
p
< 0.05 with 95% CI. Survival curves were drawn and analyzed using the Mantel–Cox log-rank test that computes also the chi square and HR values, including the 95% CI.
Results
Characteristics of the Study Population
Between July 2011 and December 2017, 68 patients from 26 French HTCs were included in the COCHE registry (see study flowchart in
Fig. 1
and
Table 1
). A total of 1,248 months of follow-up data were collected for both COCHE and control groups, corresponding to a median of 18 months (1–24) per patient. The patients' characteristics are described in
Table 1
. The reason for inclusion in the COCHE registry was ACS/CAD in 50 (73.5%) patients, AF in 17 (25%) patients, and both in one patient (simultaneous diagnosis at inclusion). Among the 50 patients with ACS/CAD, 22 had ACS (44%) (ST-elevation myocardial infarction
n
= 3; non-ST-elevation myocardial infarction
n
= 16; unstable angina
n
= 3), and 28 (56%) had CAD (stable angina or silent myocardial ischemia). The patient with both AF and ACS/CAD had silent myocardial ischemia without stent implantation. He had mild hemophilia (basal FVIII level: 20%). For the 18 patients with AF, the median CHA
2
D
2
-VASc score was 3 (1–7), and two patients had a score = 1. Their median HAS-BLED score was 2 (0–4). Factor VIII/IX (FVIII/FIX) replacement therapies included only standard concentrates for all patients, but for one who received recombinant activated factor VII due to presence of an anti-FVIII inhibitor. Neither extended half-life (EHL) clotting factor concentrates nor emicizumab was used because they were not available in France during this study.
Fig. 1
Description of patients and controls included in the COCHE study. (
A
) COCHE study flow chart. (
B
) Changes in antithrombotic treatments during the 2-year follow-up. AC, anticoagulant drug alone; ASA, aspirin; CABG, coronary artery bypass grafting; Clopi, clopidogrel; DAPT, dual antiplatelet therapy; DAPT + one anticoagulant drug; DES, drug-eluting stent; DOA, direct oral anticoagulant; DPT, dual pathway therapy (antiplatelet + anticoagulant); HA, hemophilia A; HB, hemophilia B; mod, moderate; PCI, percutaneous coronary intervention; SAPT, single antiplatelet therapy; sev, severe; TT, triple therapy; VKA, vitamin K antagonist.
Table 1 Characteristics of patients included in the COCHE study
COCHE group Control group
Total CAD AF CAD + AF
N
patients
68 50 17 1 68
Median age, y [min–max] 65 [39–85] 64 [39–85] 66 [51–75] 68 63 [42–87]
Hemophilia type
n
patients
A 60 43 16 1 60
B 8 7 1 0 8
Hemophilia severity
n
patients
Mild
Median factor level [min–max] 48
17% [5–36] 32
20.5% [5–36] 15
16% [6–35] 1
20% 48
18% [6–37]
Moderate
Median factor level [min–max] 10
3% [1–5] 9
3% [2–5] 1
(1%) 0 10
3.5% (2–5)
Severe 10
1 inhibitor +
9
1 inhibitor +
1 0 10
Prophylaxis?
n
patients
YES
Total 18 (26.5%) 16 (32%) 2 (11.8%) 0 6 (8.8%)
Mild 8 (16.7%) 8 (17.3%) 0 0
Mod/sev 10 (50%) 8 (44.4%) 2 (100%) 6 (30%)
NO
Total 50 (73.5%) 34 (68%) 15 (88.2%) 1 (100%) 62 (91.2%)
Mild 40 (83.3%) 24 (32%)
Mod/sev 10 (50%) 10 (55.6%) 15 (100%)
0 1 (100%)
0 48 (100%)
14 (70%)
Abbreviations: AF, atrial fibrillation; CAD, coronary artery disease; mod/sev, moderate and severe hemophilia.
Antithrombotic Treatments and Antihemorrhagic Prophylaxis
In the COCHE group, antithrombotic treatments were started at diagnosis of ACS/CAD or AF (= inclusion) during hospitalization or consultation (
Fig. 1
). Two patients stopped the early antithrombotic treatment during the month after inclusion because they had a CHA
2
D
2
-VASc score of 1 (one patient with AF and severe hemophilia) or because silent myocardial ischemia was detected by coronarography (one patient with CAD and mild hemophilia). The initial antithrombotic treatments comprised single antiplatelet therapy (SAPT,
n
= 37), DAPT (
n
= 18), anticoagulant treatment alone (AC,
n
= 10), dual pathway therapy (DPT) with one antiplatelet and one anticoagulant drug (
n
= 2), and triple therapy (TT) in which DPT was associated with another antiplatelet drug (
n
= 1) (see
Table 1
and
Supplementary Table S1
(available in the online version) for the characteristics of the patients with initial DPT and TT). Among the 18 patients with AF, 5 (
n
= 3 with mild hemophilia A, FVIII: 13–36%;
n
= 1 with mild hemophilia B, FIX: 28%; and
n
= 1 with moderate hemophilia A, FVIII: 1%) received SAPT (aspirin), as previously recommended for PWHs. During the follow-up, in 23 patients (
n
= 9 with moderate/severe and
n
= 14 with mild hemophilia) the initial antithrombotic treatment was changed to another antithrombotic treatment (
n
= 13) or completely stopped (
n
= 10) (
Table 1
).
Antihemorrhagic prophylaxis (2–3 infusions per week for FVIII concentrates, or 1–2 infusions per week for FIX concentrates) was performed in 18 patients (
Fig. 1
and
Table 1
). The cumulative duration of prophylaxis was 204 months: 108 months (mean: 11.1 months per patient) in patients with severe, 30 months (mean: 10 months per patient) in patients with moderate, and 66 months (mean: 5.5 months per patient) in patients with mild hemophilia. In patients with severe/moderate hemophilia, prophylaxis (
n
= 10) was started after the introduction of the antithrombotic treatment, or was already in place before the CVD diagnosis. Conversely, in patients with mild hemophilia, prophylaxis (
n
= 8) was mainly initiated after the occurrence of a bleeding event (
n
= 6/8; 75%). The other two patients continued the antihemorrhagic treatment initiated for the cardiovascular procedures during hospitalization. In controls, prophylaxis was only performed in patients with severe hemophilia (6/10, 60%).
Major Bleeding Complications during the Follow-Up
Throughout the follow-up, 100 and 33 bleeding events occurred in the 68 COCHE patients and in the 68 controls, respectively. The number of patients who had at least one major bleeding event was higher in the COCHE group (29/68; 42.6%) than in the control group (14/68; 20.6%). Accordingly, the major bleeding-free survival curves were significantly different between the COCHE and control groups (
Fig. 2A
), and between patients with mild hemophilia from these two groups (
Fig. 2B
). Bleeding events were more frequent in patients receiving antiplatelet therapy (AT) than in controls regardless of the severity of hemophilia and the antithrombotic drug used, as described in
Table 2
. The types of major bleeding events in the COCHE group were hemarthrosis (
n
= 52; 52%) in 9 patients, hematoma (
n
= 30; 30%) in 16 patients, gastrointestinal bleeding (GIB;
n
= 10; 10%) in 8 patients, and others (
n
= 8) in 5 patients. In the control group, the 33 bleeding events were hemarthrosis (
n
= 23; 69.7%) in 10 patients, hematoma (
n
= 9; 27.3%) in 8 patients, and epistaxis (
n
= 1). GIB episodes were significantly more frequent in the COCHE group than in controls (8/68 patients vs. 0/68 patients; OR = 15.00 [95% CI: 1.84–268];
p
= 0
.
0141). GIB always occurred during an antithrombotic treatment that included an antiplatelet drug: SAPT (
n
= 5 patients), TT (
n
= 1 patient), and DAPT (
n
= 1 patient). None of the patients with GIB received proton-pump inhibitors (PPIs).
Fig. 2
Major bleeding-free survival curves for the COCHE and control groups. (
A
) In all patients. (
B
) In function of hemophilia severity.
Table 2 Influence of antithrombotic treatments on the risk of major bleeding events in patients with hemophilia in the COCHE and control groups
Mean ABR (95% CI) HR for bleeding (95% CI)
p
Cumulative number of analyzed months
n
Patients
In all patients, whatever the hemophilia severity
Control group 0.317 (0.226–0.408) 1 1,248 68
COCHE total 0.961 (0.924–0.999) 2.64 (1.78–3.92) <0.0001 1,248 68
With AT 1.033 (0.996–1.07) 2.73 (1.82–4.11) <0.0001 1,104 68
Without AT
a
0.417 (0.089–0.744) 1.78 (0.40–7.87) 0.448 144 10
In patients with moderate/severe hemophilia
Control group 0.86 (0.77–0.94) 1 426 20
COCHE total 2.22 (2.10–2.31) 1.96 (1.21–3.18) 0.0061 426 20
With AT 2.36 (2.17–2.53) 2.04 (1.23–3.39) 0.0058 372 20
-SAPT 2.76 (2.64–2.88) 2.05 (1.16–3.62) 0.0132 306 18
-DAPT 4.81 (2.42–13.63) 5.58 (1.49–20.96) 0.0109 60 7
Without AT 0.889 (0.63–1.15) 1.52 (0.25–9.12) 0.6475 54 4
In patients with mild hemophilia
Control group 0.044 (0–0.09) 1 822 48
COCHE total 0.336 (0.273–0.432) 4.93 (2.21–11) <0.0001 822 48
With AT
b
0.361 (0.293–0.463) 4.97 (2.16–11.43) 0.0002 732 48
-SAPT 0.232 (0.177–0.286) 3.76 (1.13–12.55) 0.0313 472 34
-DAPT
c
0.517 (0.324–0.711) 5.31 (1.23–22.92) 0.0252 116 12
-AC 0.353 (0.01–0.606) 9.91 (1.34–73.47) 0.0248 102 10
-DPT
d
1.143 (0.793–1.492) 15.64 (1.57–115.80) 0.019 42 2
Without AT 0.133 (0–0.328) 2.39 (0.15–37.24) 0.3173 90 6
Abbreviations: ABR, annualized bleeding rate; AC, anticoagulant drug alone; AT, antithrombotic treatment; DAPT, dual antiplatelet therapy; DPT, dual pathway therapy; HR, hazard ratio; SAPT, single antiplatelet therapy.
a All 68 patients enrolled in the study started antithrombotic treatment, but 10 discontinued it during the follow-up period.
b In this group, only 1 patient received a tritherapy (DAPT + AC) during 6 months, therefore no statistical analysis was performed for this treatment.
c
The occurrence of bleeding in patients receiving DAPT was significantly higher than in patients with SAPT (HR: 13.12; 95% CI: 2.99–57.48;
p
= 0.0006).
d
The occurrence of bleeding in patients receiving DPT was significantly higher than in patients with other antithrombotic treatments (HR: 8.63; 95% CI: 1.41–52.81;
p
= 0.0198).
In patients with moderate/severe hemophilia receiving an AT (SAPT or DAPT), the risk of bleeding was significantly higher than in controls (
Table 2
). Furthermore, for severe hemophilia, COCHE patients without prophylaxis had a mean ABR significantly higher than COCHE patients with prophylaxis (6.875 [95% CI: 6.58–7.17] vs. 1.231 [95% CI: 0.966–1.496]; OR = 16.69 [8.20–47.26];
p <
0.0001). However, in COCHE patients with prophylaxis, the mean ABR remained threefold higher than in controls with prophylaxis (1.231 vs. 0.4 [95% CI: 0.031–0.769]; OR = 3.73 [1.11–12.56];
p
= 0.0374). The beneficial effect of prophylaxis was also observed in COCHE patients with moderate hemophilia. Indeed, the mean ABR was 0.813 (95% CI: 0.6–1.03) and 0 in patients without and with prophylaxis, respectively (OR = 42.43 [1.86–966.1];
p
= 0
.
0028).
In patients with mild hemophilia, more patients reported major bleeding events in the COCHE than in the control group: 17/48 patients (35.4%) and 2/48 patients (4.2%) (OR = 12.61 [95% CI: 2.72–58.52],
p
= 0
.
0002). The risk of major bleeding events remained high whatever the AT (
Table 2
). Moreover, within the COCHE cohort, the risk of bleeding was significantly higher for patients taking DAPT than for patients taking SAPT (HR: 13.12; 95% CI: 2.99–57.48,
p =
0.0006), and for patients taking DPT than for all other patients taking AT (HR: 8.63; 95% CI: 1.41–52.81;
p =
0.0198) (
Supplementary Table S2
, available in the online version). Moreover, the mean ABR was slightly, but not significantly, higher (1.5-fold) in patients treated with AC than in those treated with SAPT. In the SAPT subgroup, the mean ABR values were comparable in patients taking aspirin and clopidogrel (0.273 and 0.2; see
Supplementary Table S3
, available in the online version). In the AC group, the mean ABR of patients taking VKA and DOA could not be compared, due to their limited number (
n
= 10). In the groups of patients with mild hemophilia and clotting factor levels from 6 to 20%, the percentages of patients with bleeding episodes (
Fig. 3A
) and the mean ABR values (
Fig. 3B
) were significantly higher in COCHE patients with AT but without prophylaxis than in their cross-matched controls. For basal FVIII/FIX levels >20%, no difference was observed between patients receiving an AT and controls.
Fig. 3
Major bleeding events in function of hemophilia severity and basal clotting factor level. (
A
) Percentage of patients who reported at least one major bleeding episode during the 2-year follow-up period. (
B
) Mean annualized bleeding rate. CF: basal clotting factor; ABR: annualized bleeding rate.
Despite the small number of patients with AF (
n
= 18), the number of patients who reported bleeding episodes was significantly higher in patients with HAS-BLED score ≥3 than in those with HAS BLED score <3 (5/8 patients vs. 0/10, respectively; OR = 33 [95% CI: 1.43–761.2];
p
= 0
.
0065). The median clotting factor level of patients with HAS-BLED scores ≥3 and <3 was similar (16.5% [1–36] vs. 19.5% [0–34];
p >
0.05) as well as the proportion of patients on prophylaxis (2/8 [25%] vs. 3/10 [30%];
p >
0.05).
Cardiovascular Complications
During the follow-up, a total of 13 cardiovascular events occurred in 11/68 COCHE patients (16.2%) versus only 1 in 1/68 controls (1.5%). This corresponded in COCHE patients to a mean ACvR of 0.125 (95% CI: 0.06–0.19). Cardiovascular event-free survival curves for the COCHE and control groups were significantly different (
Fig. 4
). These cardiovascular events were ACS, recurrent or at another site (
n
= 8), and mesenteric ischemia (
n
= 1) in the ACS subgroup; stroke (
n
= 1) in the AF subgroup; aortic valve disease aggravation (
n
= 1); and cardiac decompensation (
n
= 2) soon after inclusion in the patients with ACS and AF. Valve disease aggravation and cardiac decompensation led to death during the first month after inclusion. The mean ACvR was similar in patients with severe (0.121), moderate (0.054), and mild hemophilia (0.143) (
p
> 0.05). Prophylaxis with clotting factors did not influence the cardiovascular event occurrence. Indeed, the mean ACvR of COCHE patients was similar during periods of prophylaxis and of on-demand treatment: 0.154 (95% CI: 0–0.381) versus 0.125 (95% CI: 0–0.421) (
p
= 1) for patients with severe hemophilia, and 0 versus 0.063 (95% CI: 0–0.196) (
p
> 0.05) for individuals with moderate hemophilia.
Fig. 4
Cardiovascular event-free survival curves for the COCHE and control groups.
Discussion
The COCHE study is the first case–control study to evaluate antithrombotic treatments for CVD management in PWHs. This is also the largest prospective series with a follow-up period of 2 years after treatment initiation. Indeed, up to now, the recommendations and expert opinions were based on small series of PWHs, case reports, and authors' experience.
13
14
15
18
19
20
However, due to their increasing life expectancy, age-related diseases become more frequent in PWHs, including CVDs that require the administration of antithrombotic treatments, like in the general population.
21
22
23
24
Recommendations for CVD management in the general population are reviewed annually by the world's leading scientific societies of cardiology, based on new high-level methodological studies.
25
26
27
28
They now take into account the patient's hemorrhagic profile, whatever the cause, and constitute a major support to guide antithrombotic treatment in PWHs. Therefore, studies in this population are needed to verify or test whether these general recommendations are adapted to their specific condition. Due to the rarity of such situations in a rare hereditary disease, several results need to be confirmed. However some data could help to improve the management of these patients.
The COCHE study confirmed that antithrombotic treatments significantly increase the risk of bleeding in PWHs, regardless of hemophilia severity (
Supplementary Table S4
, available in the online version). Without antithrombotic treatment, the risk of bleeding is correlated with hemophilia severity.
29
This correlation is also observed with antithrombotic treatments. Indeed, the mean ABR progressively increased with hemophilia severity in both control and COCHE patients; however, the difference between groups was significant only up to a basal FVIII/FIX level of 20%. Above this level, the mean ABR tended to be higher in the COCHE group, but bleeding seemed mostly caused by trauma or invasive procedures. Therefore, in patients with mild hemophilia and FVIII/FIX level >20%, earlier substitution therapy after the trauma or a more systematic prophylaxis before invasive procedures (compared with the standard management of patients with mild hemophilia) could effectively prevent bleeding events. As expected, the mean ABR of COCHE patients with severe/moderate hemophilia without prophylaxis was approximately threefold higher than in controls. This result highlights the importance of prophylaxis in these patients as soon as an AT is prescribed and for the entire treatment duration.
In the subgroup of COCHE patients with AF, HAS-BLED scores ≥3 were associated with increased bleeding risk. The HAS-BLED score is an important tool to determine the basal hemorrhagic risk before and during antithrombotic treatment in the general population.
26
In the “Birmingham 3-step therapeutic strategy,” this score is the second step to assess the risk of bleeding and to adapt antithrombotic treatment in patients with AF. Here, we found that the HAS-BLED score is suitable also for PWHs and therefore, the “Birmingham 3-step strategy” could be relevant also for this population.
Over the past years, many studies demonstrated the direct influence of the antithrombotic treatment type on the bleeding risk in the general population.
11
The COCHE study found a similar influence in PWHs. Specifically, DPT was significantly associated with two- to fourfold higher bleeding risk than the other antithrombotic treatments under study. DAPT also increased the risk of bleeding by about twice compared with SAPT. These results are in line with the recommendations for antithrombotic treatments in PWHs that insist on minimizing the prescription of two or more antithrombotic drugs, such as DPT and DAPT, when possible.
13
Therefore, DPT is recommended for patients with nonvalvular AF associated with ACS, for a minimum period of 1 to 3 months, depending on the type of stent implanted (bare metal stent or DES, respectively).
11
28
The stent choice is of primary importance in PWHs. Stents that require the shortest DPT duration should be favored.
13
To reduce the bleeding risk, SAPT might be preferable to DAPT, but in the general population they are associated with higher stroke risk (1.6 times).
11
The data collected in our study do not allow concluding on this point. For PWHs with nonvalvular AF, only ACs are recommended when the CHA
2
D
2
-VASc score is ≥2, like in the general population.
25
26
VKAs are now replaced, with few exceptions, by DOAs that are associated with a twofold lower risk of fatal bleeding.
30
In COCHE patients with mild hemophilia, the bleeding risk was approximately eightfold higher in patients taking AC than in controls. Although only VKA treatment was associated with major bleeding, the COCHE study did not include enough patients treated with AC to conclude on the difference between DOA and VKA in PWHs. For patients with AF and a CHA
2
D
2
-VASc score = 1, the Canadian Cardiovascular Society (CCS) allows the use of SAPT, but only when the HAS-BLED score is high in <65-year-old patients, due to the low levels of evidence.
26
The recommendations published for all PWHs often prioritize SAPT in AF with CHA
2
D
2
-VASc score = 1, but do not take into account age and hemorrhagic score.
13
14
15
18
19
20
In the COCHE study, the small difference in the mean ABR between patients treated with AC and SAPT (∼1.5 times) suggests that both could be used in PWHs with CHA
2
D
2
-VASc = 1. However, when the HAS-BLED score is ≥3 or for patients with severe hemophilia without prophylaxis, SAPT should be preferred (as recommended by CCS).
The COCHE study confirmed that regular prophylaxis effectively protects patients with severe or moderate hemophilia from major bleeding. However, among patients with severe hemophilia receiving prophylaxis, the mean ABR was still threefold higher than among their cross-matched controls also on prophylaxis (1.231 vs. 0.4). PWHs on prophylaxis with standard FVIII concentrates, two to three times per week, have usually a FVIII trough level of 1 to 2%.
31
The same FIX trough level is obtained with standard FIX concentrates administered once or twice per week. These trough levels are certainly insufficient to effectively protect against bleeding events during antithrombotic treatments, and should be increased at least above 5% or even 10%, depending on the antithrombotic treatment type. This suggestion is supported by the mean ABR values between 0.3 and 0.5 observed in our study for mild hemophilia with FVIII/FIX levels of 6 to 10% and 11 to 20%. FVIII/FIX EHL concentrates could help to achieve these trough target levels without increasing the number of infusions.
31
32
33
In the recent guidelines for antithrombotic treatments in PWHs, the minimum FVIII/FIX trough levels for SAPT range from 1 to 5%.
13
14
15
For AC (and DAPT), the recommended FVIII/FIX trough level is ≥30%. It seems difficult to maintain this target in the long term, even with EHL concentrates, because it would require daily injections (for FVIII) or every 2 days (for FIX). In our study, the major bleeding frequency was comparable in COCHE patients with basal FVIII/FIX levels ≥20% and in controls. This threshold could be a more realistic target. In any case, antithrombotic treatment in PWHs should always be combined with a specific education program to alert the patients about the increased risk of bleeding even after a minor trauma. Multidisciplinary management is also required, including information to the cardiologist and family physician.
In our study, gastrointestinal hemorrhages were significantly more frequent in patients taking antithrombotic treatments, namely antiplatelet drugs associated or not with AC, as observed in the general population.
34
In PWHs, gastric protection with PPIs seems necessary as soon as the antiplatelet drugs are started.
35
36
Finally, the COCHE study showed that in PWHs with ischemic or thrombogenic CVD, the risk of a new cardiovascular event was at least sixfold higher than in PWHs without CVD history. Conversely, this risk of cardiovascular recurrence was independent of hemophilia severity and of prophylaxis. Therefore, antithrombotic treatment is indicated in these PWHs and should be implemented according to cardiologic recommendations adapted to hemophilia.
Given the small number of patients enrolled, we acknowledge that our results should be replicated in new studies. Furthermore, although it was a case–control study with prospective inclusion of patients, the comparison with controls who were enrolled retrospectively could potentially generate a bias.
What is known about this topic?
Age-related cardiovascular diseases (CVDs) are increasing in patients with hemophilia (PWHs) due to their longer life expectancy.
Evidence-based guidelines and medical experience on CVD optimal management in PWHs are limited, especially for antithrombotic treatments.
What does this paper add?
The major bleeding event incidence significantly increases in all PWHs taking antithrombotic treatments.
The major bleeding event incidence is directly related to hemophilia severity, presence/absence of prophylaxis, HAS-BLED score, and antithrombotic treatment type.
Gastrointestinal bleeding events are frequent in PWHs receiving antithrombotic treatments.
PWHs with CVD have an increased risk of additional cardiovascular events.
The risk of cardiovascular event recurrence in PWHs is not influenced by prophylaxis with factor VIII or IX concentrates.
Acknowledgment
The authors would like to thank Hasan Catovic and Diane Bracquart for their assistance in data collection and logistical organization of the COCHE study; co-investigators from the 26 French HTCs; and Elisabetta Andermarcher for her help in editing and rewriting in English.
Conflict of Interest None declared.
Authors' Contributions
All authors contributed to the study concept and design. B.G., G.C., and J-F.S. recruited patients, analyzed and interpreted results, and wrote the manuscript. A.L., B.W., C.F., S.C., P.G., and S.C. recruited patients.
*
Benoît Guillet and Guillaume Cayla contributed equally to the present work.
Supplementary Material
Supplementary Material
Supplementary Material
|
ANTIHEMOPHILIC FACTOR HUMAN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33099283
| 19,148,168
|
2021-03
|
What was the dosage of drug 'GEMCITABINE HYDROCHLORIDE'?
|
Capillary leak syndrome induced by neoadjuvant cisplatin and gemcitabine in a patient with bladder cancer.
Capillary leak syndrome (CLS) is a rare disorder associated with an increased capillar permeability due to an endothelial damage, causing leakage of plasma and proteins into the interstitial compartment. CLS is characterized by rapidly developing edema, hypotension and hypoproteinemia. We observed CLS in a 54-year-old man affected by muscle-invasive bladder cancer who received neoadjuvant treatment with Cisplatin and Gemcitabine. Treatment with infusion of albumin and increasing corticosteroid doses and diuretics led to a complete regression of all signs and symptoms related to the disorder. Of note, the patient showed an objective complete response to chemotherapy and underwent radical surgery on schedule.
Introduction
Capillary leak syndrome (CLS) is a rare clinical condition characterized by rapid and reversible increase in endothelial permeability, with consequent leakage of plasma proteins into the interstitial space, with peripheral edema.1 A similar phenomenon is observed during sepsis and less frequently in some manifestations of autoimmune diseases. This syndrome can be suspected in patients with hypotension, hypoalbuminemia without organ failure, partial or generalized edema, hemoconcentration and possible presence of paraproteins in the blood.
It can be idiopathic, called Clarkson's syndrome, or induced by other factors. In all cases, it can be a life-threatening condition. Among the causes that trigger this syndrome are counted some drugs, the engraftment syndrome, promyelocytic leukemia which undergoes induction treatment with either all-trans retinoic acid or arsenic trioxide, ovarian hyperstimulation syndrome, Hhemophagocytic lymphohistiocytosis, hemorrhagic fever and snakebite. Acute renal failure, hypovolemic shock and coagulopathies are often found in the conditions mentioned above. Among the drugs that have been reported to lead to CLS in the literature, there is gemcitabine. This is a chemotherapic drug used in several types of malignancies, including bladder cancer. So far, few cases, less that ten, of CLS induced by gemcitabine are found in literature. Herein we report a case of CLS developed during last cycle of neoadjuvant treatment with cisplatin and gemcitabine in a patient with muscle-invasive bladder cancer.
Case
A 54-year-old male, affected by locally advanced, muscle-invasive high grade papillary urothelial cancer of bladder, without any other significant comorbidities, was proposed for neoadjuvant chemotherapy with cisplatin 80 mg/mq and gemcitabine 1000 mg/mq 1,8 q21 for four cycles, as for guidelines.2 During first three cycles, the patient did not receive the gemcitabine on day 8 for grade 3 neutropenia. The fourth cycle was completed. Five days after from receiving last dose of gemcitabine, the patient developed fever and petechiae on legs and trunk and he was hospitalized. The blood count showed anemia (hemoglobin 9,6 g/dL), leukopenia (1900 mm3) and thrombocytopenia (21,000 mm3). The renal function, hepatic function and coagulation parameters were within normal ranges. Albuminemia was decreased (3.07 g/dL). He was infused with platelets concentrate and started granulocyte colony-stimulating factor (G-CSF), 30 million units/die. He also started antibiotic therapy. On day 6th, the patient showed contraction of diuresis, hypotension and edema of the trunk and arms, bilaterally. Eco-color-doppler of the arms excluded venous thrombosis. Cardiac ecocolordoppler and Angio-CT excluded thrombo-embolic events of arterial vessels. Edema progressively extended to lower limbs (Fig. 1) and the persistence of fever, neutropenia, hypotension posed the suspect of sepsis, excluded by serial hemocoltures at feverish peak, urine cultures and by normal blood procalcitonin levels. On day 8th, total protein value and level of albuminemia further decreased (4,4 g/dL and 2,45 g/dL, respectively) (Fig. 2). There was no proteinuria in the urine test and we started treatment with albumin 20% 50 ml once daily. He also received intravenous furosemide (20 mg, once daily) and prednisone 25 mg, once daily and received transfusions of platelets and red blood cells concentrates. The clinical manifestations persisted, without improvement, until day 12th, when we increased prednisone dose to 50 mg daily. On day 14th, we observed a reduction of edema of the trunk and arms, an increasing of blood cells count and normalization of diuresis and blood pressure. Renal function was within normal range. The complete normalization of clinical condition was observed on day 17th. No other cycles of chemotherapy were administered.Fig. 1 Edema of lower limbs on the day of lower level of albuminemia (2,45 g/dL on day 8th).
Fig. 1
Fig. 2 The graphic shows decreasing of total proteins and albumin levels and blood pressure until day 8th from last administration of gemcitabine and subsequent gradual normalization of this values, more evident after improving therapy with prednisone on day 12th.
Fig. 2
Interestingly, a Chest-Abdomen CT was performed and showed an objective complete response to neoadjuvant chemotherapy (Fig. 3).Fig. 3 Comparative CT with contrast images of the bladder neoformation, before and after neoadjuvant chemotherapy treatment; A. Image before neoadjuvant treatment; C. Image after neoadjuvant treatment: we observed a total disappearance of the parietal lesion; B. Image before neoadjuvant treatment; D. Image after neoadjuvant treatment: the filling defect is no more detectable.
Fig. 3
The patient successfully underwent radical cystectomy and bilateral pelvic lymph node dissection, with construction of cutaneous uretero-ileostomy ad modum Bricker. At histopatological examination, there was no evidence of infiltrating tumor on bladder wall, but the presence of carcinoma in situ, mild lymphocytes infiltration and focal granulomatous inflammatory reaction with macrophages and multinucleated giant cells. Nonspecific reactive lymphadenitis in 10 lymph nodes examined was detected.
Discussion
In this clinical experience, we have witnessed a rare adverse event of gemcitabine, for the first time reported in a patient with bladder cancer receiving neoadjuvant treatment.
We cannot exclude that cisplatin, associated with gemcitabine, might also have played a role in the pathogenesis of the disorder. Nevertheless, in view of the absence of the syndrome during the first cycles in which the patient had not sustained the eighth day of treatment with gemcitabine alone, a dose-dependent effect and a particular susceptibility of the patient in metabolizing the drug may be assumed.
Increasing in corticosteroid dosage led to a rapid improvement in symptoms, demonstrating an almost total ineffectiveness of prednisone at lower doses of 0.5 mg/kg, despite simultaneous diuretic therapy.
Combination of steroids and diuretics at an appropriate dosage has allowed the complete reversibility of symptoms 8–10 days after the start of treatment.
Similar experiences have already been published,3 underlying the need for prompt recognition of CLS and treatment, that need to be continued for some weeks before being able to see concrete clinical benefits.
The effectiveness of the therapy, with the complete clinical response to the chemotherapy treatment, has largely justified the risk of toxicity. The patient was subsequently operated and he returned to his previous daily routine.
Cases of CLS have recently been reported to be associated with the administration of immune checkpoint inhibitors (ICIs), including Nivolumab4 and during infection with SARS-CoV-2.5 These experiences suggest a probable pathogenesis due to a dysregulation of the immune response with cytokine alterations, in the absence of a cellular inflammatory response, impacting on endothelial permeability.
Conclusion
CLS remains a clinical challenge, not just as a side effect of chemotherapy. The main goal is a prompt recognition of the symptoms, regardless of the underlying cause, because even if CLS is a rare syndrome, it needs to be treated properly to avoid serious and irreversible damages.
Focusing on the pathophysiological mechanism that underlies this syndrome, a predictive role of response to chemotherapy could be assumed, for example by inducing an increased activity of the inflammatory response. This hypothesis could be investigated by other clinical experiences.
Declaration of competing interest
The authors report no conflicts of interest in this work.
|
UNK, CYCLIC (1000 MG/MQ Q21 FOR FOUR CYCLES)
|
DrugDosageText
|
CC BY-NC-ND
|
33101987
| 18,533,173
|
2021-01
|
What was the dosage of drug 'GEMCITABINE\GEMCITABINE HYDROCHLORIDE'?
|
Capillary leak syndrome induced by neoadjuvant cisplatin and gemcitabine in a patient with bladder cancer.
Capillary leak syndrome (CLS) is a rare disorder associated with an increased capillar permeability due to an endothelial damage, causing leakage of plasma and proteins into the interstitial compartment. CLS is characterized by rapidly developing edema, hypotension and hypoproteinemia. We observed CLS in a 54-year-old man affected by muscle-invasive bladder cancer who received neoadjuvant treatment with Cisplatin and Gemcitabine. Treatment with infusion of albumin and increasing corticosteroid doses and diuretics led to a complete regression of all signs and symptoms related to the disorder. Of note, the patient showed an objective complete response to chemotherapy and underwent radical surgery on schedule.
Introduction
Capillary leak syndrome (CLS) is a rare clinical condition characterized by rapid and reversible increase in endothelial permeability, with consequent leakage of plasma proteins into the interstitial space, with peripheral edema.1 A similar phenomenon is observed during sepsis and less frequently in some manifestations of autoimmune diseases. This syndrome can be suspected in patients with hypotension, hypoalbuminemia without organ failure, partial or generalized edema, hemoconcentration and possible presence of paraproteins in the blood.
It can be idiopathic, called Clarkson's syndrome, or induced by other factors. In all cases, it can be a life-threatening condition. Among the causes that trigger this syndrome are counted some drugs, the engraftment syndrome, promyelocytic leukemia which undergoes induction treatment with either all-trans retinoic acid or arsenic trioxide, ovarian hyperstimulation syndrome, Hhemophagocytic lymphohistiocytosis, hemorrhagic fever and snakebite. Acute renal failure, hypovolemic shock and coagulopathies are often found in the conditions mentioned above. Among the drugs that have been reported to lead to CLS in the literature, there is gemcitabine. This is a chemotherapic drug used in several types of malignancies, including bladder cancer. So far, few cases, less that ten, of CLS induced by gemcitabine are found in literature. Herein we report a case of CLS developed during last cycle of neoadjuvant treatment with cisplatin and gemcitabine in a patient with muscle-invasive bladder cancer.
Case
A 54-year-old male, affected by locally advanced, muscle-invasive high grade papillary urothelial cancer of bladder, without any other significant comorbidities, was proposed for neoadjuvant chemotherapy with cisplatin 80 mg/mq and gemcitabine 1000 mg/mq 1,8 q21 for four cycles, as for guidelines.2 During first three cycles, the patient did not receive the gemcitabine on day 8 for grade 3 neutropenia. The fourth cycle was completed. Five days after from receiving last dose of gemcitabine, the patient developed fever and petechiae on legs and trunk and he was hospitalized. The blood count showed anemia (hemoglobin 9,6 g/dL), leukopenia (1900 mm3) and thrombocytopenia (21,000 mm3). The renal function, hepatic function and coagulation parameters were within normal ranges. Albuminemia was decreased (3.07 g/dL). He was infused with platelets concentrate and started granulocyte colony-stimulating factor (G-CSF), 30 million units/die. He also started antibiotic therapy. On day 6th, the patient showed contraction of diuresis, hypotension and edema of the trunk and arms, bilaterally. Eco-color-doppler of the arms excluded venous thrombosis. Cardiac ecocolordoppler and Angio-CT excluded thrombo-embolic events of arterial vessels. Edema progressively extended to lower limbs (Fig. 1) and the persistence of fever, neutropenia, hypotension posed the suspect of sepsis, excluded by serial hemocoltures at feverish peak, urine cultures and by normal blood procalcitonin levels. On day 8th, total protein value and level of albuminemia further decreased (4,4 g/dL and 2,45 g/dL, respectively) (Fig. 2). There was no proteinuria in the urine test and we started treatment with albumin 20% 50 ml once daily. He also received intravenous furosemide (20 mg, once daily) and prednisone 25 mg, once daily and received transfusions of platelets and red blood cells concentrates. The clinical manifestations persisted, without improvement, until day 12th, when we increased prednisone dose to 50 mg daily. On day 14th, we observed a reduction of edema of the trunk and arms, an increasing of blood cells count and normalization of diuresis and blood pressure. Renal function was within normal range. The complete normalization of clinical condition was observed on day 17th. No other cycles of chemotherapy were administered.Fig. 1 Edema of lower limbs on the day of lower level of albuminemia (2,45 g/dL on day 8th).
Fig. 1
Fig. 2 The graphic shows decreasing of total proteins and albumin levels and blood pressure until day 8th from last administration of gemcitabine and subsequent gradual normalization of this values, more evident after improving therapy with prednisone on day 12th.
Fig. 2
Interestingly, a Chest-Abdomen CT was performed and showed an objective complete response to neoadjuvant chemotherapy (Fig. 3).Fig. 3 Comparative CT with contrast images of the bladder neoformation, before and after neoadjuvant chemotherapy treatment; A. Image before neoadjuvant treatment; C. Image after neoadjuvant treatment: we observed a total disappearance of the parietal lesion; B. Image before neoadjuvant treatment; D. Image after neoadjuvant treatment: the filling defect is no more detectable.
Fig. 3
The patient successfully underwent radical cystectomy and bilateral pelvic lymph node dissection, with construction of cutaneous uretero-ileostomy ad modum Bricker. At histopatological examination, there was no evidence of infiltrating tumor on bladder wall, but the presence of carcinoma in situ, mild lymphocytes infiltration and focal granulomatous inflammatory reaction with macrophages and multinucleated giant cells. Nonspecific reactive lymphadenitis in 10 lymph nodes examined was detected.
Discussion
In this clinical experience, we have witnessed a rare adverse event of gemcitabine, for the first time reported in a patient with bladder cancer receiving neoadjuvant treatment.
We cannot exclude that cisplatin, associated with gemcitabine, might also have played a role in the pathogenesis of the disorder. Nevertheless, in view of the absence of the syndrome during the first cycles in which the patient had not sustained the eighth day of treatment with gemcitabine alone, a dose-dependent effect and a particular susceptibility of the patient in metabolizing the drug may be assumed.
Increasing in corticosteroid dosage led to a rapid improvement in symptoms, demonstrating an almost total ineffectiveness of prednisone at lower doses of 0.5 mg/kg, despite simultaneous diuretic therapy.
Combination of steroids and diuretics at an appropriate dosage has allowed the complete reversibility of symptoms 8–10 days after the start of treatment.
Similar experiences have already been published,3 underlying the need for prompt recognition of CLS and treatment, that need to be continued for some weeks before being able to see concrete clinical benefits.
The effectiveness of the therapy, with the complete clinical response to the chemotherapy treatment, has largely justified the risk of toxicity. The patient was subsequently operated and he returned to his previous daily routine.
Cases of CLS have recently been reported to be associated with the administration of immune checkpoint inhibitors (ICIs), including Nivolumab4 and during infection with SARS-CoV-2.5 These experiences suggest a probable pathogenesis due to a dysregulation of the immune response with cytokine alterations, in the absence of a cellular inflammatory response, impacting on endothelial permeability.
Conclusion
CLS remains a clinical challenge, not just as a side effect of chemotherapy. The main goal is a prompt recognition of the symptoms, regardless of the underlying cause, because even if CLS is a rare syndrome, it needs to be treated properly to avoid serious and irreversible damages.
Focusing on the pathophysiological mechanism that underlies this syndrome, a predictive role of response to chemotherapy could be assumed, for example by inducing an increased activity of the inflammatory response. This hypothesis could be investigated by other clinical experiences.
Declaration of competing interest
The authors report no conflicts of interest in this work.
|
1000 MG/MQ 1,8 Q21
|
DrugDosageText
|
CC BY-NC-ND
|
33101987
| 18,495,096
|
2021-01
|
What was the outcome of reaction 'Capillary leak syndrome'?
|
Capillary leak syndrome induced by neoadjuvant cisplatin and gemcitabine in a patient with bladder cancer.
Capillary leak syndrome (CLS) is a rare disorder associated with an increased capillar permeability due to an endothelial damage, causing leakage of plasma and proteins into the interstitial compartment. CLS is characterized by rapidly developing edema, hypotension and hypoproteinemia. We observed CLS in a 54-year-old man affected by muscle-invasive bladder cancer who received neoadjuvant treatment with Cisplatin and Gemcitabine. Treatment with infusion of albumin and increasing corticosteroid doses and diuretics led to a complete regression of all signs and symptoms related to the disorder. Of note, the patient showed an objective complete response to chemotherapy and underwent radical surgery on schedule.
Introduction
Capillary leak syndrome (CLS) is a rare clinical condition characterized by rapid and reversible increase in endothelial permeability, with consequent leakage of plasma proteins into the interstitial space, with peripheral edema.1 A similar phenomenon is observed during sepsis and less frequently in some manifestations of autoimmune diseases. This syndrome can be suspected in patients with hypotension, hypoalbuminemia without organ failure, partial or generalized edema, hemoconcentration and possible presence of paraproteins in the blood.
It can be idiopathic, called Clarkson's syndrome, or induced by other factors. In all cases, it can be a life-threatening condition. Among the causes that trigger this syndrome are counted some drugs, the engraftment syndrome, promyelocytic leukemia which undergoes induction treatment with either all-trans retinoic acid or arsenic trioxide, ovarian hyperstimulation syndrome, Hhemophagocytic lymphohistiocytosis, hemorrhagic fever and snakebite. Acute renal failure, hypovolemic shock and coagulopathies are often found in the conditions mentioned above. Among the drugs that have been reported to lead to CLS in the literature, there is gemcitabine. This is a chemotherapic drug used in several types of malignancies, including bladder cancer. So far, few cases, less that ten, of CLS induced by gemcitabine are found in literature. Herein we report a case of CLS developed during last cycle of neoadjuvant treatment with cisplatin and gemcitabine in a patient with muscle-invasive bladder cancer.
Case
A 54-year-old male, affected by locally advanced, muscle-invasive high grade papillary urothelial cancer of bladder, without any other significant comorbidities, was proposed for neoadjuvant chemotherapy with cisplatin 80 mg/mq and gemcitabine 1000 mg/mq 1,8 q21 for four cycles, as for guidelines.2 During first three cycles, the patient did not receive the gemcitabine on day 8 for grade 3 neutropenia. The fourth cycle was completed. Five days after from receiving last dose of gemcitabine, the patient developed fever and petechiae on legs and trunk and he was hospitalized. The blood count showed anemia (hemoglobin 9,6 g/dL), leukopenia (1900 mm3) and thrombocytopenia (21,000 mm3). The renal function, hepatic function and coagulation parameters were within normal ranges. Albuminemia was decreased (3.07 g/dL). He was infused with platelets concentrate and started granulocyte colony-stimulating factor (G-CSF), 30 million units/die. He also started antibiotic therapy. On day 6th, the patient showed contraction of diuresis, hypotension and edema of the trunk and arms, bilaterally. Eco-color-doppler of the arms excluded venous thrombosis. Cardiac ecocolordoppler and Angio-CT excluded thrombo-embolic events of arterial vessels. Edema progressively extended to lower limbs (Fig. 1) and the persistence of fever, neutropenia, hypotension posed the suspect of sepsis, excluded by serial hemocoltures at feverish peak, urine cultures and by normal blood procalcitonin levels. On day 8th, total protein value and level of albuminemia further decreased (4,4 g/dL and 2,45 g/dL, respectively) (Fig. 2). There was no proteinuria in the urine test and we started treatment with albumin 20% 50 ml once daily. He also received intravenous furosemide (20 mg, once daily) and prednisone 25 mg, once daily and received transfusions of platelets and red blood cells concentrates. The clinical manifestations persisted, without improvement, until day 12th, when we increased prednisone dose to 50 mg daily. On day 14th, we observed a reduction of edema of the trunk and arms, an increasing of blood cells count and normalization of diuresis and blood pressure. Renal function was within normal range. The complete normalization of clinical condition was observed on day 17th. No other cycles of chemotherapy were administered.Fig. 1 Edema of lower limbs on the day of lower level of albuminemia (2,45 g/dL on day 8th).
Fig. 1
Fig. 2 The graphic shows decreasing of total proteins and albumin levels and blood pressure until day 8th from last administration of gemcitabine and subsequent gradual normalization of this values, more evident after improving therapy with prednisone on day 12th.
Fig. 2
Interestingly, a Chest-Abdomen CT was performed and showed an objective complete response to neoadjuvant chemotherapy (Fig. 3).Fig. 3 Comparative CT with contrast images of the bladder neoformation, before and after neoadjuvant chemotherapy treatment; A. Image before neoadjuvant treatment; C. Image after neoadjuvant treatment: we observed a total disappearance of the parietal lesion; B. Image before neoadjuvant treatment; D. Image after neoadjuvant treatment: the filling defect is no more detectable.
Fig. 3
The patient successfully underwent radical cystectomy and bilateral pelvic lymph node dissection, with construction of cutaneous uretero-ileostomy ad modum Bricker. At histopatological examination, there was no evidence of infiltrating tumor on bladder wall, but the presence of carcinoma in situ, mild lymphocytes infiltration and focal granulomatous inflammatory reaction with macrophages and multinucleated giant cells. Nonspecific reactive lymphadenitis in 10 lymph nodes examined was detected.
Discussion
In this clinical experience, we have witnessed a rare adverse event of gemcitabine, for the first time reported in a patient with bladder cancer receiving neoadjuvant treatment.
We cannot exclude that cisplatin, associated with gemcitabine, might also have played a role in the pathogenesis of the disorder. Nevertheless, in view of the absence of the syndrome during the first cycles in which the patient had not sustained the eighth day of treatment with gemcitabine alone, a dose-dependent effect and a particular susceptibility of the patient in metabolizing the drug may be assumed.
Increasing in corticosteroid dosage led to a rapid improvement in symptoms, demonstrating an almost total ineffectiveness of prednisone at lower doses of 0.5 mg/kg, despite simultaneous diuretic therapy.
Combination of steroids and diuretics at an appropriate dosage has allowed the complete reversibility of symptoms 8–10 days after the start of treatment.
Similar experiences have already been published,3 underlying the need for prompt recognition of CLS and treatment, that need to be continued for some weeks before being able to see concrete clinical benefits.
The effectiveness of the therapy, with the complete clinical response to the chemotherapy treatment, has largely justified the risk of toxicity. The patient was subsequently operated and he returned to his previous daily routine.
Cases of CLS have recently been reported to be associated with the administration of immune checkpoint inhibitors (ICIs), including Nivolumab4 and during infection with SARS-CoV-2.5 These experiences suggest a probable pathogenesis due to a dysregulation of the immune response with cytokine alterations, in the absence of a cellular inflammatory response, impacting on endothelial permeability.
Conclusion
CLS remains a clinical challenge, not just as a side effect of chemotherapy. The main goal is a prompt recognition of the symptoms, regardless of the underlying cause, because even if CLS is a rare syndrome, it needs to be treated properly to avoid serious and irreversible damages.
Focusing on the pathophysiological mechanism that underlies this syndrome, a predictive role of response to chemotherapy could be assumed, for example by inducing an increased activity of the inflammatory response. This hypothesis could be investigated by other clinical experiences.
Declaration of competing interest
The authors report no conflicts of interest in this work.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33101987
| 18,495,096
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'.
|
Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
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CARBOPLATIN
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33103860
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2021-04
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary embolism'.
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Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
|
BLEOMYCIN SULFATE, CISPLATIN, ETOPOSIDE
|
DrugsGivenReaction
|
CC BY
|
33103860
| 19,210,455
|
2021-04
|
What was the dosage of drug 'BLEOMYCIN SULFATE'?
|
Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
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UNK, CYCLIC (4 CYCLES)
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DrugDosageText
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CC BY
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33103860
| 19,210,455
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2021-04
|
What was the dosage of drug 'CARBOPLATIN'?
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Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
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What was the dosage of drug 'CISPLATIN'?
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Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
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What was the dosage of drug 'ETOPOSIDE'?
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Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
|
UNK, CYCLIC (FOUR CYCLES)
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DrugDosageText
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CC BY
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33103860
| 19,210,455
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2021-04
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What was the outcome of reaction 'Pneumonitis'?
|
Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
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What was the outcome of reaction 'Pulmonary embolism'?
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Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.
Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data.
Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7.
We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months.
These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.
pmc1 INTRODUCTION
Seminoma accounts for more than half of testicular germ cell tumors (GCTs), with peak incidence at 35 to 45 years of age.1, 2 New Zealand Ministry of Health data from 2005 to 2017 show that Maori men have consistently higher rates of testicular cancer than non‐Maori men.3 About 80% of seminoma present with clinical stage 1 (CS1) disease, with an estimated relapse rate of 13% to 20% without adjuvant treatment.1, 4, 5 However, the high curability at relapse has led to ongoing debate about whether optimal postoperative management is adjuvant treatment or surveillance.1, 4, 6
Historically, adjuvant radiotherapy was given but was associated with increased incidence of subsequent malignant neoplasms (SMNs) and cardiovascular events.7, 8 When the MRC TE19 study showed noninferiority of a single dose of adjuvant carboplatin chemotherapy to radiotherapy, the use of adjuvant radiotherapy diminished.7, 9 Adjuvant carboplatin has been further explored in nonrandomized trials, using one or two cycles dosed at an area under the time–concentration curve (AUC) of 7 and effectively reduces relapse6, 8 without association with significant late toxicities or SMN.10, 11
Surveillance avoids treatment in the majority of patients and has largely become the preferred strategy.4, 8, 12 However, relapsed patients are exposed to the far greater toxicity of cisplatin‐based chemotherapy.7, 13, 14 There is no consensus on duration of surveillance, which can be up to 10 years, requiring up to 10 abdominal CT scans. This exposes patients to significant doses of radiation, raising concerns of long‐term SMN risk.4, 8, 15 From a psychological perspective, it is well known that patients with testicular cancer experience fear of relapse; however, it is unclear whether this is increased by surveillance.16, 17
Risk‐based management is proposed by some studies18, 19, 20, 21 and guidelines,22 reserving adjuvant carboplatin for patients with one or both of rete testis involvement (RTI) or tumor size more than 4 cm. However, significant heterogeneity in the predictive value of these risk factors questions the reliability of this approach.23, 24
Since 2000, the standard of care for patients with CS1 seminoma at the Waikato, Lakes and Bay of Plenty District Health Boards (DHB), New Zealand, has been to consider two cycles of adjuvant carboplatin AUC7, given 3 weeks apart. Our objectives were to analyze this cohort and determine relapse‐free survival (RFS), overall survival (OS), disease‐specific survival (DSS), cause‐specific survival (CSS), which includes deaths from seminoma and treatment, and rates of long‐term toxicity, SMN, and second GCT. We also wanted to observe the association of RTI and tumor size >4 cm with relapse.
2 METHODS
We retrospectively analyzed data of patients over 18 years old with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016. Data were sourced from a proprietary database (Aesculapius) of Medical Oncology patients seen at the Waikato and Lakes DHBs, the Bay of Plenty DHB cancer database, and the New Zealand Health Information Service. This included age, ethnicity, disease stage, tumor size, RTI status, tumor marker levels pre chemotherapy, chemotherapy regimen including number of cycles intended and delivered, relapse, mortality, cause of death, and incidence of SMN (including contralateral GCT). Mortality and SMN data acquired from the national database were updated to December 12, 2017.
Descriptive statistics were used for patient, tumor, and treatment characteristics. Relapse according to RTI and tumor size >4 cm was analyzed using Fisher's exact test, and actuarial survival was estimated with the Kaplan–Meier method with asymmetrical 95% confidence interval (CI) recommended as more accurate than the more commonly used symmetrical confidence intervals by GraphPad Prism version 8.4.3 (GraphPad, CA, USA), which was used for all analyses. The study was conducted under approval from the Southern Health and Disability Ethics Committee (ref: 16/STH/251).
3 RESULTS
3.1 Patient characteristics
There were 159 patients with CS1 seminoma treated with adjuvant carboplatin. Three patients who developed a metachronous contralateral CS1 seminoma within the study period were treated with adjuvant carboplatin on both occasions and are counted twice.
Patient and disease characteristics are shown in Table 1. Median follow‐up for survival was 106 months (interquartile range 72‐159 months). Six patients had a prior history of testicular seminoma at a median of 7 (range 6‐10) years earlier, three of whom had received radiotherapy. Three patients had stage S1 due to raised LDH.
TABLE 1 Patient characteristics
Characteristic N = 159 %
Age – median (range) years 39 (20‐73)
Ethnicity
New Zealand European 110 69.2
Maori 46 28.9
Other 3 1.9
AJCC staging (seventh edition)
T1 130 81.8
T2 23 14.5
T3 6 3.8
N0 159 100.0
N1 0 0.0
S0 139 87.4
S1 3 1.9
Sx 16 10.1
Tumor size
>4 cm 69 43.3
<4 cm 78 49.1
Not known 12 7.5
Rete testis invasion
Yes 34 21.4
No 72 45.3
Not known 53 33.3
Note: Sx: serum tumor marker status unknown.
3.2 Treatment
One hundred forty‐seven of 153 patients (96%) received their planned two cycles of carboplatin AUC7. Six patients received one cycle: one patient by intention, three due to adverse effects (one each of nausea and vomiting, neuropathy, and hypersensitivity reaction), one due to attempted suicide and one due to incarceration. Six patients received two cycles of carboplatin AUC6, one due to chronic kidney disease; the other five had no documented reason for this dose. Glomerular filtration rate was largely estimated by the Cockcroft‐Gault equation; however, in patients at extremes of body habitus, it was measured by 51Cr‐EDTA clearance.
Acute toxicity was not systematically recorded, but there were only two acute admissions during treatment: one with nausea and vomiting and the other with headache. Persistent adverse effects were rare: there was one case of ongoing grade 1 thrombocytopenia 46 months post chemotherapy.
3.3 Follow‐up
After completing chemotherapy, patients had clinical examinations and tumor markers checked every 3 to 6 months for the first 2 years and up to 5 years depending on clinician preference. Most patients only had one CT scan at month 12, but, depending on estimated risk of relapse, some had up to four CT scans over the first 5 years. Fifteen (9.4%) patients were lost to follow‐up due to noncompliance.
3.4 Outcomes
One patient aged 47 years at initial diagnosis, of NZ European descent, relapsed in his para‐aortic nodes at 22 months following two cycles of carboplatin dosed at AUC7, resulting in actuarial RFS of 99.4% (95% CI 95.6‐100) at 15 years (Figure 1A). He achieved a radiological complete response after four cycles of BEP but unfortunately died 2 months later of bleomycin pneumonitis precipitated by a large pulmonary embolus requiring high‐flow oxygen. Including the relapsed patient, there were five deaths, the remaining four due to SMN (Table 2), of whom one was Maori. No patients died from progressive seminoma. OS was 98.7% (95% CI 97.7‐100) and 91.4% (95% CI 85.9‐100) at 10 and 15 years, respectively (Figure 1B). DSS and CSS at 15 years were 100% and 99.4%, respectively.
FIGURE 1 Survival. A: relapse‐free survival; B: overall survival. Dotted lines represent asymmetrical 95% CI
TABLE 2 Subsequent Malignant Neoplasms
SMN Age at SMN diagnosis Time from chemotherapy (months) Died of SMN
Second germ cell tumors
Contralateral CS1 seminoma 36 80 No
Contralateral CS1 seminoma 37 48 No
Contralateral CS1 seminoma 41 58 No
Contralateral CS1 seminoma 41 126 No
Other SMNs
Neuroendocrine carcinoma of axilla 44 36 No
Melanoma 48 130 Yes
Glioblastoma multiforme 51 38 Yes
Rectal adenocarcinoma 51 51 No
Myeloma 56 96 Yes
Small cell lung cancer 64 132 Yes
Prostate adenocarcinoma 69 102 No
Abbreviation: CS1: clinical stage 1.
RTI status was reported in 106 patients (Table 1): 21 patients (13.2%) had both RTI and tumor size >4 cm. The relapsed patient had both risk factors. However, neither RTI nor tumor size >4 cm significantly affected the relapse rate (P = .32 and .47, respectively).
3.5 Subsequent malignant neoplasms
Eleven SMNs occurred, four of which were contralateral seminomas (Table 2). Actuarial second GCT incidence at 15 years was 3.85% (95% CI 0‐30.1). Seven non‐GCT SMNs were diagnosed at a median of 96 months post chemotherapy, with actuarial incidence 7.6% at 15 years (95% CI 0.3‐31.3). None occurred in patients who previously received radiotherapy for prior GCT. Median age at diagnosis of second GCT and SMN was 39 and 51 years, respectively.
4 DISCUSSION
The 15‐year RFS of 99.4%, OS of 91.4%, and DSS of 100% in our population provides further evidence for the efficacy of two cycles of adjuvant carboplatin for CS1 seminoma. The ideal number of cycles of carboplatin has not been defined in a randomized controlled trial (RCT), but nonrandomized studies and interstudy comparison suggest inferiority of one cycle compared to two, summarized in Table 3. Relapse rates were 0% to 8.6% vs 0% to 3.3% for one vs two cycles of carboplatin, respectively, though there was considerable heterogeneity of follow‐up duration and study populations (Table 3). The absence of an adequately powered RCT is likely due to the requirement for about 5000 patients to detect superiority of two cycles vs one cycle of adjuvant carboplatin.
TABLE 3 Studies of CS1 seminoma treated with adjuvant carboplatin (dosed at AUC7 unless stated otherwise)
Author Type of study Cycles of carboplatin Patients (N) Population Median F/U (months) Relapse Rate (%)/time Second GCT rate (%) SMN % (site/months) DFS (%) 5y DSS (%) 5y OS (%)
Carboplatin 1 cycle
Oliver 20119 RCT 1 573 pT1‐3, normal post‐op HCG 78 5.1 (NS) 0.3 (NS) 0.9 unspecified (NS) 94.7 (RFR) 100 99
Tandstad 20117 Prospective, non‐randomised 1 188 All comers (T > 4 cm 52.7%) 41 3.9 (0.9 ‐32 m) NS NS NS 100 99.2
Carboplatin 2 cycles
Aparicio 201820 Prospective non‐randomised 2 64 RTI 33 1.6 (20 m) NS NS 98.2 at 3y 100 at 3y 100 at 3y
Aparicio 201129 Prospective, non‐randomized 2 74 RTI and T > 4 cm 74 1.4 (25 m) NS NS 88.1 at 3y 100 at 3y 100 at 3y
Steiner 201030 Retrospective 2 cycles 400 mg/m2 282 All comers (T > 4 cm 48.2%, RTI NS) 75.2 (mean) 1.06 (9‐22 m) 1.9 (2‐10.8y) 1.8 (2 prostate, 2 melanoma, 1 RCC/NS) 98.1 100 NS
Argirovic 200931 Prospective 2 cycles 400 mg/m2 230 All comers 84 2.6 (median 31 m) 1.7 (median 20.3 m) 0.4 (Lung/28 m) NS 100 at 7y 99.1 at 7y
Aparicio 200532 Prospective, non‐randomized 2 214 RTI 38.8%, T > 4 cm 84.6%, both 23.4% 34 3.3 (4‐28 m) 0.9 (NS) 0.9 (1 RCC, 1 CLL/NS) 96.2 100 100
Aparicio 200333 Prospective, non‐randomized 2 cycles 400 mg/m2 60 T2 or venous/lymphatic vascular invasion 52 3.3 (median 11 m) NS 0% 96.6 100 NS
Reiter 200110 Prospective, non‐randomized 2 cycles 400 mg/m2 107 All comers 74 0 0 0.9 (rectal/26 m) 100 at 74 m 100 at 74 m 94.4 at 74 m
Krege 199734 Phase 2 single arm 2 cycles 400 mg/m2 43 All comers 28 0 NS NS NS NS NS
Carboplatin varying number of cycles or not stated
Ruf 20195 Retrospective 1 161 All comers 96 NS NS 5 (ALL/2, prostate/10‐210, CUP/16, melanoma/19‐97, NET/34, MGUS/74, RCC/111, Pancreas/164) NS 100 NS
2 82 100
Tyrrell 201721 Prospective, non‐randomized NS 175 All comers NS 6.2 (NS) NS NS NS NS NS
Diminutto 201635 Retrospective 1 107 CS1 seminoma, normal post‐op HCG
RTI 28.7%
T > 4 cm 17.4%
Both 35.7%
22.1 5.2 (11.1‐16.6 m) 0.9 (27 m) 0.9 (multiple myeloma in patient with pre‐existing MGUS/47.4) 94.8 PFS at 2y 99.5 at 2y 99.5 at 2y
2 8
Dieckmann 201636 Prospective, non‐randomized 1 362 All comers 30 5 (NS) NS NS NS 100 NS
2 66 30 1.5 (NS) 100
Glaser 201537 Retrospective NS 3508 All comers 67 NS NS NS NS NS 97.7
Powles 200811 Prospective, non‐randomized 1 28 All comers (RTI 24%, T > 4 cm 47%, both 11.1%) 108 2 (24‐72 m) 2.5 (5.8‐11.4y) 2 (SCLC, meningioma, Hodgkin, Prostate/6.7‐13.7y) NS 100 at 9y 96.5 at 9y
2 171
Oliver 200138 Phase 2 non‐randomized and randomized 1 146 All comers 52 0.7 (NS) 0.7 0 100 100 100
2 57 128 1.75 (NS) 0 3.5 96.5 100 96.5
Dieckmann 200039 Prospective, non‐randomized 1 cycle 400 mg/m2 93 All comers 48 8.6 (median 16 m) 1.1 (4y) NS 91.1 100 100
2 cycles 400 mg/m2 32 0 0 3.1 (NPC/4y) NS 100 100
Oliver 199440 Prospective non‐randomized 1 25 All comers 29 0 0 NS 99 NS NS
2 (cisplatin n = 3) 53 51 1
Abbreviations: ALL, acute lymphoblastic leukaemia; AUC, area under the time concentration curve; CLL, chronic lymphocytic leukaemia; CS1, clinical stage I; CUP, carcinoma of unknown primary; GCT, germ cell tumor; m, month; MGUS, monoclonal gammopathy of uncertain significance; NPC, nasopharyngeal carcinoma; NS, Not stated; PFS, progression‐free survival; RCC, renal cell carcinoma; RFR, relapse‐free rate; RTI, rete testis involvement; SCLC, small cell lung cancer; SMN, subsequent malignant neoplasm; T, tumor; y, year.
Controversy remains about the predictive value of tumor size >4 cm and RTI for relapse.24 They were not predictive of relapse in our study.
While we did not prospectively record adverse events in our study, others report relatively mild toxicity with carboplatin, excellent treatment completion rates, and no excess in overall mortality or death from cardiovascular disease.10, 11 A recent study by Ruf et al with median follow‐up of 142 months reported a 13.2% hypogonadism rate but no major impact on fertility among 234 patients who had received one or two cycles of carboplatin.5
There has been a general shift toward surveillance to minimize treatment burden in CS1 seminoma.4, 8, 12 A 2015 meta‐analysis including 12 075 patients from 13 trials found no OS benefit of chemotherapy or radiotherapy over surveillance despite an 80% reduction in relapse, justifying the role for surveillance.6 However surveillance requires excellent compliance with frequent clinical reviews and investigations for up to 10 years.8 Radiation from CT scanning increases the SMN risk by 1 in 1000 per 10mSV, with each abdominopelvic CT scan equivalent to 10 to 20mSV.4, 8, 15 Non‐compliance with surveillance was only 4.7% in a large Danish study; however, patients who default surveillance may compromise their chances of cure.12 While the relapse risk after adjuvant chemotherapy is much lower, it is still concerning that 9.3% of our patients were noncompliant with recommended follow‐up.
Relapsed patients are mostly treated with BEP chemotherapy, which has much greater acute and late toxicity than carboplatin, including hearing loss, tinnitus, neurotoxicity, nephrotoxicity, gonadal toxicity, increased cardiovascular risk, and possibly SMN.25, 26, 27 Our relapsed patient and one of 69 relapsed patients in SWENOTECA VII died of BEP‐related complications.19 However, no significant difference in noncancer mortality between surveillance and adjuvant carboplatin treatment has been found.6
In frail or older patients with CS1 seminoma who may be poor candidates for cisplatin‐based chemotherapy, the significant lowering of relapse risk with adjuvant carboplatin may be desirable.
Our second GCT rate of 3.85% at 15 years appears higher than in other studies (0.54%‐2.5%, Table 3), though the 95% CI includes zero, and our follow‐up is longer than in some of these studies. While the TE19 trial suggested that carboplatin reduced the second GCT rate, perhaps due to effects of in‐situ neoplasia in the contralateral testis, second GCT rates in other carboplatin groups have been similar to surveillance.11, 18
The 15‐year non‐GCT SMN rate of 7.6% also appears higher than in other studies (0.9‐5%),5, 27 although the 95% CI includes zero, and there are differences in follow‐up duration. Prospective studies have reported similar SMN rates between patients treated with adjuvant carboplatin compared with surveillance or the general population.11, 18 Our rates of prostate cancer and melanoma (both 0.6%) are lower than those reported by Ruf et al,5 who noted higher‐than‐expected incidence (both 1.2%) among patients who had adjuvant treatment. It is likely that the SMN rates reported in our smaller sample size are not significantly different to the other studies.
Despite the national incidence of testicular cancer being higher among Maori, the proportion of Maori men in our study (28.9%) was similar to regional demographic data.28 Similarly, there was no difference in actuarial survival between Maori and non‐Maori patients (log‐rank P = .854).
We acknowledge as limitations the retrospective nature of our study, lack of standardized reporting on tumor size and RTI, lack of long‐term data on infertility, hypogonadism and cardiovascular disease, and the relatively small sample size.
5 CONCLUSION
Our findings further support the efficacy of two cycles of adjuvant carboplatin AUC7 for CS1 seminoma and demonstrate its long‐term safety, comparable with other published studies.
CONFLICT OF INTEREST
Elias A. Chandran received the ANZUP/AstraZeneca Travel Fellowship 2019. The authors make no other declarations.
AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, A.C., R.N., M.B.J.; Data curation, E.A.C., A.C., R.N., Project administration, E.A.C., R.N., M.B.J.; Methodology, A.C., M.B.J.; Investigation, M.B.J.; Formal Analysis, E.A.C., M.B.J.; Writing ‐ Original Draft, E.A.C.; Writing ‐ Review & Editing, E.A.C., M.B.J.; Supervision, M.B.J.
ETHICAL STATEMENT
Data collection and analysis for this study was approved by the Southern Health and Disability Ethics Committee (ref: 16/STH/251). Patient consent statment was not applicable.
ACKNOWLEDGEMENTS
We would like to acknowledge Dr Ian Kennedy, Waikato Hospital for the use of his electronic database, Aesculapius, which greatly assisted this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
DATA AVAILABILITY STATEMENT
De‐identified raw data from this study will be available on request
|
Fatal
|
ReactionOutcome
|
CC BY
|
33103860
| 19,210,455
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Borderline serous tumour of ovary'.
|
A serous borderline ovarian tumour in a transgender male adolescent.
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.
Background
Gender diversity is increasingly recognised and the number of patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these organs.
We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3
Case presentation
A 17-year-old transgender male with obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending 4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow.
Due to concern for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed.
Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was rendered.Fig. 1 Pathologic features.
Grossly, innumerable papillary projections lined the internal surface of the cyst (a). Microscopic papillary frond-like architecture and basophilic mucoid secretions (b; haematoxylin and eosin; original magnification, ×20) were composed of proliferating cuboidal to columnar epithelial cells with eosinophilic cytoplasm and absent nuclear atypia (c; haematoxylin and eosin; original magnification, ×600). Nuclear expression of androgen receptor was seen via immunohistochemistry (d; haematoxylin and eosin; original magnification, ×600).
Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology, gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months postoperatively was normal.
Discussion
We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one endometrioid adenocarcinoma.6
Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The overall survival for patients with stage 1 disease does not differ from the general population.
The role of testosterone treatment in tumour progression is uncertain as a putative role for androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation, although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction.
The presence of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference.
Attempts to estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately.
This manuscript details the first reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and progression of these tumours.
Acknowledgements
The authors would like to thank the patient and his family.
Author contributions
K.M., K.H., and A.F. drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final manuscript.
Ethics approval and consent to participate
The need for ethics approval and consent was deemed unnecessary. The subject provided informed consent to participate.
Consent to publish
Written consent for publication was obtained from the subject.
Data availability
Clinical data from this case was abstracted from the electronic medical record in a de-identified manner.
Competing interests
The authors declare no competing interests.
Funding information
This work was supported by National Institutes of Health grants T32 DK007699.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Kate Millington, Katherine Hayes
These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill
|
FLUOXETINE HYDROCHLORIDE, NORETHINDRONE ACETATE, TESTOSTERONE
|
DrugsGivenReaction
|
CC BY
|
33106582
| 18,557,557
|
2021-02
|
What was the administration route of drug 'TESTOSTERONE CYPIONATE'?
|
A serous borderline ovarian tumour in a transgender male adolescent.
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.
Background
Gender diversity is increasingly recognised and the number of patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these organs.
We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3
Case presentation
A 17-year-old transgender male with obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending 4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow.
Due to concern for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed.
Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was rendered.Fig. 1 Pathologic features.
Grossly, innumerable papillary projections lined the internal surface of the cyst (a). Microscopic papillary frond-like architecture and basophilic mucoid secretions (b; haematoxylin and eosin; original magnification, ×20) were composed of proliferating cuboidal to columnar epithelial cells with eosinophilic cytoplasm and absent nuclear atypia (c; haematoxylin and eosin; original magnification, ×600). Nuclear expression of androgen receptor was seen via immunohistochemistry (d; haematoxylin and eosin; original magnification, ×600).
Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology, gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months postoperatively was normal.
Discussion
We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one endometrioid adenocarcinoma.6
Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The overall survival for patients with stage 1 disease does not differ from the general population.
The role of testosterone treatment in tumour progression is uncertain as a putative role for androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation, although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction.
The presence of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference.
Attempts to estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately.
This manuscript details the first reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and progression of these tumours.
Acknowledgements
The authors would like to thank the patient and his family.
Author contributions
K.M., K.H., and A.F. drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final manuscript.
Ethics approval and consent to participate
The need for ethics approval and consent was deemed unnecessary. The subject provided informed consent to participate.
Consent to publish
Written consent for publication was obtained from the subject.
Data availability
Clinical data from this case was abstracted from the electronic medical record in a de-identified manner.
Competing interests
The authors declare no competing interests.
Funding information
This work was supported by National Institutes of Health grants T32 DK007699.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Kate Millington, Katherine Hayes
These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill
|
Subcutaneous
|
DrugAdministrationRoute
|
CC BY
|
33106582
| 18,563,428
|
2021-02
|
What was the administration route of drug 'TESTOSTERONE'?
|
A serous borderline ovarian tumour in a transgender male adolescent.
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.
Background
Gender diversity is increasingly recognised and the number of patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these organs.
We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3
Case presentation
A 17-year-old transgender male with obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending 4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow.
Due to concern for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed.
Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was rendered.Fig. 1 Pathologic features.
Grossly, innumerable papillary projections lined the internal surface of the cyst (a). Microscopic papillary frond-like architecture and basophilic mucoid secretions (b; haematoxylin and eosin; original magnification, ×20) were composed of proliferating cuboidal to columnar epithelial cells with eosinophilic cytoplasm and absent nuclear atypia (c; haematoxylin and eosin; original magnification, ×600). Nuclear expression of androgen receptor was seen via immunohistochemistry (d; haematoxylin and eosin; original magnification, ×600).
Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology, gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months postoperatively was normal.
Discussion
We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one endometrioid adenocarcinoma.6
Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The overall survival for patients with stage 1 disease does not differ from the general population.
The role of testosterone treatment in tumour progression is uncertain as a putative role for androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation, although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction.
The presence of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference.
Attempts to estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately.
This manuscript details the first reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and progression of these tumours.
Acknowledgements
The authors would like to thank the patient and his family.
Author contributions
K.M., K.H., and A.F. drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final manuscript.
Ethics approval and consent to participate
The need for ethics approval and consent was deemed unnecessary. The subject provided informed consent to participate.
Consent to publish
Written consent for publication was obtained from the subject.
Data availability
Clinical data from this case was abstracted from the electronic medical record in a de-identified manner.
Competing interests
The authors declare no competing interests.
Funding information
This work was supported by National Institutes of Health grants T32 DK007699.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Kate Millington, Katherine Hayes
These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill
|
Subcutaneous
|
DrugAdministrationRoute
|
CC BY
|
33106582
| 18,557,557
|
2021-02
|
What was the dosage of drug 'FLUOXETINE HYDROCHLORIDE'?
|
A serous borderline ovarian tumour in a transgender male adolescent.
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.
Background
Gender diversity is increasingly recognised and the number of patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these organs.
We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3
Case presentation
A 17-year-old transgender male with obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending 4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow.
Due to concern for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed.
Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was rendered.Fig. 1 Pathologic features.
Grossly, innumerable papillary projections lined the internal surface of the cyst (a). Microscopic papillary frond-like architecture and basophilic mucoid secretions (b; haematoxylin and eosin; original magnification, ×20) were composed of proliferating cuboidal to columnar epithelial cells with eosinophilic cytoplasm and absent nuclear atypia (c; haematoxylin and eosin; original magnification, ×600). Nuclear expression of androgen receptor was seen via immunohistochemistry (d; haematoxylin and eosin; original magnification, ×600).
Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology, gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months postoperatively was normal.
Discussion
We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one endometrioid adenocarcinoma.6
Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The overall survival for patients with stage 1 disease does not differ from the general population.
The role of testosterone treatment in tumour progression is uncertain as a putative role for androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation, although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction.
The presence of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference.
Attempts to estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately.
This manuscript details the first reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and progression of these tumours.
Acknowledgements
The authors would like to thank the patient and his family.
Author contributions
K.M., K.H., and A.F. drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final manuscript.
Ethics approval and consent to participate
The need for ethics approval and consent was deemed unnecessary. The subject provided informed consent to participate.
Consent to publish
Written consent for publication was obtained from the subject.
Data availability
Clinical data from this case was abstracted from the electronic medical record in a de-identified manner.
Competing interests
The authors declare no competing interests.
Funding information
This work was supported by National Institutes of Health grants T32 DK007699.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Kate Millington, Katherine Hayes
These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill
|
UNKNOWN
|
DrugDosageText
|
CC BY
|
33106582
| 18,563,428
|
2021-02
|
What was the dosage of drug 'TESTOSTERONE CYPIONATE'?
|
A serous borderline ovarian tumour in a transgender male adolescent.
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.
Background
Gender diversity is increasingly recognised and the number of patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these organs.
We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3
Case presentation
A 17-year-old transgender male with obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending 4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow.
Due to concern for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed.
Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was rendered.Fig. 1 Pathologic features.
Grossly, innumerable papillary projections lined the internal surface of the cyst (a). Microscopic papillary frond-like architecture and basophilic mucoid secretions (b; haematoxylin and eosin; original magnification, ×20) were composed of proliferating cuboidal to columnar epithelial cells with eosinophilic cytoplasm and absent nuclear atypia (c; haematoxylin and eosin; original magnification, ×600). Nuclear expression of androgen receptor was seen via immunohistochemistry (d; haematoxylin and eosin; original magnification, ×600).
Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology, gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months postoperatively was normal.
Discussion
We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one endometrioid adenocarcinoma.6
Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The overall survival for patients with stage 1 disease does not differ from the general population.
The role of testosterone treatment in tumour progression is uncertain as a putative role for androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation, although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction.
The presence of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference.
Attempts to estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately.
This manuscript details the first reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and progression of these tumours.
Acknowledgements
The authors would like to thank the patient and his family.
Author contributions
K.M., K.H., and A.F. drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final manuscript.
Ethics approval and consent to participate
The need for ethics approval and consent was deemed unnecessary. The subject provided informed consent to participate.
Consent to publish
Written consent for publication was obtained from the subject.
Data availability
Clinical data from this case was abstracted from the electronic medical record in a de-identified manner.
Competing interests
The authors declare no competing interests.
Funding information
This work was supported by National Institutes of Health grants T32 DK007699.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Kate Millington, Katherine Hayes
These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill
|
UNKNOWN
|
DrugDosageText
|
CC BY
|
33106582
| 18,563,428
|
2021-02
|
What was the outcome of reaction 'Borderline ovarian tumour'?
|
A serous borderline ovarian tumour in a transgender male adolescent.
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.
Background
Gender diversity is increasingly recognised and the number of patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these organs.
We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3
Case presentation
A 17-year-old transgender male with obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending 4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow.
Due to concern for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed.
Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was rendered.Fig. 1 Pathologic features.
Grossly, innumerable papillary projections lined the internal surface of the cyst (a). Microscopic papillary frond-like architecture and basophilic mucoid secretions (b; haematoxylin and eosin; original magnification, ×20) were composed of proliferating cuboidal to columnar epithelial cells with eosinophilic cytoplasm and absent nuclear atypia (c; haematoxylin and eosin; original magnification, ×600). Nuclear expression of androgen receptor was seen via immunohistochemistry (d; haematoxylin and eosin; original magnification, ×600).
Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology, gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months postoperatively was normal.
Discussion
We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one endometrioid adenocarcinoma.6
Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The overall survival for patients with stage 1 disease does not differ from the general population.
The role of testosterone treatment in tumour progression is uncertain as a putative role for androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation, although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction.
The presence of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference.
Attempts to estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately.
This manuscript details the first reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and progression of these tumours.
Acknowledgements
The authors would like to thank the patient and his family.
Author contributions
K.M., K.H., and A.F. drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final manuscript.
Ethics approval and consent to participate
The need for ethics approval and consent was deemed unnecessary. The subject provided informed consent to participate.
Consent to publish
Written consent for publication was obtained from the subject.
Data availability
Clinical data from this case was abstracted from the electronic medical record in a de-identified manner.
Competing interests
The authors declare no competing interests.
Funding information
This work was supported by National Institutes of Health grants T32 DK007699.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Kate Millington, Katherine Hayes
These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill
|
Recovered
|
ReactionOutcome
|
CC BY
|
33106582
| 18,563,428
|
2021-02
|
What was the outcome of reaction 'Borderline serous tumour of ovary'?
|
A serous borderline ovarian tumour in a transgender male adolescent.
Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.
Background
Gender diversity is increasingly recognised and the number of patients presenting for gender-affirming care has increased. Transmasculine individuals, those who are designated female at birth and have a masculine gender identity, may elect treatment with exogenous testosterone to produce secondary sex characteristics in line with their gender identity.1 The effects of testosterone therapy on the ovaries is incompletely understood with conflicting data in the literature. Some studies report polycystic ovarian pathology following testosterone treatment, with others reporting no treatment sequelae.2 Independent of concerns surrounding testosterone treatment, many transmasculine individuals are electing to retain their uterus, fallopian tubes, and ovaries and require screening for malignancies involving these organs.
We present a trans-male adolescent with an androgen receptor (AR)-positive serous borderline tumour (SBT) discovered shortly after starting on testosterone therapy. Because of the small number of cases of ovarian neoplasms in adolescents, with even fewer in the transgender population, the potential role of sex steroids in the genesis and pathogenesis of these tumours is largely unknown. Gynaecologic and medical providers treating trans youth must take into account each patient’s goals with regard to hormone therapy and gender-affirming surgery while simultaneously assessing health risks associated with patient anatomy. This case report was prepared using the CARE guidelines.3
Case presentation
A 17-year-old transgender male with obesity, anxiety, and no prior abdominal surgical history presented to the emergency room with acute right lower quadrant pain and nausea. Medications included fluoxetine, norethindrone acetate to achieve menstrual suppression, begun 7 months prior, and subcutaneous testosterone cypionate, begun 12 weeks prior. Past medical and gynaecologic history included normal development with menarche at age 13 years and regular menstrual cycles until initiation of testosterone and norethindrone acetate. Exam demonstrated a palpable, tender, mobile mass extending 4 cm above the umbilicus. Laboratory evaluation was reassuring. Ultrasound demonstrated a large right-sided mass with solid and cystic components and absent vascular flow.
Due to concern for adnexal torsion, urgent surgery was recommended. After counselling regarding the risk, benefits, and fertility implications of ovarian cystectomy versus salpingo-oophorectomy, the patient and his parents elected salpingo-oophorectomy. He expressed plans for future gender-affirming surgery, including gonad removal. Intra-operative examination under anaesthesia showed Tanner V pubic hair, hirsutism, and clitoromegaly. A midline vertical incision was made. The right adnexa was torted three times in the presence of a large right ovarian mass with an intact ovarian capsule. A right salpingo-oophorectomy was performed. Inspection of the uterus, left tube and ovary, omentum, and palpation of the upper abdomen, liver edge, diaphragm, and pelvic and para-aortic lymph nodes showed no gross abnormalities. An omental biopsy and pelvic washings were performed.
Pathological examination showed a 15 × 14 × 9 cm tumour, with tan-red fleshy excrescences lining the internal surface (Fig. 1a). Histologically, there was a proliferation of cuboidal to columnar epithelial cells showing eosinophilic cytoplasm and arranged in papillary fronds (Fig. 1b, c). The tumour was confined to the ovary without evidence of invasion or implantation. Immunostaining for AR (AR441, DAKO, Carpinteria, CA) showed nuclear staining in lesional cells (Fig. 1d). A diagnosis of serous papillary borderline tumour (atypical proliferative serous tumour), International Federation of Gynecology and Obstetrics stage IA, was rendered.Fig. 1 Pathologic features.
Grossly, innumerable papillary projections lined the internal surface of the cyst (a). Microscopic papillary frond-like architecture and basophilic mucoid secretions (b; haematoxylin and eosin; original magnification, ×20) were composed of proliferating cuboidal to columnar epithelial cells with eosinophilic cytoplasm and absent nuclear atypia (c; haematoxylin and eosin; original magnification, ×600). Nuclear expression of androgen receptor was seen via immunohistochemistry (d; haematoxylin and eosin; original magnification, ×600).
Postoperative treatment, monitoring, and further gender-affirming hormone therapy were discussed by a multidisciplinary team involving paediatric endocrinology, oncology, gynaecology, pathology, and adult medical oncology. In the absence of peritoneal implants or extra-ovarian disease, the tumour was considered low risk. Given the potential for contralateral ovarian disease after removal of an SBT, surveillance of the remaining ovary was recommended. Testosterone was restarted 2 months following the surgery after discussing risks and benefits with the patient and his family. He continued on norethindrone acetate daily to obtain adequate menstrual suppression. Surveillance ultrasound of the remaining ovary obtained 6 months postoperatively was normal.
Discussion
We present an SBT in a trans-male adolescent receiving testosterone for medical gender transition. The sole previous report of SBT in a transmasculine individual occurred in a 38-year-old receiving testosterone therapy.4 Other ovarian neoplasms reported in this setting include one serous cystadenoma,4 two mature cystic teratomas,5 and one endometrioid adenocarcinoma.6
Ovarian epithelial tumours are rare in adolescents and carry a more favourable 10-year survival rate than the same diagnoses in adults.7 SBTs are non-invasive ovarian epithelial tumours distinct from frank carcinoma. In our paediatric hospital, borderline tumours account for <1% of ovarian neoplasms among patients aged <21 years.8,9 The overall survival for patients with stage 1 disease does not differ from the general population.
The role of testosterone treatment in tumour progression is uncertain as a putative role for androgens and the AR in the development or proliferation of ovarian tumours has not been established. Androgen signalling has a role in granulosa cell maturation and differentiation, although in vitro exposure of ovarian cancer cell lines to androgens does not result in cell proliferation.10 Patients with polycystic ovary syndrome (PCOS), who are exposed to high levels of endogenous androgens, have not shown an increased risk in ovarian cancer overall; however, Olsen et. al. showed a modest increased risk of SBT in overweight women with PCOS and high circulating androgens (odds ratio 2.6, 95% confidence interval 1.0–6.1).11 Clinical studies have failed to show an association between elevated androgen levels and ovarian cancer risk,12 and attempts to treat chemotherapy-refractive ovarian tumours with androgen deprivation have yielded moderate responses at best in small numbers of patients.13 Prior studies investigating endogenous androgens may not be applicable to exogenous testosterone treatment given to achieve male range levels and, in the case of transgender youth, for pubertal induction.
The presence of a sex hormone-sensitive cancer is a contraindication to testosterone therapy, but there are no formal recommendations for the use of testosterone in patients with SBT. Given the importance of gender-affirming therapy, which has been shown to reduce suicide risk and improve overall well-being,14 our multi-disciplinary team carefully weighed the risks and benefits of restarting testosterone therapy and, in the context of a completely resected tumour and ambiguous risks associated with endogenous steroids, ultimately recommended restart. Appropriate tumour surveillance was also unclear as there is no data to guide management in this area. The team recommended at least 5 years of periodic transvaginal ultrasounds of the contralateral ovary unless oophorectomy was completed sooner. While transvaginal ultrasounds were deemed of higher sensitivity, transabdominal were prioritised given patient preference.
Attempts to estimate the prevalence of reproductive cancers in the transgender population have been unsuccessful. Current guidelines suggest routine screening based on retained internal organs in line with cisgender screening recommendations.15 Keeping in mind that significant barriers to care exist for transgendered persons, all providers must be cognizant of and consider the health risks posed by each patient’s anatomy, for example, that transmasculine patients may retain their ovaries, and should screen patients appropriately.
This manuscript details the first reported borderline ovarian tumour in a transmasculine adolescent receiving testosterone. The role that testosterone treatment played in the development, growth, and recurrence risk of his tumour is largely unknown. Further study regarding the prevalence and management of ovarian tumours in transmasculine individuals is needed. We propose the creation of a tumour registry for reproductive tract tumours in the transgender population to gather longitudinal data and increase our understanding of the role that gender-affirming hormones play in the origin and progression of these tumours.
Acknowledgements
The authors would like to thank the patient and his family.
Author contributions
K.M., K.H., and A.F. drafted the initial manuscript. S.O.V. prepared the figure. S.R., A.M., S.O.V., J.V., A.F., and A.O.N. provided critical review and editing. All authors reviewed and approved the final manuscript.
Ethics approval and consent to participate
The need for ethics approval and consent was deemed unnecessary. The subject provided informed consent to participate.
Consent to publish
Written consent for publication was obtained from the subject.
Data availability
Clinical data from this case was abstracted from the electronic medical record in a de-identified manner.
Competing interests
The authors declare no competing interests.
Funding information
This work was supported by National Institutes of Health grants T32 DK007699.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Kate Millington, Katherine Hayes
These authors jointly supervised this work: Amanda French, Jennifer Veneris, Allison O’Neill
|
Recovering
|
ReactionOutcome
|
CC BY
|
33106582
| 18,557,557
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute myocardial infarction'.
|
Paraneoplastic Syndrome and SARS-CoV-2-Incremental Effect of 2 Thrombogenic Conditions?
We present the case of a patient with a nonbacterial thrombotic aortic valve endocarditis experiencing severe thromboembolic complications and an acute right internal carotid artery occlusion in the context of a paraneoplastic syndrome and an asymptomatic severe acute respiratory syndrome coronavirus-2 infection, despite treatment with different and overlapping anticoagulant medications. Patients with increased thrombogenicity due to an underlying disease might be at increased risk for thrombotic events during a severe acute respiratory syndrome coronavirus-2 infection.
Case
A 66-year-old male patient was transferred from another hospital due to a non-ST-elevation myocardial infarction with mildly persisting chest pain for 5 hours.
Six weeks prior to this event, the patient had suffered from a Vena saphena magna thrombosis. Diagnostic testing in the referral hospital revealed a non–small cell lung cancer with histology suggestive of an adenocarcinoma on transbronchial biopsy. Due to lymphatic and contralateral lung metastases (cT4, cN3, cM1a), palliative chemotherapy was recommended but had not been instituted. The venous thrombosis was treated with rivaroxaban 20 mg once daily, which had been taken continuously except for the day of transbronchial biopsy.
On presentation, the electrocardiogram was unremarkable, and transthoracic echocardiography revealed moderate pericardial effusion, a normal left ventricular ejection fraction without regional wall motion abnormalities, but thickened aortic valve cusps and moderate aortic regurgitation. Coronary angiography showed a 50% stenosis of the Ramus interventricularis anterior without hemodynamic impact, as assessed by the resting full-cycle ratio (0.93; Video 1 , view video online). The resting full-cycle ratio is a non-hyperemic index that scans diastole and systole for the largest drop in pressure over the entire cardiac cycle. A value ≤0.89 indicates a hemodynamically relevant stenosis.
To investigate for other potential reasons for the myocardial infarction, transesophageal echocardiography was performed and showed oscillating masses on the native aortic valve up to 12x6 mm in size, which involved all 3 cusps, predominately affecting the right coronary cusp (Fig. 1A; Video 2 , view video online). There was no patent foramen ovale, left atrial appendage thrombosis, or large and mobile aortic atheroma. The patient was afebrile, inflammatory markers were not significantly increased (leucocytes 9.6 Gpt/L [3.6-10.5 Gpt/L], C-reactive protein 18.8 mg/L [< 5.0 mg/L], procalcitonin 0.12 μg/L [< 0.05 μg/L]), and repeated blood cultures were negative, suggesting that bacterial infective endocarditis was unlikely, although serologic tests were not performed. Tests of hemostasis were unremarkable except for a slightly increased international normalized ratio (INR) under factor-Xa inhibition. There were no significant abnormalities in fibrinogen (2.3 g/L [1.8-3.5 g/L]) or complement factors C3 (1.66 g/L [0.90-1.80 g/L]) and C4 (0.33 g/L [0.10-0.40 g/L]). Cardiolipin IgM (12 U/ml [< 10 U/ml]) was borderline elevated, however ß2-glycoprotein-I IgM (< 0.9 U/ml [< 7 U/ml]) and –IgG (0.6 U/ml [< 7 U/ml]), as well as other autoimmune disease–related antibodies, was not elevated, suggesting the absence of an antiphospholipid syndrome. However, a relative lymphocytopenia (16.1% [20%-44%)) and increased lactate dehydrogenase activity (9.01 μkat/L [<4.2 μkat/L]) led to a nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 9 days after the admission for myocardial infarction, which revealed a positive polymerase chain reaction for the E-gene, indicating SARS-CoV-2 infection. The patient never displayed typical symptoms for SARS-CoV-2 infection prior to or during his hospitalization.Figure 1 (A) Oscillating thrombotic masses on the native aortic valve (B) with regression in a control 6 days after initiation of antithrombotic therapy. (C) Acute cerebral embolism to the mesencephalon (white arrow). (D) Thrombotic closure of the right internal carotid artery (solid arrow), whereas the left one is well perfused (dotted arrow). (E, F) Selective angiography of the right internal carotid artery (E) before and (F) after successful interventional therapy.
Intravenous heparin was started (partial thromboplastin time: 60-80 seconds), and oral anticoagulation with a vitamin k antagonist was initiated. Transesophageal echocardiography 6 days later demonstrated regression of the thrombotic formations (Fig. 1B; Video 3 , view video online). We administered heparin for 11 days and stopped it after therapeutic INR was documented for 2 consecutive days. At the day of stopping heparin and 4 days after the diagnosis of SARS-CoV-2 infection, the patient experienced a stroke with a left-sided hemiparesis and diplopia. The INR was therapeutic at this time point (2.39). Cerebral computed tomography excluded intracranial hemorrhage, and cerebral magnetic resonance tomography revealed multiple cerebral infarcts in the mesencephalon, with expansion into the thalamus region, the cerebellum, and in the precortical gyrus precentralis, suggesting a cardio-embolic origin (Fig. 1C). Neurologic symptoms initially improved; however, despite a persisting therapeutic INR, the patient developed an acute thrombotic occlusion of his right internal carotid artery with complete left-sided hemiparesis 4 days after the first neurologic event (Fig. 1D). The patient was transferred for cerebral mechanical thrombectomy therapy, which led to complete reperfusion (Fig. 1, E and F). The patient currently remains with left-sided hemiparesis in a specialized stroke unit. At the time of the second cerebrovascular accident, 2 swabs for SARS-CoV-2 performed 7 and 8 days after the first one were negative.
Discussion
This case describes a patient with nonbacterial thrombotic aortic valve endocarditis that developed despite treatment with a factor-Xa-inhibitor and who subsequently suffered a myocardial infarction and 2 strokes within a short period of time in the context of a paraneoplastic syndrome and asymptomatic SARS-CoV-2 infection. We hypothesize that the myocardial infarction and the first stroke originated from thromboembolism, in particular due to the diffuse pattern of lesions detected by cerebral magnetic resonance tomography. The second stroke was caused by an acute right internal carotid artery occlusion, hypothetically triggered by spontaneous local thrombosis; however, embolism of a big thrombus cannot be excluded.
Paraneoplastic syndromes are often linked to increased thrombogenicity; however, nonbacterial thrombotic aortic valve endocarditis is rare even in the situation of cancer. Adenocarcinoma seems to be associated with increased rates of this condition, and the aortic valve is most often affected.1 Current guidelines recommend anticoagulation with unfractionated or low–molecular weight heparin or a vitamin k antagonist, although there is limited evidence to support this strategy. The use of factor-Xa-inhibitors or direct thrombin inhibitors has not been evaluated.2 Some authors suggest that a vitamin k antagonist not be used in patients with malignancy-associated nonbacterial thrombotic endocarditis, as recurrent thromboembolic events while on warfarin are common, although this was observed 30 years ago.1 In our case, the patient developed the thrombosis under the treatment with a factor-Xa-inhibitor; therefore, we decided to use an overlapping anticoagulation with unfractionated heparin and a vitamin k antagonist.
SARS-CoV-2 infection is also associated with a high rate of thrombotic complications occurring even under prophylactic therapy.3 Large-vessel stroke, including partial carotid artery occlusion, has been described in younger patients suffering from coronavirus disease 2019 (COVID-19).4 Others found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19, with most patients presenting with classical vascular risk factors and traditional stroke mechanisms, although a substantial number of patients had new positive antiphospholipid antibodies.5 Hypercoagulation during SARS-CoV-2 infection has been linked to cerebral embolism in several cases.6,7
In our case, the patient was asymptomatic, and therefore, the duration of infection remains unknown. However, a second test performed 7 days after the positive one was already negative, thus suggesting that infection occurred earlier. The median duration of viral shedding was 20 days in survivors of COVID-19, according to a Chinese study.8 Remarkably, native aortic valve thrombosis and its consequences occurred despite oral anticoagulation, highlighting a possible incremental effect of 2 thrombogenic conditions. Both cancer-associated thrombosis and COVID-19-related thrombotic events share common features, such as coagulopathy and endothelial dysfunction secondary to systemic inflammation or potential local infection. The prothrombotic effect of SARS-CoV-2 coronavirus infection is thought to be mediated by binding to angiotensin-converting enzyme 2 receptors on the surface of endothelial cells, which leads to endothelial dysfunction and thrombosis.8 As heart valves are lined with endothelial cells, SARS-CoV-2 infection might hypothetically induce dysfunction of the protecting valve surface. Anticoagulation in COVID-19 seems to be beneficial; however, the best strategy is still uncertain.3
This case highlights the many-sided effects of paraneoplastic syndromes and SARS-CoV-2 infection in patients who are already at increased risk for thrombotic complications, owing to underlying disease. The treatment of those patients includes several medical disciplines that should be on alert and prepared to treat SARS-CoV-2 and its thrombotic complications. Although the optimal anticoagulation regime is uncertain in such a case, well controlled unfractionated heparin might be the therapy of choice in the acute setting.Novel Teaching Points
• Nonbacterial thrombotic aortic valve endocarditis is a rare but devastating complication in the context of a paraneoplastic syndrome.
• SARS-CoV-2 infection might increase the risk for thrombotic complications in patients already at increased risk for thrombotic complications, owing to underlying disease.
• The optimal anticoagulation regime is uncertain; however, well controlled unfractionated heparin might be the therapy of choice in the acute setting.
Supplementary Material
Video 1
Coronary angiography
Video 2
Initial transesophageal echocardiography showing oscillating thrombotic formations on the native aortic valve.
Video 3
Follow-up transesophageal echocardiography showing regression of the thrombotic formations on the native aortic valve.
Acknowledgements
We thank T. Scott Bowen for editing of grammar and syntax.
Funding Sources
The authors have no funding sources to declare.
Disclosures
Norman Mangner reports personal fees from Edwards LifeScience, Medtronic, Biotronik, Novartis, Sanofi Genzyme, and AstraZeneca, not specifically associated with the submitted work. Krunoslav Sveric reports personal fees from Novartis and GlaxoSmithKline, not specifically associated with the submitted work. Johannes C. Gerber reports personal fees from Penumbra Europe GmbH and from Daiichi Sankyo Deutschland GmbH, and non-financial support from Cerenovus (Johnson&Johnson) and MicroVention Europe, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. The other authors have no conflicts of interest to disclose.
Ethics Statement: The reported research has adhered to the relevant ethical guidelines.
See page 219 for disclosure information.
To access the supplementary material accompanying this article, visit CJC Open at https://www.cjcopen.ca/ and at https://doi.org/10.1016/j.cjco.2020.10.010.
|
RIVAROXABAN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33106785
| 19,014,282
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.
|
Paraneoplastic Syndrome and SARS-CoV-2-Incremental Effect of 2 Thrombogenic Conditions?
We present the case of a patient with a nonbacterial thrombotic aortic valve endocarditis experiencing severe thromboembolic complications and an acute right internal carotid artery occlusion in the context of a paraneoplastic syndrome and an asymptomatic severe acute respiratory syndrome coronavirus-2 infection, despite treatment with different and overlapping anticoagulant medications. Patients with increased thrombogenicity due to an underlying disease might be at increased risk for thrombotic events during a severe acute respiratory syndrome coronavirus-2 infection.
Case
A 66-year-old male patient was transferred from another hospital due to a non-ST-elevation myocardial infarction with mildly persisting chest pain for 5 hours.
Six weeks prior to this event, the patient had suffered from a Vena saphena magna thrombosis. Diagnostic testing in the referral hospital revealed a non–small cell lung cancer with histology suggestive of an adenocarcinoma on transbronchial biopsy. Due to lymphatic and contralateral lung metastases (cT4, cN3, cM1a), palliative chemotherapy was recommended but had not been instituted. The venous thrombosis was treated with rivaroxaban 20 mg once daily, which had been taken continuously except for the day of transbronchial biopsy.
On presentation, the electrocardiogram was unremarkable, and transthoracic echocardiography revealed moderate pericardial effusion, a normal left ventricular ejection fraction without regional wall motion abnormalities, but thickened aortic valve cusps and moderate aortic regurgitation. Coronary angiography showed a 50% stenosis of the Ramus interventricularis anterior without hemodynamic impact, as assessed by the resting full-cycle ratio (0.93; Video 1 , view video online). The resting full-cycle ratio is a non-hyperemic index that scans diastole and systole for the largest drop in pressure over the entire cardiac cycle. A value ≤0.89 indicates a hemodynamically relevant stenosis.
To investigate for other potential reasons for the myocardial infarction, transesophageal echocardiography was performed and showed oscillating masses on the native aortic valve up to 12x6 mm in size, which involved all 3 cusps, predominately affecting the right coronary cusp (Fig. 1A; Video 2 , view video online). There was no patent foramen ovale, left atrial appendage thrombosis, or large and mobile aortic atheroma. The patient was afebrile, inflammatory markers were not significantly increased (leucocytes 9.6 Gpt/L [3.6-10.5 Gpt/L], C-reactive protein 18.8 mg/L [< 5.0 mg/L], procalcitonin 0.12 μg/L [< 0.05 μg/L]), and repeated blood cultures were negative, suggesting that bacterial infective endocarditis was unlikely, although serologic tests were not performed. Tests of hemostasis were unremarkable except for a slightly increased international normalized ratio (INR) under factor-Xa inhibition. There were no significant abnormalities in fibrinogen (2.3 g/L [1.8-3.5 g/L]) or complement factors C3 (1.66 g/L [0.90-1.80 g/L]) and C4 (0.33 g/L [0.10-0.40 g/L]). Cardiolipin IgM (12 U/ml [< 10 U/ml]) was borderline elevated, however ß2-glycoprotein-I IgM (< 0.9 U/ml [< 7 U/ml]) and –IgG (0.6 U/ml [< 7 U/ml]), as well as other autoimmune disease–related antibodies, was not elevated, suggesting the absence of an antiphospholipid syndrome. However, a relative lymphocytopenia (16.1% [20%-44%)) and increased lactate dehydrogenase activity (9.01 μkat/L [<4.2 μkat/L]) led to a nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 9 days after the admission for myocardial infarction, which revealed a positive polymerase chain reaction for the E-gene, indicating SARS-CoV-2 infection. The patient never displayed typical symptoms for SARS-CoV-2 infection prior to or during his hospitalization.Figure 1 (A) Oscillating thrombotic masses on the native aortic valve (B) with regression in a control 6 days after initiation of antithrombotic therapy. (C) Acute cerebral embolism to the mesencephalon (white arrow). (D) Thrombotic closure of the right internal carotid artery (solid arrow), whereas the left one is well perfused (dotted arrow). (E, F) Selective angiography of the right internal carotid artery (E) before and (F) after successful interventional therapy.
Intravenous heparin was started (partial thromboplastin time: 60-80 seconds), and oral anticoagulation with a vitamin k antagonist was initiated. Transesophageal echocardiography 6 days later demonstrated regression of the thrombotic formations (Fig. 1B; Video 3 , view video online). We administered heparin for 11 days and stopped it after therapeutic INR was documented for 2 consecutive days. At the day of stopping heparin and 4 days after the diagnosis of SARS-CoV-2 infection, the patient experienced a stroke with a left-sided hemiparesis and diplopia. The INR was therapeutic at this time point (2.39). Cerebral computed tomography excluded intracranial hemorrhage, and cerebral magnetic resonance tomography revealed multiple cerebral infarcts in the mesencephalon, with expansion into the thalamus region, the cerebellum, and in the precortical gyrus precentralis, suggesting a cardio-embolic origin (Fig. 1C). Neurologic symptoms initially improved; however, despite a persisting therapeutic INR, the patient developed an acute thrombotic occlusion of his right internal carotid artery with complete left-sided hemiparesis 4 days after the first neurologic event (Fig. 1D). The patient was transferred for cerebral mechanical thrombectomy therapy, which led to complete reperfusion (Fig. 1, E and F). The patient currently remains with left-sided hemiparesis in a specialized stroke unit. At the time of the second cerebrovascular accident, 2 swabs for SARS-CoV-2 performed 7 and 8 days after the first one were negative.
Discussion
This case describes a patient with nonbacterial thrombotic aortic valve endocarditis that developed despite treatment with a factor-Xa-inhibitor and who subsequently suffered a myocardial infarction and 2 strokes within a short period of time in the context of a paraneoplastic syndrome and asymptomatic SARS-CoV-2 infection. We hypothesize that the myocardial infarction and the first stroke originated from thromboembolism, in particular due to the diffuse pattern of lesions detected by cerebral magnetic resonance tomography. The second stroke was caused by an acute right internal carotid artery occlusion, hypothetically triggered by spontaneous local thrombosis; however, embolism of a big thrombus cannot be excluded.
Paraneoplastic syndromes are often linked to increased thrombogenicity; however, nonbacterial thrombotic aortic valve endocarditis is rare even in the situation of cancer. Adenocarcinoma seems to be associated with increased rates of this condition, and the aortic valve is most often affected.1 Current guidelines recommend anticoagulation with unfractionated or low–molecular weight heparin or a vitamin k antagonist, although there is limited evidence to support this strategy. The use of factor-Xa-inhibitors or direct thrombin inhibitors has not been evaluated.2 Some authors suggest that a vitamin k antagonist not be used in patients with malignancy-associated nonbacterial thrombotic endocarditis, as recurrent thromboembolic events while on warfarin are common, although this was observed 30 years ago.1 In our case, the patient developed the thrombosis under the treatment with a factor-Xa-inhibitor; therefore, we decided to use an overlapping anticoagulation with unfractionated heparin and a vitamin k antagonist.
SARS-CoV-2 infection is also associated with a high rate of thrombotic complications occurring even under prophylactic therapy.3 Large-vessel stroke, including partial carotid artery occlusion, has been described in younger patients suffering from coronavirus disease 2019 (COVID-19).4 Others found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19, with most patients presenting with classical vascular risk factors and traditional stroke mechanisms, although a substantial number of patients had new positive antiphospholipid antibodies.5 Hypercoagulation during SARS-CoV-2 infection has been linked to cerebral embolism in several cases.6,7
In our case, the patient was asymptomatic, and therefore, the duration of infection remains unknown. However, a second test performed 7 days after the positive one was already negative, thus suggesting that infection occurred earlier. The median duration of viral shedding was 20 days in survivors of COVID-19, according to a Chinese study.8 Remarkably, native aortic valve thrombosis and its consequences occurred despite oral anticoagulation, highlighting a possible incremental effect of 2 thrombogenic conditions. Both cancer-associated thrombosis and COVID-19-related thrombotic events share common features, such as coagulopathy and endothelial dysfunction secondary to systemic inflammation or potential local infection. The prothrombotic effect of SARS-CoV-2 coronavirus infection is thought to be mediated by binding to angiotensin-converting enzyme 2 receptors on the surface of endothelial cells, which leads to endothelial dysfunction and thrombosis.8 As heart valves are lined with endothelial cells, SARS-CoV-2 infection might hypothetically induce dysfunction of the protecting valve surface. Anticoagulation in COVID-19 seems to be beneficial; however, the best strategy is still uncertain.3
This case highlights the many-sided effects of paraneoplastic syndromes and SARS-CoV-2 infection in patients who are already at increased risk for thrombotic complications, owing to underlying disease. The treatment of those patients includes several medical disciplines that should be on alert and prepared to treat SARS-CoV-2 and its thrombotic complications. Although the optimal anticoagulation regime is uncertain in such a case, well controlled unfractionated heparin might be the therapy of choice in the acute setting.Novel Teaching Points
• Nonbacterial thrombotic aortic valve endocarditis is a rare but devastating complication in the context of a paraneoplastic syndrome.
• SARS-CoV-2 infection might increase the risk for thrombotic complications in patients already at increased risk for thrombotic complications, owing to underlying disease.
• The optimal anticoagulation regime is uncertain; however, well controlled unfractionated heparin might be the therapy of choice in the acute setting.
Supplementary Material
Video 1
Coronary angiography
Video 2
Initial transesophageal echocardiography showing oscillating thrombotic formations on the native aortic valve.
Video 3
Follow-up transesophageal echocardiography showing regression of the thrombotic formations on the native aortic valve.
Acknowledgements
We thank T. Scott Bowen for editing of grammar and syntax.
Funding Sources
The authors have no funding sources to declare.
Disclosures
Norman Mangner reports personal fees from Edwards LifeScience, Medtronic, Biotronik, Novartis, Sanofi Genzyme, and AstraZeneca, not specifically associated with the submitted work. Krunoslav Sveric reports personal fees from Novartis and GlaxoSmithKline, not specifically associated with the submitted work. Johannes C. Gerber reports personal fees from Penumbra Europe GmbH and from Daiichi Sankyo Deutschland GmbH, and non-financial support from Cerenovus (Johnson&Johnson) and MicroVention Europe, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. The other authors have no conflicts of interest to disclose.
Ethics Statement: The reported research has adhered to the relevant ethical guidelines.
See page 219 for disclosure information.
To access the supplementary material accompanying this article, visit CJC Open at https://www.cjcopen.ca/ and at https://doi.org/10.1016/j.cjco.2020.10.010.
|
RIVAROXABAN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33106785
| 19,014,282
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Endocarditis noninfective'.
|
Paraneoplastic Syndrome and SARS-CoV-2-Incremental Effect of 2 Thrombogenic Conditions?
We present the case of a patient with a nonbacterial thrombotic aortic valve endocarditis experiencing severe thromboembolic complications and an acute right internal carotid artery occlusion in the context of a paraneoplastic syndrome and an asymptomatic severe acute respiratory syndrome coronavirus-2 infection, despite treatment with different and overlapping anticoagulant medications. Patients with increased thrombogenicity due to an underlying disease might be at increased risk for thrombotic events during a severe acute respiratory syndrome coronavirus-2 infection.
Case
A 66-year-old male patient was transferred from another hospital due to a non-ST-elevation myocardial infarction with mildly persisting chest pain for 5 hours.
Six weeks prior to this event, the patient had suffered from a Vena saphena magna thrombosis. Diagnostic testing in the referral hospital revealed a non–small cell lung cancer with histology suggestive of an adenocarcinoma on transbronchial biopsy. Due to lymphatic and contralateral lung metastases (cT4, cN3, cM1a), palliative chemotherapy was recommended but had not been instituted. The venous thrombosis was treated with rivaroxaban 20 mg once daily, which had been taken continuously except for the day of transbronchial biopsy.
On presentation, the electrocardiogram was unremarkable, and transthoracic echocardiography revealed moderate pericardial effusion, a normal left ventricular ejection fraction without regional wall motion abnormalities, but thickened aortic valve cusps and moderate aortic regurgitation. Coronary angiography showed a 50% stenosis of the Ramus interventricularis anterior without hemodynamic impact, as assessed by the resting full-cycle ratio (0.93; Video 1 , view video online). The resting full-cycle ratio is a non-hyperemic index that scans diastole and systole for the largest drop in pressure over the entire cardiac cycle. A value ≤0.89 indicates a hemodynamically relevant stenosis.
To investigate for other potential reasons for the myocardial infarction, transesophageal echocardiography was performed and showed oscillating masses on the native aortic valve up to 12x6 mm in size, which involved all 3 cusps, predominately affecting the right coronary cusp (Fig. 1A; Video 2 , view video online). There was no patent foramen ovale, left atrial appendage thrombosis, or large and mobile aortic atheroma. The patient was afebrile, inflammatory markers were not significantly increased (leucocytes 9.6 Gpt/L [3.6-10.5 Gpt/L], C-reactive protein 18.8 mg/L [< 5.0 mg/L], procalcitonin 0.12 μg/L [< 0.05 μg/L]), and repeated blood cultures were negative, suggesting that bacterial infective endocarditis was unlikely, although serologic tests were not performed. Tests of hemostasis were unremarkable except for a slightly increased international normalized ratio (INR) under factor-Xa inhibition. There were no significant abnormalities in fibrinogen (2.3 g/L [1.8-3.5 g/L]) or complement factors C3 (1.66 g/L [0.90-1.80 g/L]) and C4 (0.33 g/L [0.10-0.40 g/L]). Cardiolipin IgM (12 U/ml [< 10 U/ml]) was borderline elevated, however ß2-glycoprotein-I IgM (< 0.9 U/ml [< 7 U/ml]) and –IgG (0.6 U/ml [< 7 U/ml]), as well as other autoimmune disease–related antibodies, was not elevated, suggesting the absence of an antiphospholipid syndrome. However, a relative lymphocytopenia (16.1% [20%-44%)) and increased lactate dehydrogenase activity (9.01 μkat/L [<4.2 μkat/L]) led to a nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 9 days after the admission for myocardial infarction, which revealed a positive polymerase chain reaction for the E-gene, indicating SARS-CoV-2 infection. The patient never displayed typical symptoms for SARS-CoV-2 infection prior to or during his hospitalization.Figure 1 (A) Oscillating thrombotic masses on the native aortic valve (B) with regression in a control 6 days after initiation of antithrombotic therapy. (C) Acute cerebral embolism to the mesencephalon (white arrow). (D) Thrombotic closure of the right internal carotid artery (solid arrow), whereas the left one is well perfused (dotted arrow). (E, F) Selective angiography of the right internal carotid artery (E) before and (F) after successful interventional therapy.
Intravenous heparin was started (partial thromboplastin time: 60-80 seconds), and oral anticoagulation with a vitamin k antagonist was initiated. Transesophageal echocardiography 6 days later demonstrated regression of the thrombotic formations (Fig. 1B; Video 3 , view video online). We administered heparin for 11 days and stopped it after therapeutic INR was documented for 2 consecutive days. At the day of stopping heparin and 4 days after the diagnosis of SARS-CoV-2 infection, the patient experienced a stroke with a left-sided hemiparesis and diplopia. The INR was therapeutic at this time point (2.39). Cerebral computed tomography excluded intracranial hemorrhage, and cerebral magnetic resonance tomography revealed multiple cerebral infarcts in the mesencephalon, with expansion into the thalamus region, the cerebellum, and in the precortical gyrus precentralis, suggesting a cardio-embolic origin (Fig. 1C). Neurologic symptoms initially improved; however, despite a persisting therapeutic INR, the patient developed an acute thrombotic occlusion of his right internal carotid artery with complete left-sided hemiparesis 4 days after the first neurologic event (Fig. 1D). The patient was transferred for cerebral mechanical thrombectomy therapy, which led to complete reperfusion (Fig. 1, E and F). The patient currently remains with left-sided hemiparesis in a specialized stroke unit. At the time of the second cerebrovascular accident, 2 swabs for SARS-CoV-2 performed 7 and 8 days after the first one were negative.
Discussion
This case describes a patient with nonbacterial thrombotic aortic valve endocarditis that developed despite treatment with a factor-Xa-inhibitor and who subsequently suffered a myocardial infarction and 2 strokes within a short period of time in the context of a paraneoplastic syndrome and asymptomatic SARS-CoV-2 infection. We hypothesize that the myocardial infarction and the first stroke originated from thromboembolism, in particular due to the diffuse pattern of lesions detected by cerebral magnetic resonance tomography. The second stroke was caused by an acute right internal carotid artery occlusion, hypothetically triggered by spontaneous local thrombosis; however, embolism of a big thrombus cannot be excluded.
Paraneoplastic syndromes are often linked to increased thrombogenicity; however, nonbacterial thrombotic aortic valve endocarditis is rare even in the situation of cancer. Adenocarcinoma seems to be associated with increased rates of this condition, and the aortic valve is most often affected.1 Current guidelines recommend anticoagulation with unfractionated or low–molecular weight heparin or a vitamin k antagonist, although there is limited evidence to support this strategy. The use of factor-Xa-inhibitors or direct thrombin inhibitors has not been evaluated.2 Some authors suggest that a vitamin k antagonist not be used in patients with malignancy-associated nonbacterial thrombotic endocarditis, as recurrent thromboembolic events while on warfarin are common, although this was observed 30 years ago.1 In our case, the patient developed the thrombosis under the treatment with a factor-Xa-inhibitor; therefore, we decided to use an overlapping anticoagulation with unfractionated heparin and a vitamin k antagonist.
SARS-CoV-2 infection is also associated with a high rate of thrombotic complications occurring even under prophylactic therapy.3 Large-vessel stroke, including partial carotid artery occlusion, has been described in younger patients suffering from coronavirus disease 2019 (COVID-19).4 Others found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19, with most patients presenting with classical vascular risk factors and traditional stroke mechanisms, although a substantial number of patients had new positive antiphospholipid antibodies.5 Hypercoagulation during SARS-CoV-2 infection has been linked to cerebral embolism in several cases.6,7
In our case, the patient was asymptomatic, and therefore, the duration of infection remains unknown. However, a second test performed 7 days after the positive one was already negative, thus suggesting that infection occurred earlier. The median duration of viral shedding was 20 days in survivors of COVID-19, according to a Chinese study.8 Remarkably, native aortic valve thrombosis and its consequences occurred despite oral anticoagulation, highlighting a possible incremental effect of 2 thrombogenic conditions. Both cancer-associated thrombosis and COVID-19-related thrombotic events share common features, such as coagulopathy and endothelial dysfunction secondary to systemic inflammation or potential local infection. The prothrombotic effect of SARS-CoV-2 coronavirus infection is thought to be mediated by binding to angiotensin-converting enzyme 2 receptors on the surface of endothelial cells, which leads to endothelial dysfunction and thrombosis.8 As heart valves are lined with endothelial cells, SARS-CoV-2 infection might hypothetically induce dysfunction of the protecting valve surface. Anticoagulation in COVID-19 seems to be beneficial; however, the best strategy is still uncertain.3
This case highlights the many-sided effects of paraneoplastic syndromes and SARS-CoV-2 infection in patients who are already at increased risk for thrombotic complications, owing to underlying disease. The treatment of those patients includes several medical disciplines that should be on alert and prepared to treat SARS-CoV-2 and its thrombotic complications. Although the optimal anticoagulation regime is uncertain in such a case, well controlled unfractionated heparin might be the therapy of choice in the acute setting.Novel Teaching Points
• Nonbacterial thrombotic aortic valve endocarditis is a rare but devastating complication in the context of a paraneoplastic syndrome.
• SARS-CoV-2 infection might increase the risk for thrombotic complications in patients already at increased risk for thrombotic complications, owing to underlying disease.
• The optimal anticoagulation regime is uncertain; however, well controlled unfractionated heparin might be the therapy of choice in the acute setting.
Supplementary Material
Video 1
Coronary angiography
Video 2
Initial transesophageal echocardiography showing oscillating thrombotic formations on the native aortic valve.
Video 3
Follow-up transesophageal echocardiography showing regression of the thrombotic formations on the native aortic valve.
Acknowledgements
We thank T. Scott Bowen for editing of grammar and syntax.
Funding Sources
The authors have no funding sources to declare.
Disclosures
Norman Mangner reports personal fees from Edwards LifeScience, Medtronic, Biotronik, Novartis, Sanofi Genzyme, and AstraZeneca, not specifically associated with the submitted work. Krunoslav Sveric reports personal fees from Novartis and GlaxoSmithKline, not specifically associated with the submitted work. Johannes C. Gerber reports personal fees from Penumbra Europe GmbH and from Daiichi Sankyo Deutschland GmbH, and non-financial support from Cerenovus (Johnson&Johnson) and MicroVention Europe, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. The other authors have no conflicts of interest to disclose.
Ethics Statement: The reported research has adhered to the relevant ethical guidelines.
See page 219 for disclosure information.
To access the supplementary material accompanying this article, visit CJC Open at https://www.cjcopen.ca/ and at https://doi.org/10.1016/j.cjco.2020.10.010.
|
RIVAROXABAN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33106785
| 19,014,282
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'International normalised ratio increased'.
|
Paraneoplastic Syndrome and SARS-CoV-2-Incremental Effect of 2 Thrombogenic Conditions?
We present the case of a patient with a nonbacterial thrombotic aortic valve endocarditis experiencing severe thromboembolic complications and an acute right internal carotid artery occlusion in the context of a paraneoplastic syndrome and an asymptomatic severe acute respiratory syndrome coronavirus-2 infection, despite treatment with different and overlapping anticoagulant medications. Patients with increased thrombogenicity due to an underlying disease might be at increased risk for thrombotic events during a severe acute respiratory syndrome coronavirus-2 infection.
Case
A 66-year-old male patient was transferred from another hospital due to a non-ST-elevation myocardial infarction with mildly persisting chest pain for 5 hours.
Six weeks prior to this event, the patient had suffered from a Vena saphena magna thrombosis. Diagnostic testing in the referral hospital revealed a non–small cell lung cancer with histology suggestive of an adenocarcinoma on transbronchial biopsy. Due to lymphatic and contralateral lung metastases (cT4, cN3, cM1a), palliative chemotherapy was recommended but had not been instituted. The venous thrombosis was treated with rivaroxaban 20 mg once daily, which had been taken continuously except for the day of transbronchial biopsy.
On presentation, the electrocardiogram was unremarkable, and transthoracic echocardiography revealed moderate pericardial effusion, a normal left ventricular ejection fraction without regional wall motion abnormalities, but thickened aortic valve cusps and moderate aortic regurgitation. Coronary angiography showed a 50% stenosis of the Ramus interventricularis anterior without hemodynamic impact, as assessed by the resting full-cycle ratio (0.93; Video 1 , view video online). The resting full-cycle ratio is a non-hyperemic index that scans diastole and systole for the largest drop in pressure over the entire cardiac cycle. A value ≤0.89 indicates a hemodynamically relevant stenosis.
To investigate for other potential reasons for the myocardial infarction, transesophageal echocardiography was performed and showed oscillating masses on the native aortic valve up to 12x6 mm in size, which involved all 3 cusps, predominately affecting the right coronary cusp (Fig. 1A; Video 2 , view video online). There was no patent foramen ovale, left atrial appendage thrombosis, or large and mobile aortic atheroma. The patient was afebrile, inflammatory markers were not significantly increased (leucocytes 9.6 Gpt/L [3.6-10.5 Gpt/L], C-reactive protein 18.8 mg/L [< 5.0 mg/L], procalcitonin 0.12 μg/L [< 0.05 μg/L]), and repeated blood cultures were negative, suggesting that bacterial infective endocarditis was unlikely, although serologic tests were not performed. Tests of hemostasis were unremarkable except for a slightly increased international normalized ratio (INR) under factor-Xa inhibition. There were no significant abnormalities in fibrinogen (2.3 g/L [1.8-3.5 g/L]) or complement factors C3 (1.66 g/L [0.90-1.80 g/L]) and C4 (0.33 g/L [0.10-0.40 g/L]). Cardiolipin IgM (12 U/ml [< 10 U/ml]) was borderline elevated, however ß2-glycoprotein-I IgM (< 0.9 U/ml [< 7 U/ml]) and –IgG (0.6 U/ml [< 7 U/ml]), as well as other autoimmune disease–related antibodies, was not elevated, suggesting the absence of an antiphospholipid syndrome. However, a relative lymphocytopenia (16.1% [20%-44%)) and increased lactate dehydrogenase activity (9.01 μkat/L [<4.2 μkat/L]) led to a nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 9 days after the admission for myocardial infarction, which revealed a positive polymerase chain reaction for the E-gene, indicating SARS-CoV-2 infection. The patient never displayed typical symptoms for SARS-CoV-2 infection prior to or during his hospitalization.Figure 1 (A) Oscillating thrombotic masses on the native aortic valve (B) with regression in a control 6 days after initiation of antithrombotic therapy. (C) Acute cerebral embolism to the mesencephalon (white arrow). (D) Thrombotic closure of the right internal carotid artery (solid arrow), whereas the left one is well perfused (dotted arrow). (E, F) Selective angiography of the right internal carotid artery (E) before and (F) after successful interventional therapy.
Intravenous heparin was started (partial thromboplastin time: 60-80 seconds), and oral anticoagulation with a vitamin k antagonist was initiated. Transesophageal echocardiography 6 days later demonstrated regression of the thrombotic formations (Fig. 1B; Video 3 , view video online). We administered heparin for 11 days and stopped it after therapeutic INR was documented for 2 consecutive days. At the day of stopping heparin and 4 days after the diagnosis of SARS-CoV-2 infection, the patient experienced a stroke with a left-sided hemiparesis and diplopia. The INR was therapeutic at this time point (2.39). Cerebral computed tomography excluded intracranial hemorrhage, and cerebral magnetic resonance tomography revealed multiple cerebral infarcts in the mesencephalon, with expansion into the thalamus region, the cerebellum, and in the precortical gyrus precentralis, suggesting a cardio-embolic origin (Fig. 1C). Neurologic symptoms initially improved; however, despite a persisting therapeutic INR, the patient developed an acute thrombotic occlusion of his right internal carotid artery with complete left-sided hemiparesis 4 days after the first neurologic event (Fig. 1D). The patient was transferred for cerebral mechanical thrombectomy therapy, which led to complete reperfusion (Fig. 1, E and F). The patient currently remains with left-sided hemiparesis in a specialized stroke unit. At the time of the second cerebrovascular accident, 2 swabs for SARS-CoV-2 performed 7 and 8 days after the first one were negative.
Discussion
This case describes a patient with nonbacterial thrombotic aortic valve endocarditis that developed despite treatment with a factor-Xa-inhibitor and who subsequently suffered a myocardial infarction and 2 strokes within a short period of time in the context of a paraneoplastic syndrome and asymptomatic SARS-CoV-2 infection. We hypothesize that the myocardial infarction and the first stroke originated from thromboembolism, in particular due to the diffuse pattern of lesions detected by cerebral magnetic resonance tomography. The second stroke was caused by an acute right internal carotid artery occlusion, hypothetically triggered by spontaneous local thrombosis; however, embolism of a big thrombus cannot be excluded.
Paraneoplastic syndromes are often linked to increased thrombogenicity; however, nonbacterial thrombotic aortic valve endocarditis is rare even in the situation of cancer. Adenocarcinoma seems to be associated with increased rates of this condition, and the aortic valve is most often affected.1 Current guidelines recommend anticoagulation with unfractionated or low–molecular weight heparin or a vitamin k antagonist, although there is limited evidence to support this strategy. The use of factor-Xa-inhibitors or direct thrombin inhibitors has not been evaluated.2 Some authors suggest that a vitamin k antagonist not be used in patients with malignancy-associated nonbacterial thrombotic endocarditis, as recurrent thromboembolic events while on warfarin are common, although this was observed 30 years ago.1 In our case, the patient developed the thrombosis under the treatment with a factor-Xa-inhibitor; therefore, we decided to use an overlapping anticoagulation with unfractionated heparin and a vitamin k antagonist.
SARS-CoV-2 infection is also associated with a high rate of thrombotic complications occurring even under prophylactic therapy.3 Large-vessel stroke, including partial carotid artery occlusion, has been described in younger patients suffering from coronavirus disease 2019 (COVID-19).4 Others found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19, with most patients presenting with classical vascular risk factors and traditional stroke mechanisms, although a substantial number of patients had new positive antiphospholipid antibodies.5 Hypercoagulation during SARS-CoV-2 infection has been linked to cerebral embolism in several cases.6,7
In our case, the patient was asymptomatic, and therefore, the duration of infection remains unknown. However, a second test performed 7 days after the positive one was already negative, thus suggesting that infection occurred earlier. The median duration of viral shedding was 20 days in survivors of COVID-19, according to a Chinese study.8 Remarkably, native aortic valve thrombosis and its consequences occurred despite oral anticoagulation, highlighting a possible incremental effect of 2 thrombogenic conditions. Both cancer-associated thrombosis and COVID-19-related thrombotic events share common features, such as coagulopathy and endothelial dysfunction secondary to systemic inflammation or potential local infection. The prothrombotic effect of SARS-CoV-2 coronavirus infection is thought to be mediated by binding to angiotensin-converting enzyme 2 receptors on the surface of endothelial cells, which leads to endothelial dysfunction and thrombosis.8 As heart valves are lined with endothelial cells, SARS-CoV-2 infection might hypothetically induce dysfunction of the protecting valve surface. Anticoagulation in COVID-19 seems to be beneficial; however, the best strategy is still uncertain.3
This case highlights the many-sided effects of paraneoplastic syndromes and SARS-CoV-2 infection in patients who are already at increased risk for thrombotic complications, owing to underlying disease. The treatment of those patients includes several medical disciplines that should be on alert and prepared to treat SARS-CoV-2 and its thrombotic complications. Although the optimal anticoagulation regime is uncertain in such a case, well controlled unfractionated heparin might be the therapy of choice in the acute setting.Novel Teaching Points
• Nonbacterial thrombotic aortic valve endocarditis is a rare but devastating complication in the context of a paraneoplastic syndrome.
• SARS-CoV-2 infection might increase the risk for thrombotic complications in patients already at increased risk for thrombotic complications, owing to underlying disease.
• The optimal anticoagulation regime is uncertain; however, well controlled unfractionated heparin might be the therapy of choice in the acute setting.
Supplementary Material
Video 1
Coronary angiography
Video 2
Initial transesophageal echocardiography showing oscillating thrombotic formations on the native aortic valve.
Video 3
Follow-up transesophageal echocardiography showing regression of the thrombotic formations on the native aortic valve.
Acknowledgements
We thank T. Scott Bowen for editing of grammar and syntax.
Funding Sources
The authors have no funding sources to declare.
Disclosures
Norman Mangner reports personal fees from Edwards LifeScience, Medtronic, Biotronik, Novartis, Sanofi Genzyme, and AstraZeneca, not specifically associated with the submitted work. Krunoslav Sveric reports personal fees from Novartis and GlaxoSmithKline, not specifically associated with the submitted work. Johannes C. Gerber reports personal fees from Penumbra Europe GmbH and from Daiichi Sankyo Deutschland GmbH, and non-financial support from Cerenovus (Johnson&Johnson) and MicroVention Europe, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. The other authors have no conflicts of interest to disclose.
Ethics Statement: The reported research has adhered to the relevant ethical guidelines.
See page 219 for disclosure information.
To access the supplementary material accompanying this article, visit CJC Open at https://www.cjcopen.ca/ and at https://doi.org/10.1016/j.cjco.2020.10.010.
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RIVAROXABAN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33106785
| 19,014,282
|
2021-02
|
What was the administration route of drug 'RIVAROXABAN'?
|
Paraneoplastic Syndrome and SARS-CoV-2-Incremental Effect of 2 Thrombogenic Conditions?
We present the case of a patient with a nonbacterial thrombotic aortic valve endocarditis experiencing severe thromboembolic complications and an acute right internal carotid artery occlusion in the context of a paraneoplastic syndrome and an asymptomatic severe acute respiratory syndrome coronavirus-2 infection, despite treatment with different and overlapping anticoagulant medications. Patients with increased thrombogenicity due to an underlying disease might be at increased risk for thrombotic events during a severe acute respiratory syndrome coronavirus-2 infection.
Case
A 66-year-old male patient was transferred from another hospital due to a non-ST-elevation myocardial infarction with mildly persisting chest pain for 5 hours.
Six weeks prior to this event, the patient had suffered from a Vena saphena magna thrombosis. Diagnostic testing in the referral hospital revealed a non–small cell lung cancer with histology suggestive of an adenocarcinoma on transbronchial biopsy. Due to lymphatic and contralateral lung metastases (cT4, cN3, cM1a), palliative chemotherapy was recommended but had not been instituted. The venous thrombosis was treated with rivaroxaban 20 mg once daily, which had been taken continuously except for the day of transbronchial biopsy.
On presentation, the electrocardiogram was unremarkable, and transthoracic echocardiography revealed moderate pericardial effusion, a normal left ventricular ejection fraction without regional wall motion abnormalities, but thickened aortic valve cusps and moderate aortic regurgitation. Coronary angiography showed a 50% stenosis of the Ramus interventricularis anterior without hemodynamic impact, as assessed by the resting full-cycle ratio (0.93; Video 1 , view video online). The resting full-cycle ratio is a non-hyperemic index that scans diastole and systole for the largest drop in pressure over the entire cardiac cycle. A value ≤0.89 indicates a hemodynamically relevant stenosis.
To investigate for other potential reasons for the myocardial infarction, transesophageal echocardiography was performed and showed oscillating masses on the native aortic valve up to 12x6 mm in size, which involved all 3 cusps, predominately affecting the right coronary cusp (Fig. 1A; Video 2 , view video online). There was no patent foramen ovale, left atrial appendage thrombosis, or large and mobile aortic atheroma. The patient was afebrile, inflammatory markers were not significantly increased (leucocytes 9.6 Gpt/L [3.6-10.5 Gpt/L], C-reactive protein 18.8 mg/L [< 5.0 mg/L], procalcitonin 0.12 μg/L [< 0.05 μg/L]), and repeated blood cultures were negative, suggesting that bacterial infective endocarditis was unlikely, although serologic tests were not performed. Tests of hemostasis were unremarkable except for a slightly increased international normalized ratio (INR) under factor-Xa inhibition. There were no significant abnormalities in fibrinogen (2.3 g/L [1.8-3.5 g/L]) or complement factors C3 (1.66 g/L [0.90-1.80 g/L]) and C4 (0.33 g/L [0.10-0.40 g/L]). Cardiolipin IgM (12 U/ml [< 10 U/ml]) was borderline elevated, however ß2-glycoprotein-I IgM (< 0.9 U/ml [< 7 U/ml]) and –IgG (0.6 U/ml [< 7 U/ml]), as well as other autoimmune disease–related antibodies, was not elevated, suggesting the absence of an antiphospholipid syndrome. However, a relative lymphocytopenia (16.1% [20%-44%)) and increased lactate dehydrogenase activity (9.01 μkat/L [<4.2 μkat/L]) led to a nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 9 days after the admission for myocardial infarction, which revealed a positive polymerase chain reaction for the E-gene, indicating SARS-CoV-2 infection. The patient never displayed typical symptoms for SARS-CoV-2 infection prior to or during his hospitalization.Figure 1 (A) Oscillating thrombotic masses on the native aortic valve (B) with regression in a control 6 days after initiation of antithrombotic therapy. (C) Acute cerebral embolism to the mesencephalon (white arrow). (D) Thrombotic closure of the right internal carotid artery (solid arrow), whereas the left one is well perfused (dotted arrow). (E, F) Selective angiography of the right internal carotid artery (E) before and (F) after successful interventional therapy.
Intravenous heparin was started (partial thromboplastin time: 60-80 seconds), and oral anticoagulation with a vitamin k antagonist was initiated. Transesophageal echocardiography 6 days later demonstrated regression of the thrombotic formations (Fig. 1B; Video 3 , view video online). We administered heparin for 11 days and stopped it after therapeutic INR was documented for 2 consecutive days. At the day of stopping heparin and 4 days after the diagnosis of SARS-CoV-2 infection, the patient experienced a stroke with a left-sided hemiparesis and diplopia. The INR was therapeutic at this time point (2.39). Cerebral computed tomography excluded intracranial hemorrhage, and cerebral magnetic resonance tomography revealed multiple cerebral infarcts in the mesencephalon, with expansion into the thalamus region, the cerebellum, and in the precortical gyrus precentralis, suggesting a cardio-embolic origin (Fig. 1C). Neurologic symptoms initially improved; however, despite a persisting therapeutic INR, the patient developed an acute thrombotic occlusion of his right internal carotid artery with complete left-sided hemiparesis 4 days after the first neurologic event (Fig. 1D). The patient was transferred for cerebral mechanical thrombectomy therapy, which led to complete reperfusion (Fig. 1, E and F). The patient currently remains with left-sided hemiparesis in a specialized stroke unit. At the time of the second cerebrovascular accident, 2 swabs for SARS-CoV-2 performed 7 and 8 days after the first one were negative.
Discussion
This case describes a patient with nonbacterial thrombotic aortic valve endocarditis that developed despite treatment with a factor-Xa-inhibitor and who subsequently suffered a myocardial infarction and 2 strokes within a short period of time in the context of a paraneoplastic syndrome and asymptomatic SARS-CoV-2 infection. We hypothesize that the myocardial infarction and the first stroke originated from thromboembolism, in particular due to the diffuse pattern of lesions detected by cerebral magnetic resonance tomography. The second stroke was caused by an acute right internal carotid artery occlusion, hypothetically triggered by spontaneous local thrombosis; however, embolism of a big thrombus cannot be excluded.
Paraneoplastic syndromes are often linked to increased thrombogenicity; however, nonbacterial thrombotic aortic valve endocarditis is rare even in the situation of cancer. Adenocarcinoma seems to be associated with increased rates of this condition, and the aortic valve is most often affected.1 Current guidelines recommend anticoagulation with unfractionated or low–molecular weight heparin or a vitamin k antagonist, although there is limited evidence to support this strategy. The use of factor-Xa-inhibitors or direct thrombin inhibitors has not been evaluated.2 Some authors suggest that a vitamin k antagonist not be used in patients with malignancy-associated nonbacterial thrombotic endocarditis, as recurrent thromboembolic events while on warfarin are common, although this was observed 30 years ago.1 In our case, the patient developed the thrombosis under the treatment with a factor-Xa-inhibitor; therefore, we decided to use an overlapping anticoagulation with unfractionated heparin and a vitamin k antagonist.
SARS-CoV-2 infection is also associated with a high rate of thrombotic complications occurring even under prophylactic therapy.3 Large-vessel stroke, including partial carotid artery occlusion, has been described in younger patients suffering from coronavirus disease 2019 (COVID-19).4 Others found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19, with most patients presenting with classical vascular risk factors and traditional stroke mechanisms, although a substantial number of patients had new positive antiphospholipid antibodies.5 Hypercoagulation during SARS-CoV-2 infection has been linked to cerebral embolism in several cases.6,7
In our case, the patient was asymptomatic, and therefore, the duration of infection remains unknown. However, a second test performed 7 days after the positive one was already negative, thus suggesting that infection occurred earlier. The median duration of viral shedding was 20 days in survivors of COVID-19, according to a Chinese study.8 Remarkably, native aortic valve thrombosis and its consequences occurred despite oral anticoagulation, highlighting a possible incremental effect of 2 thrombogenic conditions. Both cancer-associated thrombosis and COVID-19-related thrombotic events share common features, such as coagulopathy and endothelial dysfunction secondary to systemic inflammation or potential local infection. The prothrombotic effect of SARS-CoV-2 coronavirus infection is thought to be mediated by binding to angiotensin-converting enzyme 2 receptors on the surface of endothelial cells, which leads to endothelial dysfunction and thrombosis.8 As heart valves are lined with endothelial cells, SARS-CoV-2 infection might hypothetically induce dysfunction of the protecting valve surface. Anticoagulation in COVID-19 seems to be beneficial; however, the best strategy is still uncertain.3
This case highlights the many-sided effects of paraneoplastic syndromes and SARS-CoV-2 infection in patients who are already at increased risk for thrombotic complications, owing to underlying disease. The treatment of those patients includes several medical disciplines that should be on alert and prepared to treat SARS-CoV-2 and its thrombotic complications. Although the optimal anticoagulation regime is uncertain in such a case, well controlled unfractionated heparin might be the therapy of choice in the acute setting.Novel Teaching Points
• Nonbacterial thrombotic aortic valve endocarditis is a rare but devastating complication in the context of a paraneoplastic syndrome.
• SARS-CoV-2 infection might increase the risk for thrombotic complications in patients already at increased risk for thrombotic complications, owing to underlying disease.
• The optimal anticoagulation regime is uncertain; however, well controlled unfractionated heparin might be the therapy of choice in the acute setting.
Supplementary Material
Video 1
Coronary angiography
Video 2
Initial transesophageal echocardiography showing oscillating thrombotic formations on the native aortic valve.
Video 3
Follow-up transesophageal echocardiography showing regression of the thrombotic formations on the native aortic valve.
Acknowledgements
We thank T. Scott Bowen for editing of grammar and syntax.
Funding Sources
The authors have no funding sources to declare.
Disclosures
Norman Mangner reports personal fees from Edwards LifeScience, Medtronic, Biotronik, Novartis, Sanofi Genzyme, and AstraZeneca, not specifically associated with the submitted work. Krunoslav Sveric reports personal fees from Novartis and GlaxoSmithKline, not specifically associated with the submitted work. Johannes C. Gerber reports personal fees from Penumbra Europe GmbH and from Daiichi Sankyo Deutschland GmbH, and non-financial support from Cerenovus (Johnson&Johnson) and MicroVention Europe, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. Axel Linke reports grants from Novartis, personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, Astra Zeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer, and other support from Picardia, Transverse Medical, and Claret Medical, not specifically associated with the submitted work. The other authors have no conflicts of interest to disclose.
Ethics Statement: The reported research has adhered to the relevant ethical guidelines.
See page 219 for disclosure information.
To access the supplementary material accompanying this article, visit CJC Open at https://www.cjcopen.ca/ and at https://doi.org/10.1016/j.cjco.2020.10.010.
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Oral
|
DrugAdministrationRoute
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CC BY-NC-ND
|
33106785
| 19,014,282
|
2021-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'.
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
LEVOTHYROXINE SODIUM, METFORMIN HYDROCHLORIDE, ONDANSETRON, TEMOZOLOMIDE, TESTOSTERONE
|
DrugsGivenReaction
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'.
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
LEVOTHYROXINE SODIUM, METFORMIN HYDROCHLORIDE, ONDANSETRON, TEMOZOLOMIDE, TESTOSTERONE
|
DrugsGivenReaction
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'.
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
LEVOTHYROXINE SODIUM, METFORMIN HYDROCHLORIDE, ONDANSETRON, TEMOZOLOMIDE, TESTOSTERONE
|
DrugsGivenReaction
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
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LEVOTHYROXINE SODIUM, METFORMIN HYDROCHLORIDE, ONDANSETRON, TEMOZOLOMIDE, TESTOSTERONE
|
DrugsGivenReaction
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What is the weight of the patient?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
115.6 kg.
|
Weight
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the administration route of drug 'LEVOTHYROXINE SODIUM'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the administration route of drug 'METFORMIN HYDROCHLORIDE'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the administration route of drug 'ONDANSETRON'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the administration route of drug 'TEMOZOLOMIDE'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the administration route of drug 'TESTOSTERONE'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
Intramuscular
|
DrugAdministrationRoute
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the dosage of drug 'TEMOZOLOMIDE'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
150?200 MG/M2, 5 DAYS IN A 28?DAY CYCLE (EVERY 4 WEEKS)
|
DrugDosageText
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the outcome of reaction 'Fatigue'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
Not recovered
|
ReactionOutcome
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
What was the outcome of reaction 'Nausea'?
|
Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Background
Pituitary carcinomas are rare, accounting for 0.1% of pituitary tumors (1). Cerebrospinal and/or distant metastases are present by definition. They require maximally coordinated multimodal therapies because of their aggressive behavior (2). Therapy as proposed by the European Society of Endocrinology (ESE) includes surgical resection, adjuvant radiotherapy and first-line chemotherapy with temozolomide (TMZ) (3, 4). Nonetheless, the mortality rate of pituitary carcinoma remains high, with an average life expectancy of 2.6 years (1). Evidence regarding the next line beyond TMZ is lacking. Novel treatment modalities are urgently needed for refractory cases. Immunotherapy, with immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1) has been a revolution for a wide range of malignancies, with an ever-growing list of indications. In 2018, Lin et al. successfully treated a first case of aggressive ACTH-secreting pituitary carcinoma with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination immunotherapy (5). We now report the second case of a patient with corticotroph pituitary carcinoma with disease stabilization after the introduction of ipilimumab and nivolumab.
Case
A 41-year-old patient was diagnosed with an invasive ACTH-secreting pituitary adenoma in 2012. Initial pathological examination had revealed positive chromogranin, p53 (1+) and strong ACTH staining. Ki-67 proliferation index was low (<1%). Initial treatment consisted of transsphenoidal and transcranial surgery with subsequently two sessions of stereotactic radiosurgery in 2013 and 2015.
In 2017, he was first seen at our pituitary outpatient clinic for a second opinion. His therapy consisted of ketoconazole 1000 mg/day, together with thyroid and testosterone hormone replacement therapy. Hormonal workup revealed persistent Cushing’s disease (CD) with elevated 08:00 h ACTH (225 ng/L, 08:00 h normal range: 7.2–63 ng/L) and cortisol (378.5 µg/L, 08:00 h normal range: 62–180 µg/L) and high 24-h urinary free cortisol (UFC) (1727.7 µg/24 h = 606.2 µg/L, normal range: 4.2–60 µg/24 h) despite the maximal dosage of ketoconazole. MRI of the brain showed no macroscopic disease. Pasireotide 0.6 mg twice daily was initiated, but had to be discontinued for severe iatrogenic diabetes mellitus. Cabergoline 0.25 mg twice weekly was started with unsatisfactory response. Bilateral adrenalectomy was performed in September 2017. Unfortunately, follow-up revealed small residual adrenal tissue on the left side. The patient refused a second surgery for complete removal of the adrenal remnant. Disease control was nonetheless achieved with stable 08:00 h ACTH (231 ng/L), cortisol (151.6 µg/L) and UFC (126.9 µg/24 h = 47.8 µg/L). In May 2018, the patient deteriorated with the development of diplopia due to left abducens nerve palsy. Plasma ACTH had increased (357.3 ng/L) and MRI revealed recurrence of the pituitary tumor with suprasellar and cavernous sinus invasion. Additionally, metastases were detected in the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (Fig. 1). These findings confirmed the evolution toward corticotroph pituitary carcinoma, possibly in the context of Nelson's syndrome given the rapid progression after the bilateral adrenalectomy. Biopsy of the pituitary carcinoma for reanalysis of proliferative markers could not be performed at the time; the metastases were considered unsafe for biopsy. TMZ chemotherapy (150–200 mg/m2, 5 days in a 28-day cycle) was promptly initiated. First evaluation after three cycles of TMZ showed persistent CD with stable tumor burden. Ketoconazole (800 mg/day) was restarted and TMZ therapy was continued for a total of nine cycles (April 2019), when clinical progressive disease was suspected with the development of right oculomotor and abducens nerve palsies and increasing 08:00 h ACTH (419.9 ng/L) and cortisol (208 µg/L). However, no radiological progression could be detected. The patient agreed to start with a combination ICI therapy of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks, for 4 cycles in a compassionate use setting (Table 1). Initial evaluation after the first four cycles demonstrated disease stabilization with declining ACTH and cortisol levels (ACTH: 338.9 ng/L; cortisol: 199 µg/L, 24-h urinary cortisol: 354.8 µg/24 h = 140.7 µg/L) without radiological change. Maintenance therapy with nivolumab (240 mg) was then continued every 2 weeks. Up to now, the patient has a non-progressive disease, one year after the initiation of ICI, with declining 08:00 h ACTH and UFC as shown in Fig. 2. Radiological disease stabilization is observed when comparing MRI obtained after the last TMZ cycle with follow-up imaging one year after the initiation of ICI (Fig. 1). However, there is no resolution of the diplopia. He did not experience any immune-related adverse events. His CD is still under control with 800 mg of ketoconazole daily.
Figure 1 Gadolinium-enhanced T1-weighted magnetic resonance imaging of the pituitary carcinoma. Panel A shows invasion of the cavernous sinus (arrow) and the metastases of the posterior fossa, left cerebellum and cervical drop metastases at the level of the dens and the third cervical vertebra (asterix) (May 2018). Panel B shows evaluation of the pituitary carcinoma after nine cycles of TMZ treatment (April 2019). Panel C shows stable disease (irRECIST criteria) 1 year after initiation of ICI (April 2020). IrRECIST, immune-related Response Evaluation Criteria in Solid Tumors; ICI, Immune Checkpoint Inhibitors.
Figure 2 Timeline of 08:00 h ACTH and UFC during follow-up. ACTH, Adrenocorticotropic hormone (08:00 h normal range: 7.2–63 ng/L); ICI, Immune Checkpoint Inhibitors; UFC, Urinary Free Cortisol (normal range: 4.2–60 µg/24 h). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0151.
Table 1 Data of plasma 08:00 h ACTH, 08:00 h cortisol, and UFC during follow up with the corresponding treatment.
Date 08:00 h Cortisol1 (µg/L) 08:00 h ACTH2 (ng/L) UFC3 (µg/L) Treatment
Jun/17 378.5 225 606.2 Ketoconazole 1000 mg + Pasireotide 0.6 mg twice daily started
Sep/17 151.6 231 47.8 Bilateral adrenalectomy already performed + hydrocortisone and fludrocortisone suppletion started
May/18 132 357.3 177 Hydrocortisone and fludrocortisone stopped + temozolomide 350 mg 5 days every 4 weeks + ketoconazole 800 mg restarted
Aug/18 145 418 243.8 Temozolomide 350 mg 5 days every 4 weeks (nine cycles) + ketoconazole 800 mg
Apr/19 208 419.9 284.7 Ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 weeks + ketoconazole 800 mg
Aug/19 199 338.9 140.7 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Nov/19 196 346.9 136.6 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
Feb/20 74 293.7 74.1 Nivolumab 240 mg every 2 weeks + ketoconazole 800 mg
1Cortisol, 08:00 h normal: 62–180 µg/L; 2Adrenocorticotropic hormone, 08:00 h normal range: 7.2–63 ng/L; 3Urinary free cortisol, normal range: 4.2–60 µg/24 h.
Discussion
Pituitary carcinomas are rare and progress with poor survival despite maximal multimodal therapy. Pathophysiology remains poorly understood, but development in the context of Nelson’s syndrome has been reported (6). Furthermore, histopathological or immunohistochemical (IHC) analyses have not always been able to consistently predict tumor behavior. Management guidelines beyond TMZ rely on case reports. This is the second case of a patient with ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, treated with ICI (ipilimumab and nivolumab). Given the aggressive nature of pituitary carcinoma, the non-progressive disease with a decline in ACTH values illustrates the efficacy of the immunotherapy. The current guidelines for pituitary carcinoma recommend TMZ as a first-line chemotherapy (3). TMZ is an alkylating pro-drug that methylates DNA at the O6 position of guanine, which induces DNA damage and apoptosis. Induction of mutations in DNA mismatch repair genes causes a state of hypermutation, with the formation of novel oncogenic drivers, resulting in tumor resistance to TMZ. The same process also creates novel tumor antigens, rendering patients more immunogenic and subsequently potential candidates for ICI therapy (7).
The pituitary gland itself confers a particular immunogenicity as hypophysitis is a frequently encountered endocrine adverse event to ICI with an estimated incidence of around 10%, especially with ipilimumab. It also occurs occasionally during PD-1/PD-L1 blockade (8, 9, 10). For reasons yet unknown, hypophysitis is mainly observed in male patients (4/1 ratio) (8). Ipilimumab and tremelimumab are both CTLA-4 targeting monoclonal antibodies. CTLA-4 expression is present in normal pituitary glands and pituitary adenomas, including one autopsy case who presented a necrotizing form of tremelimumab-induced hypophysitis through type II (IgG dependent) and type IV (T-cell dependent) immune mechanisms (8). The expression of PD-L1 in pituitary adenomas has also been assessed. PD-L1 expression was found in both functioning and non-functioning pituitary tumors, with higher levels in functioning (GH- and PRL-expressing) adenomas, while tumor-infiltrating lymphocytes were also observed and correlated with PD-L1 expression (11, 12).
Considering these findings, the use of ICI therapy for the treatment of pituitary carcinoma should be considered. Lin et al. were the first to publish a case of a patient with an ACTH-secreting pituitary carcinoma who initially responded to TMZ and capecitabine chemotherapy, prior to metastasizing to the liver (5). They recorded a dramatic response to a combination of ipilimumab and nivolumab immunotherapy, with a reduction in tumor volume of the pituitary lesion (59%) and liver metastasis (92%) with concomitantly a severe drop in circulating ACTH levels (from 45.550 to 66 pg/mL). Genomic sequencing of the pituitary tumor (before chemotherapy) and liver metastasis (after chemotherapy) showed evidence of alkylating chemotherapy-induced somatic mutations with the presence of a MSH6 mutation in the TMZ-treated liver metastasis. Our patient did not benefit from mutational analysis nor CTLA-4 or PD-L1 IHC, as the surgical resection of his pituitary tumor was performed at a different medical center and the remaining anatomic-pathological samples were of insufficient quality. Furthermore, the metastases were unsafe for biopsy.
Pituitary carcinomas are rare and evidence-based approach for treatment is difficult. Case reports may contribute to a better understanding of the pathophysiological mechanism involved, as well as to the possibility for personalized molecular targeted therapies. This case adds support to the possible role of ICI in the treatment of pituitary carcinoma, not responsive to the classical proposed multimodal therapy and TMZ chemotherapy. Two ongoing interventional trials, ‘DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors’ of the National Cancer Institute (NCI) and ‘Phase II Trial of Nivolumab Plus Ipilimumab in Patients With Aggressive Pituitary Tumors’ of the Memorial Sloan Kettering Cancer Center, USA, may provide further evidence for this hypothesis.
Conclusion
Treatment options for refractory pituitary carcinoma are currently limited with poor prognosis when TMZ is ineffective. We consider ICI therapy to be a valid treatment alternative after prior TMZ therapy, considering the mechanisms of TMZ-induced hypermutation involving increased immunogenicity, the pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy. This is the second case of a patient with aggressive ACTH-secreting pituitary carcinoma, refractory to TMZ chemotherapy, who demonstrated benefit by a combination of ipilimumab and nivolumab checkpoint blockade therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent has been obtained from the patient for publication of the case report and accompanying images.
|
Recovered
|
ReactionOutcome
|
CC BY
|
33112279
| 18,702,402
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'.
|
Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors.
Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12-30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts.Clinical Trial Registry: NCT02519114.
Introduction
In recent years, the use of haploidentical donor cells for the treatment of hematological malignancies has been increasing and has proven effective and safe, especially with the use of PTCY [1, 2]. There is limited documentation about haploSCT in MM, but small retrospective studies show this is feasible with relatively low non-relapse mortality (NRM). Results in terms of PFS are however similar to HLA-identical SCT [3–5]. HaploSCT offers an attractive opportunity to introduce natural killer (NK) cell alloreactivity based on a KIR-ligand mismatch. In myeloid malignancies, this NK alloreactivity, in the context of a T cell deplete haploSCT, leads to a decreased relapse rate and improved survival without causing GVHD [6–8]. Unlike in T cell–depleted haploSCT, the benefit of NK cell alloreactivity in T cell replete haploidentical SCT is less clear and the limited number of small-sized studies concerning this effect is not conclusive [9–12]. The differences concerning NK cell alloreactivity in these studies might be due to the disease heterogeneity of the included patients and differences in the conditioning regimen and stem cell source. Some studies point towards a better outcome when bone marrow stem cells were used compared to peripheral blood stem cells, which was shown to correlate with the T cell content of the graft that is higher in peripheral blood stem cell products [12]. This correlation is in line with reports on the inhibitory effect of T cells on the development of alloreactive NK cells [13].
There is much evidence to support the role of NK cells in fighting MM [14–17]. It has been proven that therapeutic interventions like lenalidomide and elotuzumab result in increased NK cell–mediated anti-myeloma responses [18, 19]. In preclinical studies performed by our research group, we show that NK cells are able to kill MM cells, and this killing is improved in the presence of NK alloreactivity [20, 21]. This was shown in vitro as well as in a humanized mouse model. Two small clinical studies also implicated a beneficial role for KIR-ligand mismatch in MM. In one study, the role of administration of alloreactive NK cells before autologous SCT was examined. High remission rates were observed, although they were short-lived [22]. In another study, the impact of KIR-ligand mismatch in a HLA-identical and mismatched SCT setting was investigated and showed that KIR-ligand mismatch in the graft-versus-host direction was protective for relapse [23].
The aim of this phase 2 study was to prospectively evaluate if KIR-ligand mismatched haploidentical bone marrow transplantation (BMT) with PTCY improves PFS in poor-risk MM patients.
Methods
Patients
In this prospective, single-arm, multicenter trial, we recruited poor-risk MM patients aged below 66 years with good clinical performance from hospitals in the Netherlands. Poor risk was defined as high-risk cytogenetics (del17p and/or t(4;14) and/or t(14;16)), or relapse within a year after autologous SCT, or relapse after three or more previous lines of therapy. Furthermore, patients had to be responsive to their last line of therapy, defined as at least partial response according to the International Myeloma Working Group consensus criteria [24]. Another prerequisite of enrolment was the permissiveness to NK alloreactivity and availability of a KIR-ligand mismatched haploidentical family donor. Patients were excluded if donor-specific HLA-antibodies were present.
Donor selection
All patients were transplanted with a KIR-ligand mismatched haploidentical family donor. The opportunity for KIR-ligand mismatched haploBMT was determined by Luminex sequence-specific oligonucleotide hybridization (SSO) typing for the three possible inhibitory KIR-ligands: HLA-C group 1 (ligands for KIR2DL2/3), HLA-C group 2 (ligands for KIR2DL1), and HLA-Bw4 including HLA-A harboring Bw4 motifs as ligands for KIR3DL1 (A*23, A*24, A*32).
In case of an opportunity for KIR-ligand mismatched haploBMT, a KIR-ligand mismatched haploidentical family donor was searched in the wide family tree of the patients. In case a probable KIR-ligand mismatched donor was identified by low resolution, a second blood sample was drawn from this potential donor for confirmation in high resolution, for KIR typing, by low-resolution Luminex SSO assay. Protein expression of the mismatched KIR was confirmed by immune phenotyping of the peripheral blood NK cells for KIR expression as described below.
Immune phenotyping for KIRs during donor selection and NK cell reconstitution
Peripheral blood mononuclear cells were isolated by gradient density centrifugation and stained with monoclonal antibodies with specificity for CD3 (SK7, BD), CD56 (B159, BD), NKG2A (Z199, Beckman Coulter), KIR2DL1 (143211, R&D), KIR2DL2/3/S2 (DX27, Miltenyi Biotech), or KIR3DL1 (DX9, Miltenyi Biotech) followed by acquisition of the samples on a BD FACS Canto II machine. Acquired data were analyzed using the Diva software by gating on living CD3- CD56+ lymphocytes followed by analysis of the percentage of positive cells for the individual KIRs.
Conditioning and transplant procedure
Conditioning regimen consisted of cyclophosphamide 14.5 mg/kg on day - 6 and - 5, fludarabine 30 mg/m2 from day - 6 to - 2 and 200 cGY total body irradiation at day - 1 in all but one patient that received busulfan instead of cyclophosphamide pre-transplant. Donor bone marrow cells were infused on day 0. Bone marrow cells were used in all but one patient, since they are preferred over peripheral blood stem cells because of a lower risk of acute and chronic GVHD [25, 26].
GVHD prophylaxis and supportive care
GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg at day + 3 and + 4. Mycophenolate mofetil was used from day + 5 to + 35. Tacrolimus 0.1 mg/kg was added to this combination from day + 5 to + 180.
To prevent infections, patients received immunoglobulins 0.2 g/kg once every 4 weeks from 1 week before conditioning until the immunosuppressive drugs were stopped. Anti-microbial prophylaxis furthermore consisted of cotrimoxazole and valaciclovir, and during neutropenia, ciprofloxacin and fluconazole were given as selective digestive decontamination.
Study endpoints and statistical analysis
The primary endpoint was PFS at 1.5 years. Since haploBMT is a demanding and costly treatment for the patients, we considered the effect that has to be realized by this procedure needed to be substantial and chose for the PFS goal of 50% in 1.5 years compared to around 25% with conventional alloSCT according to historical data.
To test this hypothesis, Simon’s two-stage design was used. We hypothesized that the 1.5-year PFS will be 50% after haploBMT, while this is a maximum 25% in the hypothetical standard treatment group (conventional alloSCT according to historical data). To demonstrate this difference with a power of 80% and a type 1 error rate, alpha (one-sided) of 0.05%, 24 patients were needed. If 1 or less of the first 9 patients experienced 1.5-year PFS, the relevant predefined positive effect was considered very unlikely and the study would be stopped.
Secondary endpoints were engraftment, bone marrow reconstitution, NK cell reconstitution and repertoire, GVHD, infections, and NRM.
To ensure safety, we build in decision rules to prematurely terminate the study if the NRM at 100 days exceeded a certain percentage that was calculated beforehand based on a modification of the standard 3 + 3 scheme.
Analyses were performed as of April 2020. Pre-transplantation patient characteristics were given as median and range for continuous variables and as frequency and proportion for categorical variables. PFS was analyzed using a Kaplan-Meier estimate. For NRM, relapse, and GVHD, a competing risk framework was used. The analysis was performed with the R software.
Results and discussion
In total, 12 poor-risk patients were included from 3 hospitals in the Netherlands from April 2016 to May 2018 with a follow-up until April 2020 and the median time to follow-up is 30.2 months (range 11.8–44.9 months). Pre-transplantation patient characteristics are described in Table 1. They were all heavily pre-treated with both proteasome inhibition and immunomodulatory drugs; none of the patients received antibody treatment before inclusion. One patient had known high-risk cytogenetics and three patients showed progression within 12 months after autologous SCT. We excluded one patient for further analysis due to disease progression just before BMT, since this was a predefined exclusion criterion. This patient, however, was transplanted because pre-transplant M-protein levels became available during conditioning therapy. KIR/HLA incompatibility of the different donors is described in Table 2.Table 1 Patient characteristics
Gender, n (%)
Male 10 (91)
Female 1 (9)
Age, median in years (range) 61 (40–66)
Response to last therapy, n (%)
PR 5 (45)
VGPR 5 (45)
CR 1 (9)
Previous lines of treatment, median (range) 3 (2–7)
Previous SCT, n (%)
1x autologous 8 (73)
2x autologous 3 (27)
Allogeneic 1 (9)
Table 2 Donor and recipient HLA typing and NK mismatch
Patient NR. Patient HLA present Patient HLA absent Donor HLA present Donor HLA absent Mismatch iKIR mismatch
P1 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P2 C2 Bw4, C1 C1, C2 Bw4 C1 2DL2/2DL3
P3 Bw4, C2 C1 Bw4, C1, C2 x C1 2DL2/2DL3
P4 C1, C2 Bw4 Bw4, C2 C1 Bw4 3DL1
P5 Bw4, C1 C2 C1, C2 Bw4 C2 2DL1
P6 C1 Bw4, C2 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P7 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P8 C1, C2 Bw4 Bw4, C1, C2 X Bw4 3DL1
P9 Bw4, C2 C1 Bw4, C1, C2 X C1 2DL2/2DL3
P10 C1 C2,Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P11 C1 C2, Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P12 C1, Bw4 C2 Bw4, C1, C2 x C2 2DL1
HLA human leukocyte antigen, iKIR inhibitory killer cell immunoglobulin-like receptor
Clinical endpoints
Of the 11 evaluable patients, 10 achieved primary engraftment (91%), with a median time to neutrophil and platelet engraftment of 18 (12–30 days) and 30 (20–49 days) days, respectively. Grade 2–4 acute GVHD occurred in 2 of 11 patients (none grade 3–4) and chronic GVHD occurred in 4 of 11 patients. Two of the 11 patients died of treatment-related mortality (18%) within the first year.
Of the 9 for the primary endpoint evaluable patients, all patients relapsed within 1 year (Fig. 1a). The median time to relapse was 90 days (range 30–360 days), and 8 of 9 patients had to eventually start anti-myeloma treatment. The median time for the next treatment was 186 days (range 40–330 days); two-thirds of the patients at first only biochemically relapsed without a need for treatment. Overall survival was 73% after 1 year and 52% after 2 years (Fig. 1b).Fig. 1 Clinical outcomes after HaploBMT. a Probability of progression-free survival. b Overall survival
Noteworthy is one patient, who relapsed quickly after SCT with an increase of her involved free light chain, displayed a spontaneous decrease 60 days after BMT to pre-transplant levels (Fig. 2). During this period, no additional anti-myeloma treatment was started. Only immune-suppressive treatment with mycophenolate mofetil was stopped at day + 35, as per protocol. She did not require any treatment until 400 days after the stem cell transplantation. Interesting is also a second, heavily pre-treated patient that was already progressive at day 40 after SCT, but had a complete remission on daratumumab and has continuous bone marrow–proven remission more than 2 years after stopping this treatment.Fig. 2 Serum-free light-chain response after HaploBMT in one individual patient. Progression 30 days after transplantation and responsive thereafter without treatment
NK cell reconstruction
At day 30, all of the 8 analyzed patients showed NK cell recovery, though with an immature phenotype (NKG2A+, KIR-). At day 60 in both the peripheral blood and bone marrow, mature NK cells (KIR+) could be identified (Fig. 3a–d). We have no data on the functionality of these cells.Fig. 3 a–d Assessment of NK cell phenotype after stem cell transplantation. Mononuclear cells were isolated from peripheral blood (PBL) or bone marrow (BM). To analyze KIR expression in the donor, PBL were harvested before from the donor before transplantation. To determine NK reconstitution upon transplantation, PBL or BM cells were isolated from the patient at 30 (d30) or 60 (d60) days after transplantation. Isolated cells were stained and the percentage of CD3-CD56+ NK cells expressing KIR2DL1, KIR2DL2/3, KIR3DL1, or NKG2A was determined by flow cytometry. Patients and their donors are depicted as P1–P8 in the legend and every dot represents one data point of cells analyzed at day 30 (d30) or day 60 (d60) after transplantation
Discussion
With this study, we tested the safety and the efficacy of a KIR-mismatched haploidentical BMT in high risk MM patients. We observed that the treatment is safe since there was a high engraftment rate, low NRM (18% at 1 year), and no unexpected adverse events. In the only two other retrospective studies concerning haploSCT with PTCY in MM where there was no selection on KIR-mismatch, comparable results were seen with respect to NRM (10–21% in 1.5 to 2 years); however, they had a slightly higher PFS (17–33% in 1.5 to 2 years). In our small study, unfortunately, there is a 1.5-year PFS of 0%. This 1.5-year PFS seems lower than in conventional alloSCT studies. However, the study is underpowered to draw these conclusions, since the study was prematurely terminated due to the defined stopping rules based on a 1.5-year PFS of 50%. Furthermore, this low PFS was also not unexpected since these were heavily pre-treated patients with very high-risk chemo-resistant myelomas. Though these patients showed a biochemical relapse, many of them did not require treatment for a long time after which is very unlikely for this fast progressive patient population. Even though it is difficult to draw conclusions in such a small, heterogenous group of patients, our results show that KIR-ligand mismatch in this patient category is not only harmful but also not more effective than non-matched haploSCT or conventional alloSCT in curing MM [3, 4].
We hypothesize that the late reconstitution of functional mature NK cells is responsible for the lack of response. This has already been described in other patient groups after PTCY: within days after SCT, mature graft-derived NK cells appear, but they are rapidly eliminated by PTCY. Full reconstitution of a mature and functional NK cell population took 6 to 12 months [12]. The median time point of relapse in our patients occurred shortly after transplantation (around 3 months). We detected that 30 days after haploBMSCT, most NK cells still had an immature phenotype without KIR expression and were not able to stop disease progression at this early stage after transplantation when myeloma cell load was still low. We hypothesize that the delayed NK cell reconstitution may be overruled by the infusion of mature, functional donor NK cells shortly after PTCY administration. In myeloid malignancies, this concept has already been used and seems successful in a small group of high-risk patients [27]. In this context, it may also be helpful to bridge the time to full NK cell restoration after the SCT with additional anti-MM therapy like elotuzumab or daratumumab, or to combine these two modalities. This concept is supported by the patient that showed a long-lasting complete response after temporary treatment with daratumumab. Another option would be to improve NK cell function and thereby increase the alloreactive effect by blocking antibodies, such as monalizumab, a novel checkpoint inhibitor against NKG2a [28].
In conclusion, in this study, we show that haploidentical BMT in MM patients is safe and feasible in terms of engraftment and late NK cell reconstitution. HaploBMT in MM forms a possible platform for future immunotherapeutic strategies in which the KIR-ligand mismatch might be beneficial. Though this study is limited in patient numbers, none of the patients showed a clinically relevant increase of PFS; therefore, we conclude that in the setting of haploBMT in combination with PTCY, however, a KIR mismatch probably is not clinically relevant.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patients and their families for participating in the study.
Authorship contributions
C.E., P.B., E.M., L.W., and G.B. contributed to the conception, design, and planning of the study; C.E. and G.G. contributed to the analysis of the data; C.E., P.B., E.M., C.V., and L.W. contributed to the acquisition of the data; C.E., G.G., L.W., and G.B. contributed to the interpretation of the results; G.G. and C.E. contributed to the drafting of the manuscript; and all authors contributed to critically reviewing or revising the manuscript for important intellectual content.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
G. Bos is C.E.O. CiMaas bv, Maastricht, The Netherlands. All other authors declare that they have no conflicts of interest.
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BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, MYCOPHENOLATE MOFETIL, TACROLIMUS
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DrugsGivenReaction
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CC BY
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33112968
| 18,787,258
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2021-01
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What was the dosage of drug 'FLUDARABINE PHOSPHATE'?
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Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors.
Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12-30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts.Clinical Trial Registry: NCT02519114.
Introduction
In recent years, the use of haploidentical donor cells for the treatment of hematological malignancies has been increasing and has proven effective and safe, especially with the use of PTCY [1, 2]. There is limited documentation about haploSCT in MM, but small retrospective studies show this is feasible with relatively low non-relapse mortality (NRM). Results in terms of PFS are however similar to HLA-identical SCT [3–5]. HaploSCT offers an attractive opportunity to introduce natural killer (NK) cell alloreactivity based on a KIR-ligand mismatch. In myeloid malignancies, this NK alloreactivity, in the context of a T cell deplete haploSCT, leads to a decreased relapse rate and improved survival without causing GVHD [6–8]. Unlike in T cell–depleted haploSCT, the benefit of NK cell alloreactivity in T cell replete haploidentical SCT is less clear and the limited number of small-sized studies concerning this effect is not conclusive [9–12]. The differences concerning NK cell alloreactivity in these studies might be due to the disease heterogeneity of the included patients and differences in the conditioning regimen and stem cell source. Some studies point towards a better outcome when bone marrow stem cells were used compared to peripheral blood stem cells, which was shown to correlate with the T cell content of the graft that is higher in peripheral blood stem cell products [12]. This correlation is in line with reports on the inhibitory effect of T cells on the development of alloreactive NK cells [13].
There is much evidence to support the role of NK cells in fighting MM [14–17]. It has been proven that therapeutic interventions like lenalidomide and elotuzumab result in increased NK cell–mediated anti-myeloma responses [18, 19]. In preclinical studies performed by our research group, we show that NK cells are able to kill MM cells, and this killing is improved in the presence of NK alloreactivity [20, 21]. This was shown in vitro as well as in a humanized mouse model. Two small clinical studies also implicated a beneficial role for KIR-ligand mismatch in MM. In one study, the role of administration of alloreactive NK cells before autologous SCT was examined. High remission rates were observed, although they were short-lived [22]. In another study, the impact of KIR-ligand mismatch in a HLA-identical and mismatched SCT setting was investigated and showed that KIR-ligand mismatch in the graft-versus-host direction was protective for relapse [23].
The aim of this phase 2 study was to prospectively evaluate if KIR-ligand mismatched haploidentical bone marrow transplantation (BMT) with PTCY improves PFS in poor-risk MM patients.
Methods
Patients
In this prospective, single-arm, multicenter trial, we recruited poor-risk MM patients aged below 66 years with good clinical performance from hospitals in the Netherlands. Poor risk was defined as high-risk cytogenetics (del17p and/or t(4;14) and/or t(14;16)), or relapse within a year after autologous SCT, or relapse after three or more previous lines of therapy. Furthermore, patients had to be responsive to their last line of therapy, defined as at least partial response according to the International Myeloma Working Group consensus criteria [24]. Another prerequisite of enrolment was the permissiveness to NK alloreactivity and availability of a KIR-ligand mismatched haploidentical family donor. Patients were excluded if donor-specific HLA-antibodies were present.
Donor selection
All patients were transplanted with a KIR-ligand mismatched haploidentical family donor. The opportunity for KIR-ligand mismatched haploBMT was determined by Luminex sequence-specific oligonucleotide hybridization (SSO) typing for the three possible inhibitory KIR-ligands: HLA-C group 1 (ligands for KIR2DL2/3), HLA-C group 2 (ligands for KIR2DL1), and HLA-Bw4 including HLA-A harboring Bw4 motifs as ligands for KIR3DL1 (A*23, A*24, A*32).
In case of an opportunity for KIR-ligand mismatched haploBMT, a KIR-ligand mismatched haploidentical family donor was searched in the wide family tree of the patients. In case a probable KIR-ligand mismatched donor was identified by low resolution, a second blood sample was drawn from this potential donor for confirmation in high resolution, for KIR typing, by low-resolution Luminex SSO assay. Protein expression of the mismatched KIR was confirmed by immune phenotyping of the peripheral blood NK cells for KIR expression as described below.
Immune phenotyping for KIRs during donor selection and NK cell reconstitution
Peripheral blood mononuclear cells were isolated by gradient density centrifugation and stained with monoclonal antibodies with specificity for CD3 (SK7, BD), CD56 (B159, BD), NKG2A (Z199, Beckman Coulter), KIR2DL1 (143211, R&D), KIR2DL2/3/S2 (DX27, Miltenyi Biotech), or KIR3DL1 (DX9, Miltenyi Biotech) followed by acquisition of the samples on a BD FACS Canto II machine. Acquired data were analyzed using the Diva software by gating on living CD3- CD56+ lymphocytes followed by analysis of the percentage of positive cells for the individual KIRs.
Conditioning and transplant procedure
Conditioning regimen consisted of cyclophosphamide 14.5 mg/kg on day - 6 and - 5, fludarabine 30 mg/m2 from day - 6 to - 2 and 200 cGY total body irradiation at day - 1 in all but one patient that received busulfan instead of cyclophosphamide pre-transplant. Donor bone marrow cells were infused on day 0. Bone marrow cells were used in all but one patient, since they are preferred over peripheral blood stem cells because of a lower risk of acute and chronic GVHD [25, 26].
GVHD prophylaxis and supportive care
GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg at day + 3 and + 4. Mycophenolate mofetil was used from day + 5 to + 35. Tacrolimus 0.1 mg/kg was added to this combination from day + 5 to + 180.
To prevent infections, patients received immunoglobulins 0.2 g/kg once every 4 weeks from 1 week before conditioning until the immunosuppressive drugs were stopped. Anti-microbial prophylaxis furthermore consisted of cotrimoxazole and valaciclovir, and during neutropenia, ciprofloxacin and fluconazole were given as selective digestive decontamination.
Study endpoints and statistical analysis
The primary endpoint was PFS at 1.5 years. Since haploBMT is a demanding and costly treatment for the patients, we considered the effect that has to be realized by this procedure needed to be substantial and chose for the PFS goal of 50% in 1.5 years compared to around 25% with conventional alloSCT according to historical data.
To test this hypothesis, Simon’s two-stage design was used. We hypothesized that the 1.5-year PFS will be 50% after haploBMT, while this is a maximum 25% in the hypothetical standard treatment group (conventional alloSCT according to historical data). To demonstrate this difference with a power of 80% and a type 1 error rate, alpha (one-sided) of 0.05%, 24 patients were needed. If 1 or less of the first 9 patients experienced 1.5-year PFS, the relevant predefined positive effect was considered very unlikely and the study would be stopped.
Secondary endpoints were engraftment, bone marrow reconstitution, NK cell reconstitution and repertoire, GVHD, infections, and NRM.
To ensure safety, we build in decision rules to prematurely terminate the study if the NRM at 100 days exceeded a certain percentage that was calculated beforehand based on a modification of the standard 3 + 3 scheme.
Analyses were performed as of April 2020. Pre-transplantation patient characteristics were given as median and range for continuous variables and as frequency and proportion for categorical variables. PFS was analyzed using a Kaplan-Meier estimate. For NRM, relapse, and GVHD, a competing risk framework was used. The analysis was performed with the R software.
Results and discussion
In total, 12 poor-risk patients were included from 3 hospitals in the Netherlands from April 2016 to May 2018 with a follow-up until April 2020 and the median time to follow-up is 30.2 months (range 11.8–44.9 months). Pre-transplantation patient characteristics are described in Table 1. They were all heavily pre-treated with both proteasome inhibition and immunomodulatory drugs; none of the patients received antibody treatment before inclusion. One patient had known high-risk cytogenetics and three patients showed progression within 12 months after autologous SCT. We excluded one patient for further analysis due to disease progression just before BMT, since this was a predefined exclusion criterion. This patient, however, was transplanted because pre-transplant M-protein levels became available during conditioning therapy. KIR/HLA incompatibility of the different donors is described in Table 2.Table 1 Patient characteristics
Gender, n (%)
Male 10 (91)
Female 1 (9)
Age, median in years (range) 61 (40–66)
Response to last therapy, n (%)
PR 5 (45)
VGPR 5 (45)
CR 1 (9)
Previous lines of treatment, median (range) 3 (2–7)
Previous SCT, n (%)
1x autologous 8 (73)
2x autologous 3 (27)
Allogeneic 1 (9)
Table 2 Donor and recipient HLA typing and NK mismatch
Patient NR. Patient HLA present Patient HLA absent Donor HLA present Donor HLA absent Mismatch iKIR mismatch
P1 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P2 C2 Bw4, C1 C1, C2 Bw4 C1 2DL2/2DL3
P3 Bw4, C2 C1 Bw4, C1, C2 x C1 2DL2/2DL3
P4 C1, C2 Bw4 Bw4, C2 C1 Bw4 3DL1
P5 Bw4, C1 C2 C1, C2 Bw4 C2 2DL1
P6 C1 Bw4, C2 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P7 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P8 C1, C2 Bw4 Bw4, C1, C2 X Bw4 3DL1
P9 Bw4, C2 C1 Bw4, C1, C2 X C1 2DL2/2DL3
P10 C1 C2,Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P11 C1 C2, Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P12 C1, Bw4 C2 Bw4, C1, C2 x C2 2DL1
HLA human leukocyte antigen, iKIR inhibitory killer cell immunoglobulin-like receptor
Clinical endpoints
Of the 11 evaluable patients, 10 achieved primary engraftment (91%), with a median time to neutrophil and platelet engraftment of 18 (12–30 days) and 30 (20–49 days) days, respectively. Grade 2–4 acute GVHD occurred in 2 of 11 patients (none grade 3–4) and chronic GVHD occurred in 4 of 11 patients. Two of the 11 patients died of treatment-related mortality (18%) within the first year.
Of the 9 for the primary endpoint evaluable patients, all patients relapsed within 1 year (Fig. 1a). The median time to relapse was 90 days (range 30–360 days), and 8 of 9 patients had to eventually start anti-myeloma treatment. The median time for the next treatment was 186 days (range 40–330 days); two-thirds of the patients at first only biochemically relapsed without a need for treatment. Overall survival was 73% after 1 year and 52% after 2 years (Fig. 1b).Fig. 1 Clinical outcomes after HaploBMT. a Probability of progression-free survival. b Overall survival
Noteworthy is one patient, who relapsed quickly after SCT with an increase of her involved free light chain, displayed a spontaneous decrease 60 days after BMT to pre-transplant levels (Fig. 2). During this period, no additional anti-myeloma treatment was started. Only immune-suppressive treatment with mycophenolate mofetil was stopped at day + 35, as per protocol. She did not require any treatment until 400 days after the stem cell transplantation. Interesting is also a second, heavily pre-treated patient that was already progressive at day 40 after SCT, but had a complete remission on daratumumab and has continuous bone marrow–proven remission more than 2 years after stopping this treatment.Fig. 2 Serum-free light-chain response after HaploBMT in one individual patient. Progression 30 days after transplantation and responsive thereafter without treatment
NK cell reconstruction
At day 30, all of the 8 analyzed patients showed NK cell recovery, though with an immature phenotype (NKG2A+, KIR-). At day 60 in both the peripheral blood and bone marrow, mature NK cells (KIR+) could be identified (Fig. 3a–d). We have no data on the functionality of these cells.Fig. 3 a–d Assessment of NK cell phenotype after stem cell transplantation. Mononuclear cells were isolated from peripheral blood (PBL) or bone marrow (BM). To analyze KIR expression in the donor, PBL were harvested before from the donor before transplantation. To determine NK reconstitution upon transplantation, PBL or BM cells were isolated from the patient at 30 (d30) or 60 (d60) days after transplantation. Isolated cells were stained and the percentage of CD3-CD56+ NK cells expressing KIR2DL1, KIR2DL2/3, KIR3DL1, or NKG2A was determined by flow cytometry. Patients and their donors are depicted as P1–P8 in the legend and every dot represents one data point of cells analyzed at day 30 (d30) or day 60 (d60) after transplantation
Discussion
With this study, we tested the safety and the efficacy of a KIR-mismatched haploidentical BMT in high risk MM patients. We observed that the treatment is safe since there was a high engraftment rate, low NRM (18% at 1 year), and no unexpected adverse events. In the only two other retrospective studies concerning haploSCT with PTCY in MM where there was no selection on KIR-mismatch, comparable results were seen with respect to NRM (10–21% in 1.5 to 2 years); however, they had a slightly higher PFS (17–33% in 1.5 to 2 years). In our small study, unfortunately, there is a 1.5-year PFS of 0%. This 1.5-year PFS seems lower than in conventional alloSCT studies. However, the study is underpowered to draw these conclusions, since the study was prematurely terminated due to the defined stopping rules based on a 1.5-year PFS of 50%. Furthermore, this low PFS was also not unexpected since these were heavily pre-treated patients with very high-risk chemo-resistant myelomas. Though these patients showed a biochemical relapse, many of them did not require treatment for a long time after which is very unlikely for this fast progressive patient population. Even though it is difficult to draw conclusions in such a small, heterogenous group of patients, our results show that KIR-ligand mismatch in this patient category is not only harmful but also not more effective than non-matched haploSCT or conventional alloSCT in curing MM [3, 4].
We hypothesize that the late reconstitution of functional mature NK cells is responsible for the lack of response. This has already been described in other patient groups after PTCY: within days after SCT, mature graft-derived NK cells appear, but they are rapidly eliminated by PTCY. Full reconstitution of a mature and functional NK cell population took 6 to 12 months [12]. The median time point of relapse in our patients occurred shortly after transplantation (around 3 months). We detected that 30 days after haploBMSCT, most NK cells still had an immature phenotype without KIR expression and were not able to stop disease progression at this early stage after transplantation when myeloma cell load was still low. We hypothesize that the delayed NK cell reconstitution may be overruled by the infusion of mature, functional donor NK cells shortly after PTCY administration. In myeloid malignancies, this concept has already been used and seems successful in a small group of high-risk patients [27]. In this context, it may also be helpful to bridge the time to full NK cell restoration after the SCT with additional anti-MM therapy like elotuzumab or daratumumab, or to combine these two modalities. This concept is supported by the patient that showed a long-lasting complete response after temporary treatment with daratumumab. Another option would be to improve NK cell function and thereby increase the alloreactive effect by blocking antibodies, such as monalizumab, a novel checkpoint inhibitor against NKG2a [28].
In conclusion, in this study, we show that haploidentical BMT in MM patients is safe and feasible in terms of engraftment and late NK cell reconstitution. HaploBMT in MM forms a possible platform for future immunotherapeutic strategies in which the KIR-ligand mismatch might be beneficial. Though this study is limited in patient numbers, none of the patients showed a clinically relevant increase of PFS; therefore, we conclude that in the setting of haploBMT in combination with PTCY, however, a KIR mismatch probably is not clinically relevant.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patients and their families for participating in the study.
Authorship contributions
C.E., P.B., E.M., L.W., and G.B. contributed to the conception, design, and planning of the study; C.E. and G.G. contributed to the analysis of the data; C.E., P.B., E.M., C.V., and L.W. contributed to the acquisition of the data; C.E., G.G., L.W., and G.B. contributed to the interpretation of the results; G.G. and C.E. contributed to the drafting of the manuscript; and all authors contributed to critically reviewing or revising the manuscript for important intellectual content.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
G. Bos is C.E.O. CiMaas bv, Maastricht, The Netherlands. All other authors declare that they have no conflicts of interest.
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DAY 6 TO 2 BEFORE TRANSPLANTATION.
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DrugDosageText
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CC BY
|
33112968
| 18,787,258
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2021-01
|
What was the dosage of drug 'MYCOPHENOLATE MOFETIL'?
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Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors.
Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12-30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts.Clinical Trial Registry: NCT02519114.
Introduction
In recent years, the use of haploidentical donor cells for the treatment of hematological malignancies has been increasing and has proven effective and safe, especially with the use of PTCY [1, 2]. There is limited documentation about haploSCT in MM, but small retrospective studies show this is feasible with relatively low non-relapse mortality (NRM). Results in terms of PFS are however similar to HLA-identical SCT [3–5]. HaploSCT offers an attractive opportunity to introduce natural killer (NK) cell alloreactivity based on a KIR-ligand mismatch. In myeloid malignancies, this NK alloreactivity, in the context of a T cell deplete haploSCT, leads to a decreased relapse rate and improved survival without causing GVHD [6–8]. Unlike in T cell–depleted haploSCT, the benefit of NK cell alloreactivity in T cell replete haploidentical SCT is less clear and the limited number of small-sized studies concerning this effect is not conclusive [9–12]. The differences concerning NK cell alloreactivity in these studies might be due to the disease heterogeneity of the included patients and differences in the conditioning regimen and stem cell source. Some studies point towards a better outcome when bone marrow stem cells were used compared to peripheral blood stem cells, which was shown to correlate with the T cell content of the graft that is higher in peripheral blood stem cell products [12]. This correlation is in line with reports on the inhibitory effect of T cells on the development of alloreactive NK cells [13].
There is much evidence to support the role of NK cells in fighting MM [14–17]. It has been proven that therapeutic interventions like lenalidomide and elotuzumab result in increased NK cell–mediated anti-myeloma responses [18, 19]. In preclinical studies performed by our research group, we show that NK cells are able to kill MM cells, and this killing is improved in the presence of NK alloreactivity [20, 21]. This was shown in vitro as well as in a humanized mouse model. Two small clinical studies also implicated a beneficial role for KIR-ligand mismatch in MM. In one study, the role of administration of alloreactive NK cells before autologous SCT was examined. High remission rates were observed, although they were short-lived [22]. In another study, the impact of KIR-ligand mismatch in a HLA-identical and mismatched SCT setting was investigated and showed that KIR-ligand mismatch in the graft-versus-host direction was protective for relapse [23].
The aim of this phase 2 study was to prospectively evaluate if KIR-ligand mismatched haploidentical bone marrow transplantation (BMT) with PTCY improves PFS in poor-risk MM patients.
Methods
Patients
In this prospective, single-arm, multicenter trial, we recruited poor-risk MM patients aged below 66 years with good clinical performance from hospitals in the Netherlands. Poor risk was defined as high-risk cytogenetics (del17p and/or t(4;14) and/or t(14;16)), or relapse within a year after autologous SCT, or relapse after three or more previous lines of therapy. Furthermore, patients had to be responsive to their last line of therapy, defined as at least partial response according to the International Myeloma Working Group consensus criteria [24]. Another prerequisite of enrolment was the permissiveness to NK alloreactivity and availability of a KIR-ligand mismatched haploidentical family donor. Patients were excluded if donor-specific HLA-antibodies were present.
Donor selection
All patients were transplanted with a KIR-ligand mismatched haploidentical family donor. The opportunity for KIR-ligand mismatched haploBMT was determined by Luminex sequence-specific oligonucleotide hybridization (SSO) typing for the three possible inhibitory KIR-ligands: HLA-C group 1 (ligands for KIR2DL2/3), HLA-C group 2 (ligands for KIR2DL1), and HLA-Bw4 including HLA-A harboring Bw4 motifs as ligands for KIR3DL1 (A*23, A*24, A*32).
In case of an opportunity for KIR-ligand mismatched haploBMT, a KIR-ligand mismatched haploidentical family donor was searched in the wide family tree of the patients. In case a probable KIR-ligand mismatched donor was identified by low resolution, a second blood sample was drawn from this potential donor for confirmation in high resolution, for KIR typing, by low-resolution Luminex SSO assay. Protein expression of the mismatched KIR was confirmed by immune phenotyping of the peripheral blood NK cells for KIR expression as described below.
Immune phenotyping for KIRs during donor selection and NK cell reconstitution
Peripheral blood mononuclear cells were isolated by gradient density centrifugation and stained with monoclonal antibodies with specificity for CD3 (SK7, BD), CD56 (B159, BD), NKG2A (Z199, Beckman Coulter), KIR2DL1 (143211, R&D), KIR2DL2/3/S2 (DX27, Miltenyi Biotech), or KIR3DL1 (DX9, Miltenyi Biotech) followed by acquisition of the samples on a BD FACS Canto II machine. Acquired data were analyzed using the Diva software by gating on living CD3- CD56+ lymphocytes followed by analysis of the percentage of positive cells for the individual KIRs.
Conditioning and transplant procedure
Conditioning regimen consisted of cyclophosphamide 14.5 mg/kg on day - 6 and - 5, fludarabine 30 mg/m2 from day - 6 to - 2 and 200 cGY total body irradiation at day - 1 in all but one patient that received busulfan instead of cyclophosphamide pre-transplant. Donor bone marrow cells were infused on day 0. Bone marrow cells were used in all but one patient, since they are preferred over peripheral blood stem cells because of a lower risk of acute and chronic GVHD [25, 26].
GVHD prophylaxis and supportive care
GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg at day + 3 and + 4. Mycophenolate mofetil was used from day + 5 to + 35. Tacrolimus 0.1 mg/kg was added to this combination from day + 5 to + 180.
To prevent infections, patients received immunoglobulins 0.2 g/kg once every 4 weeks from 1 week before conditioning until the immunosuppressive drugs were stopped. Anti-microbial prophylaxis furthermore consisted of cotrimoxazole and valaciclovir, and during neutropenia, ciprofloxacin and fluconazole were given as selective digestive decontamination.
Study endpoints and statistical analysis
The primary endpoint was PFS at 1.5 years. Since haploBMT is a demanding and costly treatment for the patients, we considered the effect that has to be realized by this procedure needed to be substantial and chose for the PFS goal of 50% in 1.5 years compared to around 25% with conventional alloSCT according to historical data.
To test this hypothesis, Simon’s two-stage design was used. We hypothesized that the 1.5-year PFS will be 50% after haploBMT, while this is a maximum 25% in the hypothetical standard treatment group (conventional alloSCT according to historical data). To demonstrate this difference with a power of 80% and a type 1 error rate, alpha (one-sided) of 0.05%, 24 patients were needed. If 1 or less of the first 9 patients experienced 1.5-year PFS, the relevant predefined positive effect was considered very unlikely and the study would be stopped.
Secondary endpoints were engraftment, bone marrow reconstitution, NK cell reconstitution and repertoire, GVHD, infections, and NRM.
To ensure safety, we build in decision rules to prematurely terminate the study if the NRM at 100 days exceeded a certain percentage that was calculated beforehand based on a modification of the standard 3 + 3 scheme.
Analyses were performed as of April 2020. Pre-transplantation patient characteristics were given as median and range for continuous variables and as frequency and proportion for categorical variables. PFS was analyzed using a Kaplan-Meier estimate. For NRM, relapse, and GVHD, a competing risk framework was used. The analysis was performed with the R software.
Results and discussion
In total, 12 poor-risk patients were included from 3 hospitals in the Netherlands from April 2016 to May 2018 with a follow-up until April 2020 and the median time to follow-up is 30.2 months (range 11.8–44.9 months). Pre-transplantation patient characteristics are described in Table 1. They were all heavily pre-treated with both proteasome inhibition and immunomodulatory drugs; none of the patients received antibody treatment before inclusion. One patient had known high-risk cytogenetics and three patients showed progression within 12 months after autologous SCT. We excluded one patient for further analysis due to disease progression just before BMT, since this was a predefined exclusion criterion. This patient, however, was transplanted because pre-transplant M-protein levels became available during conditioning therapy. KIR/HLA incompatibility of the different donors is described in Table 2.Table 1 Patient characteristics
Gender, n (%)
Male 10 (91)
Female 1 (9)
Age, median in years (range) 61 (40–66)
Response to last therapy, n (%)
PR 5 (45)
VGPR 5 (45)
CR 1 (9)
Previous lines of treatment, median (range) 3 (2–7)
Previous SCT, n (%)
1x autologous 8 (73)
2x autologous 3 (27)
Allogeneic 1 (9)
Table 2 Donor and recipient HLA typing and NK mismatch
Patient NR. Patient HLA present Patient HLA absent Donor HLA present Donor HLA absent Mismatch iKIR mismatch
P1 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P2 C2 Bw4, C1 C1, C2 Bw4 C1 2DL2/2DL3
P3 Bw4, C2 C1 Bw4, C1, C2 x C1 2DL2/2DL3
P4 C1, C2 Bw4 Bw4, C2 C1 Bw4 3DL1
P5 Bw4, C1 C2 C1, C2 Bw4 C2 2DL1
P6 C1 Bw4, C2 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P7 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P8 C1, C2 Bw4 Bw4, C1, C2 X Bw4 3DL1
P9 Bw4, C2 C1 Bw4, C1, C2 X C1 2DL2/2DL3
P10 C1 C2,Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P11 C1 C2, Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P12 C1, Bw4 C2 Bw4, C1, C2 x C2 2DL1
HLA human leukocyte antigen, iKIR inhibitory killer cell immunoglobulin-like receptor
Clinical endpoints
Of the 11 evaluable patients, 10 achieved primary engraftment (91%), with a median time to neutrophil and platelet engraftment of 18 (12–30 days) and 30 (20–49 days) days, respectively. Grade 2–4 acute GVHD occurred in 2 of 11 patients (none grade 3–4) and chronic GVHD occurred in 4 of 11 patients. Two of the 11 patients died of treatment-related mortality (18%) within the first year.
Of the 9 for the primary endpoint evaluable patients, all patients relapsed within 1 year (Fig. 1a). The median time to relapse was 90 days (range 30–360 days), and 8 of 9 patients had to eventually start anti-myeloma treatment. The median time for the next treatment was 186 days (range 40–330 days); two-thirds of the patients at first only biochemically relapsed without a need for treatment. Overall survival was 73% after 1 year and 52% after 2 years (Fig. 1b).Fig. 1 Clinical outcomes after HaploBMT. a Probability of progression-free survival. b Overall survival
Noteworthy is one patient, who relapsed quickly after SCT with an increase of her involved free light chain, displayed a spontaneous decrease 60 days after BMT to pre-transplant levels (Fig. 2). During this period, no additional anti-myeloma treatment was started. Only immune-suppressive treatment with mycophenolate mofetil was stopped at day + 35, as per protocol. She did not require any treatment until 400 days after the stem cell transplantation. Interesting is also a second, heavily pre-treated patient that was already progressive at day 40 after SCT, but had a complete remission on daratumumab and has continuous bone marrow–proven remission more than 2 years after stopping this treatment.Fig. 2 Serum-free light-chain response after HaploBMT in one individual patient. Progression 30 days after transplantation and responsive thereafter without treatment
NK cell reconstruction
At day 30, all of the 8 analyzed patients showed NK cell recovery, though with an immature phenotype (NKG2A+, KIR-). At day 60 in both the peripheral blood and bone marrow, mature NK cells (KIR+) could be identified (Fig. 3a–d). We have no data on the functionality of these cells.Fig. 3 a–d Assessment of NK cell phenotype after stem cell transplantation. Mononuclear cells were isolated from peripheral blood (PBL) or bone marrow (BM). To analyze KIR expression in the donor, PBL were harvested before from the donor before transplantation. To determine NK reconstitution upon transplantation, PBL or BM cells were isolated from the patient at 30 (d30) or 60 (d60) days after transplantation. Isolated cells were stained and the percentage of CD3-CD56+ NK cells expressing KIR2DL1, KIR2DL2/3, KIR3DL1, or NKG2A was determined by flow cytometry. Patients and their donors are depicted as P1–P8 in the legend and every dot represents one data point of cells analyzed at day 30 (d30) or day 60 (d60) after transplantation
Discussion
With this study, we tested the safety and the efficacy of a KIR-mismatched haploidentical BMT in high risk MM patients. We observed that the treatment is safe since there was a high engraftment rate, low NRM (18% at 1 year), and no unexpected adverse events. In the only two other retrospective studies concerning haploSCT with PTCY in MM where there was no selection on KIR-mismatch, comparable results were seen with respect to NRM (10–21% in 1.5 to 2 years); however, they had a slightly higher PFS (17–33% in 1.5 to 2 years). In our small study, unfortunately, there is a 1.5-year PFS of 0%. This 1.5-year PFS seems lower than in conventional alloSCT studies. However, the study is underpowered to draw these conclusions, since the study was prematurely terminated due to the defined stopping rules based on a 1.5-year PFS of 50%. Furthermore, this low PFS was also not unexpected since these were heavily pre-treated patients with very high-risk chemo-resistant myelomas. Though these patients showed a biochemical relapse, many of them did not require treatment for a long time after which is very unlikely for this fast progressive patient population. Even though it is difficult to draw conclusions in such a small, heterogenous group of patients, our results show that KIR-ligand mismatch in this patient category is not only harmful but also not more effective than non-matched haploSCT or conventional alloSCT in curing MM [3, 4].
We hypothesize that the late reconstitution of functional mature NK cells is responsible for the lack of response. This has already been described in other patient groups after PTCY: within days after SCT, mature graft-derived NK cells appear, but they are rapidly eliminated by PTCY. Full reconstitution of a mature and functional NK cell population took 6 to 12 months [12]. The median time point of relapse in our patients occurred shortly after transplantation (around 3 months). We detected that 30 days after haploBMSCT, most NK cells still had an immature phenotype without KIR expression and were not able to stop disease progression at this early stage after transplantation when myeloma cell load was still low. We hypothesize that the delayed NK cell reconstitution may be overruled by the infusion of mature, functional donor NK cells shortly after PTCY administration. In myeloid malignancies, this concept has already been used and seems successful in a small group of high-risk patients [27]. In this context, it may also be helpful to bridge the time to full NK cell restoration after the SCT with additional anti-MM therapy like elotuzumab or daratumumab, or to combine these two modalities. This concept is supported by the patient that showed a long-lasting complete response after temporary treatment with daratumumab. Another option would be to improve NK cell function and thereby increase the alloreactive effect by blocking antibodies, such as monalizumab, a novel checkpoint inhibitor against NKG2a [28].
In conclusion, in this study, we show that haploidentical BMT in MM patients is safe and feasible in terms of engraftment and late NK cell reconstitution. HaploBMT in MM forms a possible platform for future immunotherapeutic strategies in which the KIR-ligand mismatch might be beneficial. Though this study is limited in patient numbers, none of the patients showed a clinically relevant increase of PFS; therefore, we conclude that in the setting of haploBMT in combination with PTCY, however, a KIR mismatch probably is not clinically relevant.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patients and their families for participating in the study.
Authorship contributions
C.E., P.B., E.M., L.W., and G.B. contributed to the conception, design, and planning of the study; C.E. and G.G. contributed to the analysis of the data; C.E., P.B., E.M., C.V., and L.W. contributed to the acquisition of the data; C.E., G.G., L.W., and G.B. contributed to the interpretation of the results; G.G. and C.E. contributed to the drafting of the manuscript; and all authors contributed to critically reviewing or revising the manuscript for important intellectual content.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
G. Bos is C.E.O. CiMaas bv, Maastricht, The Netherlands. All other authors declare that they have no conflicts of interest.
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ON DAY + 5 TO + 35 POST TRANSPLANT
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DrugDosageText
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CC BY
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33112968
| 18,787,258
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2021-01
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What was the dosage of drug 'TACROLIMUS'?
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Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors.
Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12-30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts.Clinical Trial Registry: NCT02519114.
Introduction
In recent years, the use of haploidentical donor cells for the treatment of hematological malignancies has been increasing and has proven effective and safe, especially with the use of PTCY [1, 2]. There is limited documentation about haploSCT in MM, but small retrospective studies show this is feasible with relatively low non-relapse mortality (NRM). Results in terms of PFS are however similar to HLA-identical SCT [3–5]. HaploSCT offers an attractive opportunity to introduce natural killer (NK) cell alloreactivity based on a KIR-ligand mismatch. In myeloid malignancies, this NK alloreactivity, in the context of a T cell deplete haploSCT, leads to a decreased relapse rate and improved survival without causing GVHD [6–8]. Unlike in T cell–depleted haploSCT, the benefit of NK cell alloreactivity in T cell replete haploidentical SCT is less clear and the limited number of small-sized studies concerning this effect is not conclusive [9–12]. The differences concerning NK cell alloreactivity in these studies might be due to the disease heterogeneity of the included patients and differences in the conditioning regimen and stem cell source. Some studies point towards a better outcome when bone marrow stem cells were used compared to peripheral blood stem cells, which was shown to correlate with the T cell content of the graft that is higher in peripheral blood stem cell products [12]. This correlation is in line with reports on the inhibitory effect of T cells on the development of alloreactive NK cells [13].
There is much evidence to support the role of NK cells in fighting MM [14–17]. It has been proven that therapeutic interventions like lenalidomide and elotuzumab result in increased NK cell–mediated anti-myeloma responses [18, 19]. In preclinical studies performed by our research group, we show that NK cells are able to kill MM cells, and this killing is improved in the presence of NK alloreactivity [20, 21]. This was shown in vitro as well as in a humanized mouse model. Two small clinical studies also implicated a beneficial role for KIR-ligand mismatch in MM. In one study, the role of administration of alloreactive NK cells before autologous SCT was examined. High remission rates were observed, although they were short-lived [22]. In another study, the impact of KIR-ligand mismatch in a HLA-identical and mismatched SCT setting was investigated and showed that KIR-ligand mismatch in the graft-versus-host direction was protective for relapse [23].
The aim of this phase 2 study was to prospectively evaluate if KIR-ligand mismatched haploidentical bone marrow transplantation (BMT) with PTCY improves PFS in poor-risk MM patients.
Methods
Patients
In this prospective, single-arm, multicenter trial, we recruited poor-risk MM patients aged below 66 years with good clinical performance from hospitals in the Netherlands. Poor risk was defined as high-risk cytogenetics (del17p and/or t(4;14) and/or t(14;16)), or relapse within a year after autologous SCT, or relapse after three or more previous lines of therapy. Furthermore, patients had to be responsive to their last line of therapy, defined as at least partial response according to the International Myeloma Working Group consensus criteria [24]. Another prerequisite of enrolment was the permissiveness to NK alloreactivity and availability of a KIR-ligand mismatched haploidentical family donor. Patients were excluded if donor-specific HLA-antibodies were present.
Donor selection
All patients were transplanted with a KIR-ligand mismatched haploidentical family donor. The opportunity for KIR-ligand mismatched haploBMT was determined by Luminex sequence-specific oligonucleotide hybridization (SSO) typing for the three possible inhibitory KIR-ligands: HLA-C group 1 (ligands for KIR2DL2/3), HLA-C group 2 (ligands for KIR2DL1), and HLA-Bw4 including HLA-A harboring Bw4 motifs as ligands for KIR3DL1 (A*23, A*24, A*32).
In case of an opportunity for KIR-ligand mismatched haploBMT, a KIR-ligand mismatched haploidentical family donor was searched in the wide family tree of the patients. In case a probable KIR-ligand mismatched donor was identified by low resolution, a second blood sample was drawn from this potential donor for confirmation in high resolution, for KIR typing, by low-resolution Luminex SSO assay. Protein expression of the mismatched KIR was confirmed by immune phenotyping of the peripheral blood NK cells for KIR expression as described below.
Immune phenotyping for KIRs during donor selection and NK cell reconstitution
Peripheral blood mononuclear cells were isolated by gradient density centrifugation and stained with monoclonal antibodies with specificity for CD3 (SK7, BD), CD56 (B159, BD), NKG2A (Z199, Beckman Coulter), KIR2DL1 (143211, R&D), KIR2DL2/3/S2 (DX27, Miltenyi Biotech), or KIR3DL1 (DX9, Miltenyi Biotech) followed by acquisition of the samples on a BD FACS Canto II machine. Acquired data were analyzed using the Diva software by gating on living CD3- CD56+ lymphocytes followed by analysis of the percentage of positive cells for the individual KIRs.
Conditioning and transplant procedure
Conditioning regimen consisted of cyclophosphamide 14.5 mg/kg on day - 6 and - 5, fludarabine 30 mg/m2 from day - 6 to - 2 and 200 cGY total body irradiation at day - 1 in all but one patient that received busulfan instead of cyclophosphamide pre-transplant. Donor bone marrow cells were infused on day 0. Bone marrow cells were used in all but one patient, since they are preferred over peripheral blood stem cells because of a lower risk of acute and chronic GVHD [25, 26].
GVHD prophylaxis and supportive care
GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg at day + 3 and + 4. Mycophenolate mofetil was used from day + 5 to + 35. Tacrolimus 0.1 mg/kg was added to this combination from day + 5 to + 180.
To prevent infections, patients received immunoglobulins 0.2 g/kg once every 4 weeks from 1 week before conditioning until the immunosuppressive drugs were stopped. Anti-microbial prophylaxis furthermore consisted of cotrimoxazole and valaciclovir, and during neutropenia, ciprofloxacin and fluconazole were given as selective digestive decontamination.
Study endpoints and statistical analysis
The primary endpoint was PFS at 1.5 years. Since haploBMT is a demanding and costly treatment for the patients, we considered the effect that has to be realized by this procedure needed to be substantial and chose for the PFS goal of 50% in 1.5 years compared to around 25% with conventional alloSCT according to historical data.
To test this hypothesis, Simon’s two-stage design was used. We hypothesized that the 1.5-year PFS will be 50% after haploBMT, while this is a maximum 25% in the hypothetical standard treatment group (conventional alloSCT according to historical data). To demonstrate this difference with a power of 80% and a type 1 error rate, alpha (one-sided) of 0.05%, 24 patients were needed. If 1 or less of the first 9 patients experienced 1.5-year PFS, the relevant predefined positive effect was considered very unlikely and the study would be stopped.
Secondary endpoints were engraftment, bone marrow reconstitution, NK cell reconstitution and repertoire, GVHD, infections, and NRM.
To ensure safety, we build in decision rules to prematurely terminate the study if the NRM at 100 days exceeded a certain percentage that was calculated beforehand based on a modification of the standard 3 + 3 scheme.
Analyses were performed as of April 2020. Pre-transplantation patient characteristics were given as median and range for continuous variables and as frequency and proportion for categorical variables. PFS was analyzed using a Kaplan-Meier estimate. For NRM, relapse, and GVHD, a competing risk framework was used. The analysis was performed with the R software.
Results and discussion
In total, 12 poor-risk patients were included from 3 hospitals in the Netherlands from April 2016 to May 2018 with a follow-up until April 2020 and the median time to follow-up is 30.2 months (range 11.8–44.9 months). Pre-transplantation patient characteristics are described in Table 1. They were all heavily pre-treated with both proteasome inhibition and immunomodulatory drugs; none of the patients received antibody treatment before inclusion. One patient had known high-risk cytogenetics and three patients showed progression within 12 months after autologous SCT. We excluded one patient for further analysis due to disease progression just before BMT, since this was a predefined exclusion criterion. This patient, however, was transplanted because pre-transplant M-protein levels became available during conditioning therapy. KIR/HLA incompatibility of the different donors is described in Table 2.Table 1 Patient characteristics
Gender, n (%)
Male 10 (91)
Female 1 (9)
Age, median in years (range) 61 (40–66)
Response to last therapy, n (%)
PR 5 (45)
VGPR 5 (45)
CR 1 (9)
Previous lines of treatment, median (range) 3 (2–7)
Previous SCT, n (%)
1x autologous 8 (73)
2x autologous 3 (27)
Allogeneic 1 (9)
Table 2 Donor and recipient HLA typing and NK mismatch
Patient NR. Patient HLA present Patient HLA absent Donor HLA present Donor HLA absent Mismatch iKIR mismatch
P1 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P2 C2 Bw4, C1 C1, C2 Bw4 C1 2DL2/2DL3
P3 Bw4, C2 C1 Bw4, C1, C2 x C1 2DL2/2DL3
P4 C1, C2 Bw4 Bw4, C2 C1 Bw4 3DL1
P5 Bw4, C1 C2 C1, C2 Bw4 C2 2DL1
P6 C1 Bw4, C2 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P7 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P8 C1, C2 Bw4 Bw4, C1, C2 X Bw4 3DL1
P9 Bw4, C2 C1 Bw4, C1, C2 X C1 2DL2/2DL3
P10 C1 C2,Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P11 C1 C2, Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P12 C1, Bw4 C2 Bw4, C1, C2 x C2 2DL1
HLA human leukocyte antigen, iKIR inhibitory killer cell immunoglobulin-like receptor
Clinical endpoints
Of the 11 evaluable patients, 10 achieved primary engraftment (91%), with a median time to neutrophil and platelet engraftment of 18 (12–30 days) and 30 (20–49 days) days, respectively. Grade 2–4 acute GVHD occurred in 2 of 11 patients (none grade 3–4) and chronic GVHD occurred in 4 of 11 patients. Two of the 11 patients died of treatment-related mortality (18%) within the first year.
Of the 9 for the primary endpoint evaluable patients, all patients relapsed within 1 year (Fig. 1a). The median time to relapse was 90 days (range 30–360 days), and 8 of 9 patients had to eventually start anti-myeloma treatment. The median time for the next treatment was 186 days (range 40–330 days); two-thirds of the patients at first only biochemically relapsed without a need for treatment. Overall survival was 73% after 1 year and 52% after 2 years (Fig. 1b).Fig. 1 Clinical outcomes after HaploBMT. a Probability of progression-free survival. b Overall survival
Noteworthy is one patient, who relapsed quickly after SCT with an increase of her involved free light chain, displayed a spontaneous decrease 60 days after BMT to pre-transplant levels (Fig. 2). During this period, no additional anti-myeloma treatment was started. Only immune-suppressive treatment with mycophenolate mofetil was stopped at day + 35, as per protocol. She did not require any treatment until 400 days after the stem cell transplantation. Interesting is also a second, heavily pre-treated patient that was already progressive at day 40 after SCT, but had a complete remission on daratumumab and has continuous bone marrow–proven remission more than 2 years after stopping this treatment.Fig. 2 Serum-free light-chain response after HaploBMT in one individual patient. Progression 30 days after transplantation and responsive thereafter without treatment
NK cell reconstruction
At day 30, all of the 8 analyzed patients showed NK cell recovery, though with an immature phenotype (NKG2A+, KIR-). At day 60 in both the peripheral blood and bone marrow, mature NK cells (KIR+) could be identified (Fig. 3a–d). We have no data on the functionality of these cells.Fig. 3 a–d Assessment of NK cell phenotype after stem cell transplantation. Mononuclear cells were isolated from peripheral blood (PBL) or bone marrow (BM). To analyze KIR expression in the donor, PBL were harvested before from the donor before transplantation. To determine NK reconstitution upon transplantation, PBL or BM cells were isolated from the patient at 30 (d30) or 60 (d60) days after transplantation. Isolated cells were stained and the percentage of CD3-CD56+ NK cells expressing KIR2DL1, KIR2DL2/3, KIR3DL1, or NKG2A was determined by flow cytometry. Patients and their donors are depicted as P1–P8 in the legend and every dot represents one data point of cells analyzed at day 30 (d30) or day 60 (d60) after transplantation
Discussion
With this study, we tested the safety and the efficacy of a KIR-mismatched haploidentical BMT in high risk MM patients. We observed that the treatment is safe since there was a high engraftment rate, low NRM (18% at 1 year), and no unexpected adverse events. In the only two other retrospective studies concerning haploSCT with PTCY in MM where there was no selection on KIR-mismatch, comparable results were seen with respect to NRM (10–21% in 1.5 to 2 years); however, they had a slightly higher PFS (17–33% in 1.5 to 2 years). In our small study, unfortunately, there is a 1.5-year PFS of 0%. This 1.5-year PFS seems lower than in conventional alloSCT studies. However, the study is underpowered to draw these conclusions, since the study was prematurely terminated due to the defined stopping rules based on a 1.5-year PFS of 50%. Furthermore, this low PFS was also not unexpected since these were heavily pre-treated patients with very high-risk chemo-resistant myelomas. Though these patients showed a biochemical relapse, many of them did not require treatment for a long time after which is very unlikely for this fast progressive patient population. Even though it is difficult to draw conclusions in such a small, heterogenous group of patients, our results show that KIR-ligand mismatch in this patient category is not only harmful but also not more effective than non-matched haploSCT or conventional alloSCT in curing MM [3, 4].
We hypothesize that the late reconstitution of functional mature NK cells is responsible for the lack of response. This has already been described in other patient groups after PTCY: within days after SCT, mature graft-derived NK cells appear, but they are rapidly eliminated by PTCY. Full reconstitution of a mature and functional NK cell population took 6 to 12 months [12]. The median time point of relapse in our patients occurred shortly after transplantation (around 3 months). We detected that 30 days after haploBMSCT, most NK cells still had an immature phenotype without KIR expression and were not able to stop disease progression at this early stage after transplantation when myeloma cell load was still low. We hypothesize that the delayed NK cell reconstitution may be overruled by the infusion of mature, functional donor NK cells shortly after PTCY administration. In myeloid malignancies, this concept has already been used and seems successful in a small group of high-risk patients [27]. In this context, it may also be helpful to bridge the time to full NK cell restoration after the SCT with additional anti-MM therapy like elotuzumab or daratumumab, or to combine these two modalities. This concept is supported by the patient that showed a long-lasting complete response after temporary treatment with daratumumab. Another option would be to improve NK cell function and thereby increase the alloreactive effect by blocking antibodies, such as monalizumab, a novel checkpoint inhibitor against NKG2a [28].
In conclusion, in this study, we show that haploidentical BMT in MM patients is safe and feasible in terms of engraftment and late NK cell reconstitution. HaploBMT in MM forms a possible platform for future immunotherapeutic strategies in which the KIR-ligand mismatch might be beneficial. Though this study is limited in patient numbers, none of the patients showed a clinically relevant increase of PFS; therefore, we conclude that in the setting of haploBMT in combination with PTCY, however, a KIR mismatch probably is not clinically relevant.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patients and their families for participating in the study.
Authorship contributions
C.E., P.B., E.M., L.W., and G.B. contributed to the conception, design, and planning of the study; C.E. and G.G. contributed to the analysis of the data; C.E., P.B., E.M., C.V., and L.W. contributed to the acquisition of the data; C.E., G.G., L.W., and G.B. contributed to the interpretation of the results; G.G. and C.E. contributed to the drafting of the manuscript; and all authors contributed to critically reviewing or revising the manuscript for important intellectual content.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
G. Bos is C.E.O. CiMaas bv, Maastricht, The Netherlands. All other authors declare that they have no conflicts of interest.
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ON DAY + 5 TO + 180 POST TRANSPLANT.
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DrugDosageText
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CC BY
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33112968
| 18,787,258
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2021-01
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What was the outcome of reaction 'Death'?
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Haploidentical transplantation in patients with multiple myeloma making use of natural killer cell alloreactive donors.
Disease relapse is an important problem after allogeneic stem cell transplantations in multiple myeloma (MM). To test the hypothesis that natural killer (NK) cell alloreactivity in the setting of a haploidentical stem cell transplantation (haploSCT) can reduce the risk of myeloma relapse, we performed a small prospective phase 2 study in which we transplanted poor-risk MM patients using a killer cell immunoglobulin-like receptor (KIR)-ligand mismatched haploidentical donor. Patients received bone marrow grafts after reduced-intensity conditioning, with post-transplantation cyclophosphamide (PTCY) graft-versus-host-disease (GVHD) prophylaxis. The primary endpoint was 1.5-year progression-free survival (PFS); stopping rules were installed in case interim results made a benefit of 50% PFS at 1.5 years unlikely. After inclusion of 12 patients, of which 9 were evaluable for the primary endpoint, all patients relapsed within a median time of 90 days. All except 1 patient showed engraftment, with a median time to neutrophil recovery of 18 (12-30) days. The study was prematurely terminated based on the predefined stopping rules after the inclusion of 12 patients. With this small study, we show that in chemo-resistant myeloma patients, NK cell KIR-mismatch is not superior to conventional alloSCT. This strategy, however, can serve as a platform for new treatment concepts.Clinical Trial Registry: NCT02519114.
Introduction
In recent years, the use of haploidentical donor cells for the treatment of hematological malignancies has been increasing and has proven effective and safe, especially with the use of PTCY [1, 2]. There is limited documentation about haploSCT in MM, but small retrospective studies show this is feasible with relatively low non-relapse mortality (NRM). Results in terms of PFS are however similar to HLA-identical SCT [3–5]. HaploSCT offers an attractive opportunity to introduce natural killer (NK) cell alloreactivity based on a KIR-ligand mismatch. In myeloid malignancies, this NK alloreactivity, in the context of a T cell deplete haploSCT, leads to a decreased relapse rate and improved survival without causing GVHD [6–8]. Unlike in T cell–depleted haploSCT, the benefit of NK cell alloreactivity in T cell replete haploidentical SCT is less clear and the limited number of small-sized studies concerning this effect is not conclusive [9–12]. The differences concerning NK cell alloreactivity in these studies might be due to the disease heterogeneity of the included patients and differences in the conditioning regimen and stem cell source. Some studies point towards a better outcome when bone marrow stem cells were used compared to peripheral blood stem cells, which was shown to correlate with the T cell content of the graft that is higher in peripheral blood stem cell products [12]. This correlation is in line with reports on the inhibitory effect of T cells on the development of alloreactive NK cells [13].
There is much evidence to support the role of NK cells in fighting MM [14–17]. It has been proven that therapeutic interventions like lenalidomide and elotuzumab result in increased NK cell–mediated anti-myeloma responses [18, 19]. In preclinical studies performed by our research group, we show that NK cells are able to kill MM cells, and this killing is improved in the presence of NK alloreactivity [20, 21]. This was shown in vitro as well as in a humanized mouse model. Two small clinical studies also implicated a beneficial role for KIR-ligand mismatch in MM. In one study, the role of administration of alloreactive NK cells before autologous SCT was examined. High remission rates were observed, although they were short-lived [22]. In another study, the impact of KIR-ligand mismatch in a HLA-identical and mismatched SCT setting was investigated and showed that KIR-ligand mismatch in the graft-versus-host direction was protective for relapse [23].
The aim of this phase 2 study was to prospectively evaluate if KIR-ligand mismatched haploidentical bone marrow transplantation (BMT) with PTCY improves PFS in poor-risk MM patients.
Methods
Patients
In this prospective, single-arm, multicenter trial, we recruited poor-risk MM patients aged below 66 years with good clinical performance from hospitals in the Netherlands. Poor risk was defined as high-risk cytogenetics (del17p and/or t(4;14) and/or t(14;16)), or relapse within a year after autologous SCT, or relapse after three or more previous lines of therapy. Furthermore, patients had to be responsive to their last line of therapy, defined as at least partial response according to the International Myeloma Working Group consensus criteria [24]. Another prerequisite of enrolment was the permissiveness to NK alloreactivity and availability of a KIR-ligand mismatched haploidentical family donor. Patients were excluded if donor-specific HLA-antibodies were present.
Donor selection
All patients were transplanted with a KIR-ligand mismatched haploidentical family donor. The opportunity for KIR-ligand mismatched haploBMT was determined by Luminex sequence-specific oligonucleotide hybridization (SSO) typing for the three possible inhibitory KIR-ligands: HLA-C group 1 (ligands for KIR2DL2/3), HLA-C group 2 (ligands for KIR2DL1), and HLA-Bw4 including HLA-A harboring Bw4 motifs as ligands for KIR3DL1 (A*23, A*24, A*32).
In case of an opportunity for KIR-ligand mismatched haploBMT, a KIR-ligand mismatched haploidentical family donor was searched in the wide family tree of the patients. In case a probable KIR-ligand mismatched donor was identified by low resolution, a second blood sample was drawn from this potential donor for confirmation in high resolution, for KIR typing, by low-resolution Luminex SSO assay. Protein expression of the mismatched KIR was confirmed by immune phenotyping of the peripheral blood NK cells for KIR expression as described below.
Immune phenotyping for KIRs during donor selection and NK cell reconstitution
Peripheral blood mononuclear cells were isolated by gradient density centrifugation and stained with monoclonal antibodies with specificity for CD3 (SK7, BD), CD56 (B159, BD), NKG2A (Z199, Beckman Coulter), KIR2DL1 (143211, R&D), KIR2DL2/3/S2 (DX27, Miltenyi Biotech), or KIR3DL1 (DX9, Miltenyi Biotech) followed by acquisition of the samples on a BD FACS Canto II machine. Acquired data were analyzed using the Diva software by gating on living CD3- CD56+ lymphocytes followed by analysis of the percentage of positive cells for the individual KIRs.
Conditioning and transplant procedure
Conditioning regimen consisted of cyclophosphamide 14.5 mg/kg on day - 6 and - 5, fludarabine 30 mg/m2 from day - 6 to - 2 and 200 cGY total body irradiation at day - 1 in all but one patient that received busulfan instead of cyclophosphamide pre-transplant. Donor bone marrow cells were infused on day 0. Bone marrow cells were used in all but one patient, since they are preferred over peripheral blood stem cells because of a lower risk of acute and chronic GVHD [25, 26].
GVHD prophylaxis and supportive care
GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg at day + 3 and + 4. Mycophenolate mofetil was used from day + 5 to + 35. Tacrolimus 0.1 mg/kg was added to this combination from day + 5 to + 180.
To prevent infections, patients received immunoglobulins 0.2 g/kg once every 4 weeks from 1 week before conditioning until the immunosuppressive drugs were stopped. Anti-microbial prophylaxis furthermore consisted of cotrimoxazole and valaciclovir, and during neutropenia, ciprofloxacin and fluconazole were given as selective digestive decontamination.
Study endpoints and statistical analysis
The primary endpoint was PFS at 1.5 years. Since haploBMT is a demanding and costly treatment for the patients, we considered the effect that has to be realized by this procedure needed to be substantial and chose for the PFS goal of 50% in 1.5 years compared to around 25% with conventional alloSCT according to historical data.
To test this hypothesis, Simon’s two-stage design was used. We hypothesized that the 1.5-year PFS will be 50% after haploBMT, while this is a maximum 25% in the hypothetical standard treatment group (conventional alloSCT according to historical data). To demonstrate this difference with a power of 80% and a type 1 error rate, alpha (one-sided) of 0.05%, 24 patients were needed. If 1 or less of the first 9 patients experienced 1.5-year PFS, the relevant predefined positive effect was considered very unlikely and the study would be stopped.
Secondary endpoints were engraftment, bone marrow reconstitution, NK cell reconstitution and repertoire, GVHD, infections, and NRM.
To ensure safety, we build in decision rules to prematurely terminate the study if the NRM at 100 days exceeded a certain percentage that was calculated beforehand based on a modification of the standard 3 + 3 scheme.
Analyses were performed as of April 2020. Pre-transplantation patient characteristics were given as median and range for continuous variables and as frequency and proportion for categorical variables. PFS was analyzed using a Kaplan-Meier estimate. For NRM, relapse, and GVHD, a competing risk framework was used. The analysis was performed with the R software.
Results and discussion
In total, 12 poor-risk patients were included from 3 hospitals in the Netherlands from April 2016 to May 2018 with a follow-up until April 2020 and the median time to follow-up is 30.2 months (range 11.8–44.9 months). Pre-transplantation patient characteristics are described in Table 1. They were all heavily pre-treated with both proteasome inhibition and immunomodulatory drugs; none of the patients received antibody treatment before inclusion. One patient had known high-risk cytogenetics and three patients showed progression within 12 months after autologous SCT. We excluded one patient for further analysis due to disease progression just before BMT, since this was a predefined exclusion criterion. This patient, however, was transplanted because pre-transplant M-protein levels became available during conditioning therapy. KIR/HLA incompatibility of the different donors is described in Table 2.Table 1 Patient characteristics
Gender, n (%)
Male 10 (91)
Female 1 (9)
Age, median in years (range) 61 (40–66)
Response to last therapy, n (%)
PR 5 (45)
VGPR 5 (45)
CR 1 (9)
Previous lines of treatment, median (range) 3 (2–7)
Previous SCT, n (%)
1x autologous 8 (73)
2x autologous 3 (27)
Allogeneic 1 (9)
Table 2 Donor and recipient HLA typing and NK mismatch
Patient NR. Patient HLA present Patient HLA absent Donor HLA present Donor HLA absent Mismatch iKIR mismatch
P1 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P2 C2 Bw4, C1 C1, C2 Bw4 C1 2DL2/2DL3
P3 Bw4, C2 C1 Bw4, C1, C2 x C1 2DL2/2DL3
P4 C1, C2 Bw4 Bw4, C2 C1 Bw4 3DL1
P5 Bw4, C1 C2 C1, C2 Bw4 C2 2DL1
P6 C1 Bw4, C2 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P7 Bw4, C1 C2 Bw4, C1, C2 X C2 2DL1
P8 C1, C2 Bw4 Bw4, C1, C2 X Bw4 3DL1
P9 Bw4, C2 C1 Bw4, C1, C2 X C1 2DL2/2DL3
P10 C1 C2,Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P11 C1 C2, Bw4 Bw4, C1, C2 X C2, Bw4 2DL1/3DL1
P12 C1, Bw4 C2 Bw4, C1, C2 x C2 2DL1
HLA human leukocyte antigen, iKIR inhibitory killer cell immunoglobulin-like receptor
Clinical endpoints
Of the 11 evaluable patients, 10 achieved primary engraftment (91%), with a median time to neutrophil and platelet engraftment of 18 (12–30 days) and 30 (20–49 days) days, respectively. Grade 2–4 acute GVHD occurred in 2 of 11 patients (none grade 3–4) and chronic GVHD occurred in 4 of 11 patients. Two of the 11 patients died of treatment-related mortality (18%) within the first year.
Of the 9 for the primary endpoint evaluable patients, all patients relapsed within 1 year (Fig. 1a). The median time to relapse was 90 days (range 30–360 days), and 8 of 9 patients had to eventually start anti-myeloma treatment. The median time for the next treatment was 186 days (range 40–330 days); two-thirds of the patients at first only biochemically relapsed without a need for treatment. Overall survival was 73% after 1 year and 52% after 2 years (Fig. 1b).Fig. 1 Clinical outcomes after HaploBMT. a Probability of progression-free survival. b Overall survival
Noteworthy is one patient, who relapsed quickly after SCT with an increase of her involved free light chain, displayed a spontaneous decrease 60 days after BMT to pre-transplant levels (Fig. 2). During this period, no additional anti-myeloma treatment was started. Only immune-suppressive treatment with mycophenolate mofetil was stopped at day + 35, as per protocol. She did not require any treatment until 400 days after the stem cell transplantation. Interesting is also a second, heavily pre-treated patient that was already progressive at day 40 after SCT, but had a complete remission on daratumumab and has continuous bone marrow–proven remission more than 2 years after stopping this treatment.Fig. 2 Serum-free light-chain response after HaploBMT in one individual patient. Progression 30 days after transplantation and responsive thereafter without treatment
NK cell reconstruction
At day 30, all of the 8 analyzed patients showed NK cell recovery, though with an immature phenotype (NKG2A+, KIR-). At day 60 in both the peripheral blood and bone marrow, mature NK cells (KIR+) could be identified (Fig. 3a–d). We have no data on the functionality of these cells.Fig. 3 a–d Assessment of NK cell phenotype after stem cell transplantation. Mononuclear cells were isolated from peripheral blood (PBL) or bone marrow (BM). To analyze KIR expression in the donor, PBL were harvested before from the donor before transplantation. To determine NK reconstitution upon transplantation, PBL or BM cells were isolated from the patient at 30 (d30) or 60 (d60) days after transplantation. Isolated cells were stained and the percentage of CD3-CD56+ NK cells expressing KIR2DL1, KIR2DL2/3, KIR3DL1, or NKG2A was determined by flow cytometry. Patients and their donors are depicted as P1–P8 in the legend and every dot represents one data point of cells analyzed at day 30 (d30) or day 60 (d60) after transplantation
Discussion
With this study, we tested the safety and the efficacy of a KIR-mismatched haploidentical BMT in high risk MM patients. We observed that the treatment is safe since there was a high engraftment rate, low NRM (18% at 1 year), and no unexpected adverse events. In the only two other retrospective studies concerning haploSCT with PTCY in MM where there was no selection on KIR-mismatch, comparable results were seen with respect to NRM (10–21% in 1.5 to 2 years); however, they had a slightly higher PFS (17–33% in 1.5 to 2 years). In our small study, unfortunately, there is a 1.5-year PFS of 0%. This 1.5-year PFS seems lower than in conventional alloSCT studies. However, the study is underpowered to draw these conclusions, since the study was prematurely terminated due to the defined stopping rules based on a 1.5-year PFS of 50%. Furthermore, this low PFS was also not unexpected since these were heavily pre-treated patients with very high-risk chemo-resistant myelomas. Though these patients showed a biochemical relapse, many of them did not require treatment for a long time after which is very unlikely for this fast progressive patient population. Even though it is difficult to draw conclusions in such a small, heterogenous group of patients, our results show that KIR-ligand mismatch in this patient category is not only harmful but also not more effective than non-matched haploSCT or conventional alloSCT in curing MM [3, 4].
We hypothesize that the late reconstitution of functional mature NK cells is responsible for the lack of response. This has already been described in other patient groups after PTCY: within days after SCT, mature graft-derived NK cells appear, but they are rapidly eliminated by PTCY. Full reconstitution of a mature and functional NK cell population took 6 to 12 months [12]. The median time point of relapse in our patients occurred shortly after transplantation (around 3 months). We detected that 30 days after haploBMSCT, most NK cells still had an immature phenotype without KIR expression and were not able to stop disease progression at this early stage after transplantation when myeloma cell load was still low. We hypothesize that the delayed NK cell reconstitution may be overruled by the infusion of mature, functional donor NK cells shortly after PTCY administration. In myeloid malignancies, this concept has already been used and seems successful in a small group of high-risk patients [27]. In this context, it may also be helpful to bridge the time to full NK cell restoration after the SCT with additional anti-MM therapy like elotuzumab or daratumumab, or to combine these two modalities. This concept is supported by the patient that showed a long-lasting complete response after temporary treatment with daratumumab. Another option would be to improve NK cell function and thereby increase the alloreactive effect by blocking antibodies, such as monalizumab, a novel checkpoint inhibitor against NKG2a [28].
In conclusion, in this study, we show that haploidentical BMT in MM patients is safe and feasible in terms of engraftment and late NK cell reconstitution. HaploBMT in MM forms a possible platform for future immunotherapeutic strategies in which the KIR-ligand mismatch might be beneficial. Though this study is limited in patient numbers, none of the patients showed a clinically relevant increase of PFS; therefore, we conclude that in the setting of haploBMT in combination with PTCY, however, a KIR mismatch probably is not clinically relevant.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The authors thank the patients and their families for participating in the study.
Authorship contributions
C.E., P.B., E.M., L.W., and G.B. contributed to the conception, design, and planning of the study; C.E. and G.G. contributed to the analysis of the data; C.E., P.B., E.M., C.V., and L.W. contributed to the acquisition of the data; C.E., G.G., L.W., and G.B. contributed to the interpretation of the results; G.G. and C.E. contributed to the drafting of the manuscript; and all authors contributed to critically reviewing or revising the manuscript for important intellectual content.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
G. Bos is C.E.O. CiMaas bv, Maastricht, The Netherlands. All other authors declare that they have no conflicts of interest.
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Fatal
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ReactionOutcome
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CC BY
|
33112968
| 18,787,258
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atonic seizures'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
CLOBAZAM, LAMOTRIGINE, LEVETIRACETAM, PRIMIDONE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epilepsy'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
RUFINAMIDE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,373,247
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Generalised tonic-clonic seizure'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
CLOBAZAM, LAMOTRIGINE, LEVETIRACETAM, PRIMIDONE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple-drug resistance'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
CLOBAZAM, LAMOTRIGINE, LEVETIRACETAM, PRIMIDONE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Petit mal epilepsy'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
CLOBAZAM, LAMOTRIGINE, LEVETIRACETAM, PRIMIDONE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
CLOBAZAM, LAMOTRIGINE, LEVETIRACETAM, PRIMIDONE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sedation'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
CLOBAZAM, LAMOTRIGINE, LEVETIRACETAM, PRIMIDONE, RUFINAMIDE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,783,468
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tonic convulsion'.
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
CLOBAZAM, LAMOTRIGINE, LEVETIRACETAM, PRIMIDONE
|
DrugsGivenReaction
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
What was the administration route of drug 'RUFINAMIDE'?
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC
|
33113098
| 19,373,247
|
2021-06
|
What was the outcome of reaction 'Atonic seizures'?
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
Recovering
|
ReactionOutcome
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
What was the outcome of reaction 'Generalised tonic-clonic seizure'?
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
Recovering
|
ReactionOutcome
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
What was the outcome of reaction 'Petit mal epilepsy'?
|
Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
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Recovering
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ReactionOutcome
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CC BY-NC
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33113098
| 19,651,858
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2021-06
|
What was the outcome of reaction 'Tonic convulsion'?
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Lennox-Gastaut Syndrome: Perspective of a Parent and a Physician.
This article is co-authored by a parent of a 32-year-old male patient with Lennox-Gastaut syndrome (LGS) and his epileptologist. It discusses the parent's experience of having a child with LGS from diagnosis through living day-to-day with the disease and the physician's perspective when treating this devastating epilepsy syndrome. The patient's mother, who is his legal representative, provided written consent for publication of this article.
Key Summary Points
Lennox–Gastaut syndrome is a devastating epilepsy syndrome which is characteristically refractory to antiseizure medications.
Despite drug resistance, antiseizure medications are the mainstay of treatment.
The study looks at the perspective of a parent and a physician regarding treatment of this syndrome.
Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13079411.
Patient’s Story From His Mother’s Perspective
I never thought I would feel relief when my son was given the diagnosis of Lennox–Gastaut syndrome. After many years of seizures, tests, medication trials and changes, and suggestions of very invasive surgeries, we finally received a definitive diagnosis that I could wrap my mind around. I knew what we were facing and we would handle it as we had handled the previous health issues my son had been dealing with since birth.
Initially we had assumed that the seizures started due to brain damage from his preterm birth. My son was 19 months old when his seizures began, and it was not until he was 10 years old that we got the diagnosis that gave us a sense of direction. We knew that, by definition, his seizures would be forever changing and very hard to control; but it is easier when you know what you are facing. For years, we kept records of each seizure as well as how often they were, how long they lasted, and what precipitated them. We did not do that any longer. It sounds weird but we were able to relax for a minute.
I never opted for surgical intervention as a form of seizure control. My son had and still has many other underlying serious medical conditions that took precedence over his seizures. Throughout his early years, he was off and on a ventilator for severe lung damage from birth. He was essentially fighting to breathe every day of his life and just to remain healthy. We did not enroll in any drug trials and, unfortunately, there were not a whole lot of new medications coming out for Lennox–Gastaut when he was young. He did receive some physical therapy for his delays over the years that would be interrupted from time to time by a seizure or an illness.
Over the years, my son has been on almost every anti-epileptic medication on the market. Some of the older medications caused adverse side effects, such as extreme drowsiness, weight loss, and agitation. Each medication was increased every 3 to 6 months with no real positive effect on seizure control for a prolonged amount of time. They all required frequent blood work to monitor the drug levels versus the effectiveness and were eventually stopped as he was started on a new medication.
As he got older, some newer medications did help with different aspects. One made his personality come out more and made him more alert with less side effects. Another controlled a different type of seizure. Another was added to stop a movement disorder that he developed in addition to his seizures. However, none of them controlled his seizures completely; yet we did not let that stop our lives. We still played, we still attended family functions, we still attempted to participate in life as much as we could, and we still do.
After 30 years of fighting this “syndrome”, this thing that we could not control or predict, we have come as close as we have ever been to stopping it. To not seeing it every day. To being able to focus solely on our daily life without any interruptions. To not have to worry that even in the middle of the night a horrible seizure can come out of the blue and disrupt a good night’s sleep. We have gone from almost one hundred seizures per day down to about two per month. I never thought that we would see this day. To say that two seizures per month was a good thing would have been unthinkable to us 30 years ago without the awareness brought to Lennox–Gastaut syndrome and the dedication of the researchers and neurologists from around the world. Moreover, for that… we are forever grateful.
Physician’s Perspective
Lennox–Gastaut syndrome (LGS) is a form of encephalopathic generalized epilepsy (EGE) and is a devastating epilepsy syndrome that typically begins within the second and sixth year of life. It is characteristically refractory to antiseizure drugs (ASDs). The diagnostic clinical triad of LGS is (1) multiple mixed seizure types, including tonic, atonic, and atypical absence with high seizure frequency, and often with status epilepticus, (2) impaired intellectual function or behavior disturbance, (3) abnormal EEG background with diffuse slow activity and characteristic epileptiform discharges described as slow spike-and-wave discharges while awake [1]. LGS accounts for approximately 1–4% of all childhood epilepsies [2, 3]. EGE represents approximately 11.6% of all childhood epilepsies [4].
Treatment for LGS includes efforts to manage the underlying cause of their associated cognitive and behavioral dysfunction, attempting to control seizures, and providing support for the patient’s family or caretaker [1]. Despite characteristic drug resistance, ASD therapy is the primary treatment. It is a challenge to optimize seizure control and medication side effects, while maintaining a favorable quality of life. The multiple seizure types in LGS often require broad-spectrum ASDs and combination therapies. Certain medications have proven higher utility in LGS, including valproic acid, lamotrigine, and topiramate [5–7]. Felbamate is effective in seizure reduction and neurocognitive profile but is limited by serious side effects of hepatic failure and aplastic anemia [8]. Clobazam and rufinamide are also approved for LGS, and other ASDs have been reported to have possible benefit but without consistent efficacy, such as levetiracetam, zonisamide, and clonazepam [1, 9, 10]. Oral purified cannabidiol (Epidiolex), the natural cannabidiol from the marijuana plant, is an oral solution that was approved by the US Food and Drug Administration (FDA) for use in LGS in June 2018 and has shown significant effectiveness in clinical trials for refractory seizures [11–14] and for improvement in global functioning of these patients [15–18]. This was also the case for my patient.
My patient has static encephalopathy and spastic quadriplegia with diffuse cerebral volume loss. He was born by cesarean section at 28 weeks and was ventilator dependent. He has been severely delayed since birth, which worsened when his seizures started at 19 months old. His seizure history includes at least four seizure types: type 1, staring blankly then smiles and may drool; type 2, tonic; type 3, generalized tonic–clonic (GTC); type 4, atonic with fall. He had been on lamotrigine and levetiracetam for many years with effectiveness but continued to have daily to weekly seizures with frequent seizure clusters. His current doses are lamotrigine 150 mg three times daily and levetiracetam 1000 mg three times daily and he could not tolerate higher doses. Past medication included phenobarbital, valproic acid, phenytoin, carbamazepine, and topiramate, all of which did not produce significant seizure control or caused side effects.
His mother reports him having a decline in functioning at around 10 years of age. Prior to that he was pulling up and was taking a bottle himself, but after the decline he never walked or talked; a feeding tube was placed for nutritional supplementation and a tracheostomy was placed as a result of repeated aspiration. At that time, he was initiated on primidone for abnormal movements and had remained on a dose of 100 mg three times daily. It was reported that his seizure frequency on lamotrigine, levetiracetam, and primidone was daily of type 1 and weekly seizures of type 2, 3, and 4. He was initiated on rufinamide in the fall of 2010 and titrated according to response to 600 mg twice daily. As a result, his atonic seizures (type 4) resolved completely. Higher doses of rufinamide resulted in increased seizures. A vagus nerve stimulator was considered but felt to be too risky with his respiratory status. There was a lapse in care for several years and he returned to the epilepsy specialist clinic in 2018 following the approval of cannabidiol. At that point, he initially tried clobazam, but had sedation and no reduction in seizures. He was initiated on orally administered cannabidiol in January 2019. Within the first month of treatment on 2.5 mg/kg/dose twice daily his type 1 seizures had resolved, type 2 seizures were reported to be less severe and shorter in duration, and there were no type 3 seizures. His mother reported that he was more awake and alert and was doing more activity. She reported that he was “like he used to be”. He started sleeping through the night and holding himself up better. It also improved his bowel motility. Since that time, his response to titration of cannabidiol has continued to reduce his seizure frequency and improve his functioning. His primary seizure that has remained refractory is type 3, his GTC. His main precipitant is having a bowel movement and stress. These seizures continue to occur approximately two times per month and dosing titration has and will continue, to obtain maximal benefit.
When deciding on medication therapy for this patient, several issues were considered. First and foremost, it is critical to understand and confirm the diagnosis. For this patient, it is unclear why the diagnosis was not confirmed until he was 10 years old, but it seems that this timeframe related to his significant functional decline. Secondly, patient characteristics must be considered to tailor a medication choice. Medications can carry risks to organ systems and to quality of life. For my patient, his mother reports that it took years to make a diagnosis of Lennox–Gastaut and, therefore, treatments tried prior to this had the risk of being suboptimal. Additionally, with LGS the treatment options available are generally ineffective and refractory. As his mother stated, he tried many antiseizure medications and yet remained with excessive seizures. Over the years, certain treatments were found that were both more effective and more tolerable for this patient. With the approval of orally administered cannabidiol, the patient has been able to add its unique mechanism of action to his medication regimen and his seizure frequency has reduced substantially, down to approximately two per month.
To get my patient to a seizure frequency where he is today has not been an easy feat. It often takes trial and error of medications and dosing to obtain success with medications and this is particularly true for devastating epilepsy syndromes. Effective communication with the patient’s response and the caretaker’s input is invaluable to obtain an optimal treatment regimen for a particular patient. I am thankful that my patient has achieved a significant reduction in seizures from baseline and that his care can focus on other aspects of his health. Success with medicine can be achieved, even with refractory epilepsy syndromes, and will continue to be optimized as more focused research and targeted treatments are developed. I look forward to the opportunity to see this progress unfold.
Acknowledgements
Thank you to the participants of this study, both the patient and his mother.
Funding
No funding or sponsorship was received for this study or publication of this article.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
The patient, his mother Barbara Glasgow, and Dr. Heather Ravvin McKee have nothing to disclose.
Compliance with Ethics Guidelines
The patient’s mother, who is his legal representative, provided written consent for publication of this article. This article does not contain any new studies with human or animal subjects performed by any of the authors.
|
Recovering
|
ReactionOutcome
|
CC BY-NC
|
33113098
| 19,651,858
|
2021-06
|
What was the administration route of drug 'PERAMIVIR'?
|
Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.
Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.
Introduction
Bone marrow necrosis (BMN) is an extremely infrequent phenomenon, defined as necrosis of the myeloid tissue and medullary stroma. The prevalence of BMN was reported to be between 0.3% and 2% antemortem of patients eligible for bone marrow examination, and BMN is often detected on autopsy (1,2). The causes of BMN have been identified, including hematological malignancies, solid tumors, infectious disease, chemical exposure, radiation, sickle cell disease, antiphospholipid syndrome, and disseminated intravascular coagulation (2-13). Moreover, acute lymphoblastic leukemia (ALL) accompanied by BMN has been reported to have a poor prognosis (14). The main clinical symptoms of BMN are fever and bone pain. Laboratory findings, such as severe pancytopenia and elevated levels of lactate dehydrogenase (LDH) are generally indicative of BMN (1,2). However, these features can be absent in some cases (15). Magnetic resonance imaging (MRI) findings can be helpful but are nonspecific in the evaluation of bone marrow disorders (16). The morphological assessment of bone marrow aspirate and the pathological findings of bone marrow biopsy (BMB) specimens are most essential for the diagnosis of BMN. Many hematologists report difficulty in assessing the disease status of hematological malignancies by bone marrow aspiration (BMA) because they cannot obtain appropriate samples in cases of extensive BMN and ‘dry tap’, defined as failure to obtain bone marrow on attempted marrow aspiration (6). We herein report a case in which an appropriate disease evaluation was performed using bone marrow aspirate obtained from the sternum of a patient with recurrent ALL accompanied by BMN after re-induction therapy. The MRI features of BMN are also taken into consideration.
Case Report
A 52-year-old male patient received cord blood transplantation for Philadelphia chromosome-positive ALL without T315I mutation. One year later, he was diagnosed with recurrent ALL accompanied by severe bone pain. He was transferred to our institution for re-induction therapy. A BMA specimen could not be obtained due to ‘dry tap’; however, BMB showed numerous blast cells before re-induction therapy, as shown in Fig. 1a. On hospital admission, he had high-grade fever, and a blood culture test was negative; however, a rapid diagnostic test for influenza virus using a nasopharyngeal swab specimen was positive for influenza A. Thus, the patient was treated with mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy and intravenous peramivir (300 mg, once daily). His high-grade fever temporarily improved after treatment; however, his severe fever symptom was exacerbated again on day 16 of MEC therapy. At the time, Aspergillus fumigatus invasion was detected and intravenous voriconazole (VRCZ) was initiated (Fig. 2). His high-grade fever did not improve, despite the antifungal treatment, even after almost recovering from pancytopenia during the nadir period (white blood cell count, 6.8×103/μL with 0% blast cells; hemoglobin, 8.7 g/dL; and platelet count, 14.8×103/μL).
Figure 1. Pathological findings of bone marrow biopsy (BMB) and bone marrow aspiration (BMA). (a) Pathological findings of BMB on admission. Hematoxylin and Eosin (H&E) staining (×400). (b) Pathological findings of BMA on day 28 of mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy. May-Giemsa staining (×400). (c) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×200). (d) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×400).
Figure 2. The clinical course. BMA: bone marrow aspiration, BMB: bone marrow biopsy, CPFG: caspofungin, L-AMB: liposomal amphotericin B, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MEPM: meropenem, MRI: magnetic resonance imaging, PIPC/TAZ: piperacillin/tazobactam, TEIC: teicoplanin, VRCZ: voriconazole, WBC: white blood cell
To estimate the disease status, a BMA test was performed from the right iliac bone on day 28 of MEC therapy, but we only obtained a muddy and jelly-like specimen. When this sample was centrifuged, a cloudy pink precipitate was obtained (Fig. 3). A BMA smear from the specimen showed irregular and indistinct margins, and the cytoplasm appeared fused, as shown in Fig. 1b. In addition, a peripheral blood analysis revealed a high LDH level of 551 IU/L. Subsequently, both BMA and BMB tests were performed from the left iliac bone on day 35 of MEC therapy. We could not obtain sufficient BMA specimens because of ‘dry tap’ aspiration. The findings of the BMB tests showed that most of the bone marrow space was replaced by eosinophilic debris. Although a very small number of blast cells remained, an accurate evaluation was difficult, as shown in Fig. 1c, d. We switched the antifungal agent from VRCZ to liposomal amphotericin B (L-AMB; 3 mg/kg, daily) on day 35 of MEC therapy because his high-grade fever had not improved. On day 45 of MEC therapy, the patient's lower back and lower limb pain gradually worsened. MRI showed heterogeneous patchy areas of high signal intensity at the right iliac bone and sacrum on T1-weighted and T2-weighted imaging. In contrast, MRI showed heterogeneous patchy areas of signal intensity at the left iliac bone on T1-weighted and T2-weighted imaging. In addition, high short T1 inversion recovery imaging of both the bilateral iliac bone and sacrum showed partially high signal intensity, as shown in Fig. 4. These findings appeared to reflect a bone marrow abnormality, including BMN, however a further qualitative evaluation was difficult. On day 50 of MEC therapy, his bone pain drastically deteriorated. On day 51 of MEC therapy, BMA from the sternum revealed 59% blast cells, and ALL induction failure with T315I mutation was confirmed (Fig. 2). The patient was treated with inotuzumab ozogamicin, which was ineffective. Furthermore, invasive pulmonary aspergillosis was also refractory, although we added micafungin to L-AMB on day 50 of MEC therapy. The patient did not desire further treatment and was transferred to a nearby hospital to receive the best supportive care.
Figure 3. Centrifuged bone marrow sample. (a) A centrifuged sample of the present patient with bone marrow necrosis (BMN). (b) A centrifuged sample of another patient with acute lymphoblastic leukemia, without BMN.
Figure 4. Magnetic resonance images showing different abnormal signals in the bilateral iliac bone marrow (arrow). (a) Axial T1-weighted magnetic resonance image. (b) Axial T2-weighted magnetic resonance image. (c) Coronal high short T1 inversion recovery image.
Discussion
We detected two important clinical issues. The first is that the MRI features of BMN can vary depending on the location and stage. The second is that severe BMN can hinder the assessment of underlying hematological malignancies.
First, MRI of BMN can differ based on the condition. In general, MRI allows clinicians to noninvasively evaluate abnormal bone marrow and is complementary to a bone marrow examination. On MRI, the signal intensity of the bone marrow mainly reflects the proportion of fatty and serous materials. Tang et al. reported that the MRI features of BMN showed slight variation, depending on the stage. They categorized the different stages of BMN into four classes (Table a) (16). In an earlier BMN stage (class A or B), fatty cells remained in the bone marrow. Thus, T1-weighted MRI showed hyperintensity. The signal on T1-weighted MRI became hypointense as the fatty material was gradually lost. The characteristic MRI features of BMN include extensive, diffuse, geographic patterns of signal abnormalities, and the MRI findings of these four different stages, as we mentioned above, can coexist in the same site. Moreover, the central regions of the BMN were sometimes surrounded by peripheral bands of low intensity, and the peripheral rims became enhanced when gadolinium was administered (16). Although these features are nonspecific, clinicians should take these MRI features into consideration when assessing patients with suspected BMN.
Table a. Classification Based on the Qualitative Assessment of Alterations in MRI Signal Intensity in BMN.
BMN stage Class A Class B Class C Class D Hematological malignancies
T1 weighted Hyperintensity Hyperintensity Hypointensity Hypointensity Hypointensity
T2 weighted Isointensity-mild hyperintensity Hyperintensity Hyperintensity Hypointensity Nonspecific
STIR Hypointensity Unknown Unknown Unknown Hyperintensity
What does this finding mainly reflect? Fatty materials Blood and proteinaceous materials Denaturation of protein Fibrosis tissue
This table was made by the authors based on reference 16-18.
BMN: bone marrow necrosis, MRI: magnetic resonance imaging, STIR: short TI inversion recovery
In our case, MRI was performed after obtaining the BMA and BMB findings, which matched BMN in the bilateral iliac bone. The MRI features of the right iliac bone, the surface side of the left iliac bone, and the central side of the left iliac bone corresponded to classes B, D, and B, respectively (Table b).
Table b. Pathological Features and MRI Findings of Bone Marrow.
Right iliac Left iliac
BMA on day 28 of MEC Muddy and jelly-like specimen (Figure 1b, 3) None
BMA on day 35 of MEC None Dry tap
BMB on day 35 of MEC None Bone marrow space was mostly replaced by eosinophilic debris (Figure 1c, d)
MRI feature on day 45 of MEC Class B Class B (central) Class D (peripheral)
BMA: bone marrow aspiration, BMB: bone marrow biopsy, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MRI: magnetic resonance imaging
Of note, the pathological BMB finding of the left iliac bone showed necrotic tissue without fibrotic tissue, which was in contrast to the MRI findings. BMB from the left iliac bone was performed 10 days before MRI. During that time, the bone marrow fibrosis was considered to have progressed. Thus, clinicians should note that MRI of BMN can differ depending on the location and timing. MRI performed just before a bone marrow examination is very useful, and clinicians could choose the best part for proper evaluation of BMN. Class A (earliest stage) and class D (end stage) mainly show fatty marrow and fibrosis, respectively (Table a, b), and BMA can result in ‘dry tap’ aspiration. Moreover, the disease status of BMN in each of the stages is likely to be less active. Thus, a bone marrow examination from the part containing class B or C findings on MRI may be helpful when assessing BMN.
Second, hematologists have sometimes experienced difficulty when assessing the therapeutic effects in patients with hematological malignancies and BMN because BMN and relapsing hematological malignancies have similar clinical symptoms, including fever and bone pain, as well as laboratory data, such as cytopenia and elevated LDH. Moreover, as mentioned above, MRI is a useful and noninvasive method for assessing the features of BMN, which can differ by stage. However, MRI cannot precisely distinguish BMN from hematological malignancies because the MRI features of hematological malignancies are partially similar to those of BMN. In patients with hematological malignancies, are hypointense signals are observed on T1 images, while the signal characteristics are nonspecific on T2 images (Table a) (17,18). In addition, in some cases, BMA specimens cannot be obtained due to ‘dry tap,’ and even if the specimens are obtained, they may be jelly-like or muddy, which makes it difficult to accurately evaluate the therapeutic effect (2). This diagnostic dilemma caused by necrotic tissue without evaluable cells could be solved by repeated BMA and BMB from not only the bilateral iliac bone but also the sternum, as was performed in our case. However, clinicians are not always able to assess the underlying hematological malignancies by bone marrow examinations from either the bilateral iliac bone or sternum because of the extremely extensive BMN. Miyoshi et al. reported a case of BMN in which an evaluable specimen of underlying ALL could not be obtained, even with repeated bone marrow examinations from both the sternum and iliac bone (5). In view of the severity of the illness of this patient, combination chemotherapy for lymphoid malignancies was immediately started based on the clinical features, which included systemic lymphadenopathy, hepatosplenomegaly, pancytopenia, and high LDH. One month later, leukemia cells appeared in the peripheral blood, leading to a diagnosis of ALL. In addition, Moritake et al. showed that leukemic cell-eliciting Fas-ligand and macrophage-eliciting tumor necrosis factor-alpha could be associated with the molecular mechanism underlying BMN with ALL (19). Thus, because these cytokines from leukemic cells can cause BMN, reducing the tumor burden via chemotherapy, as was reported by Miyoshi et al., could be effective for relieving BMN and may be useful for making a reliable disease assessment.
In conclusion, MRI is helpful for an extensive assessment of the site and status of BMN. Although the disease status is sometimes difficult to assess in the case of hematological malignancies with BMN due ‘dry tap’ or a non-evaluable muddy and jelly-like specimen, a more appropriate examination site could be selected by performing MRI just before a bone marrow examination.
Written informed consent for publication was obtained from the patient's wife.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Dr. Taro Shimono, Clinical Professor, Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine for significant advice.
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Intravenous (not otherwise specified)
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DrugAdministrationRoute
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CC BY-NC-ND
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33116012
| 20,408,999
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2021-04-01
|
What was the administration route of drug 'VORICONAZOLE'?
|
Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.
Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.
Introduction
Bone marrow necrosis (BMN) is an extremely infrequent phenomenon, defined as necrosis of the myeloid tissue and medullary stroma. The prevalence of BMN was reported to be between 0.3% and 2% antemortem of patients eligible for bone marrow examination, and BMN is often detected on autopsy (1,2). The causes of BMN have been identified, including hematological malignancies, solid tumors, infectious disease, chemical exposure, radiation, sickle cell disease, antiphospholipid syndrome, and disseminated intravascular coagulation (2-13). Moreover, acute lymphoblastic leukemia (ALL) accompanied by BMN has been reported to have a poor prognosis (14). The main clinical symptoms of BMN are fever and bone pain. Laboratory findings, such as severe pancytopenia and elevated levels of lactate dehydrogenase (LDH) are generally indicative of BMN (1,2). However, these features can be absent in some cases (15). Magnetic resonance imaging (MRI) findings can be helpful but are nonspecific in the evaluation of bone marrow disorders (16). The morphological assessment of bone marrow aspirate and the pathological findings of bone marrow biopsy (BMB) specimens are most essential for the diagnosis of BMN. Many hematologists report difficulty in assessing the disease status of hematological malignancies by bone marrow aspiration (BMA) because they cannot obtain appropriate samples in cases of extensive BMN and ‘dry tap’, defined as failure to obtain bone marrow on attempted marrow aspiration (6). We herein report a case in which an appropriate disease evaluation was performed using bone marrow aspirate obtained from the sternum of a patient with recurrent ALL accompanied by BMN after re-induction therapy. The MRI features of BMN are also taken into consideration.
Case Report
A 52-year-old male patient received cord blood transplantation for Philadelphia chromosome-positive ALL without T315I mutation. One year later, he was diagnosed with recurrent ALL accompanied by severe bone pain. He was transferred to our institution for re-induction therapy. A BMA specimen could not be obtained due to ‘dry tap’; however, BMB showed numerous blast cells before re-induction therapy, as shown in Fig. 1a. On hospital admission, he had high-grade fever, and a blood culture test was negative; however, a rapid diagnostic test for influenza virus using a nasopharyngeal swab specimen was positive for influenza A. Thus, the patient was treated with mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy and intravenous peramivir (300 mg, once daily). His high-grade fever temporarily improved after treatment; however, his severe fever symptom was exacerbated again on day 16 of MEC therapy. At the time, Aspergillus fumigatus invasion was detected and intravenous voriconazole (VRCZ) was initiated (Fig. 2). His high-grade fever did not improve, despite the antifungal treatment, even after almost recovering from pancytopenia during the nadir period (white blood cell count, 6.8×103/μL with 0% blast cells; hemoglobin, 8.7 g/dL; and platelet count, 14.8×103/μL).
Figure 1. Pathological findings of bone marrow biopsy (BMB) and bone marrow aspiration (BMA). (a) Pathological findings of BMB on admission. Hematoxylin and Eosin (H&E) staining (×400). (b) Pathological findings of BMA on day 28 of mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy. May-Giemsa staining (×400). (c) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×200). (d) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×400).
Figure 2. The clinical course. BMA: bone marrow aspiration, BMB: bone marrow biopsy, CPFG: caspofungin, L-AMB: liposomal amphotericin B, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MEPM: meropenem, MRI: magnetic resonance imaging, PIPC/TAZ: piperacillin/tazobactam, TEIC: teicoplanin, VRCZ: voriconazole, WBC: white blood cell
To estimate the disease status, a BMA test was performed from the right iliac bone on day 28 of MEC therapy, but we only obtained a muddy and jelly-like specimen. When this sample was centrifuged, a cloudy pink precipitate was obtained (Fig. 3). A BMA smear from the specimen showed irregular and indistinct margins, and the cytoplasm appeared fused, as shown in Fig. 1b. In addition, a peripheral blood analysis revealed a high LDH level of 551 IU/L. Subsequently, both BMA and BMB tests were performed from the left iliac bone on day 35 of MEC therapy. We could not obtain sufficient BMA specimens because of ‘dry tap’ aspiration. The findings of the BMB tests showed that most of the bone marrow space was replaced by eosinophilic debris. Although a very small number of blast cells remained, an accurate evaluation was difficult, as shown in Fig. 1c, d. We switched the antifungal agent from VRCZ to liposomal amphotericin B (L-AMB; 3 mg/kg, daily) on day 35 of MEC therapy because his high-grade fever had not improved. On day 45 of MEC therapy, the patient's lower back and lower limb pain gradually worsened. MRI showed heterogeneous patchy areas of high signal intensity at the right iliac bone and sacrum on T1-weighted and T2-weighted imaging. In contrast, MRI showed heterogeneous patchy areas of signal intensity at the left iliac bone on T1-weighted and T2-weighted imaging. In addition, high short T1 inversion recovery imaging of both the bilateral iliac bone and sacrum showed partially high signal intensity, as shown in Fig. 4. These findings appeared to reflect a bone marrow abnormality, including BMN, however a further qualitative evaluation was difficult. On day 50 of MEC therapy, his bone pain drastically deteriorated. On day 51 of MEC therapy, BMA from the sternum revealed 59% blast cells, and ALL induction failure with T315I mutation was confirmed (Fig. 2). The patient was treated with inotuzumab ozogamicin, which was ineffective. Furthermore, invasive pulmonary aspergillosis was also refractory, although we added micafungin to L-AMB on day 50 of MEC therapy. The patient did not desire further treatment and was transferred to a nearby hospital to receive the best supportive care.
Figure 3. Centrifuged bone marrow sample. (a) A centrifuged sample of the present patient with bone marrow necrosis (BMN). (b) A centrifuged sample of another patient with acute lymphoblastic leukemia, without BMN.
Figure 4. Magnetic resonance images showing different abnormal signals in the bilateral iliac bone marrow (arrow). (a) Axial T1-weighted magnetic resonance image. (b) Axial T2-weighted magnetic resonance image. (c) Coronal high short T1 inversion recovery image.
Discussion
We detected two important clinical issues. The first is that the MRI features of BMN can vary depending on the location and stage. The second is that severe BMN can hinder the assessment of underlying hematological malignancies.
First, MRI of BMN can differ based on the condition. In general, MRI allows clinicians to noninvasively evaluate abnormal bone marrow and is complementary to a bone marrow examination. On MRI, the signal intensity of the bone marrow mainly reflects the proportion of fatty and serous materials. Tang et al. reported that the MRI features of BMN showed slight variation, depending on the stage. They categorized the different stages of BMN into four classes (Table a) (16). In an earlier BMN stage (class A or B), fatty cells remained in the bone marrow. Thus, T1-weighted MRI showed hyperintensity. The signal on T1-weighted MRI became hypointense as the fatty material was gradually lost. The characteristic MRI features of BMN include extensive, diffuse, geographic patterns of signal abnormalities, and the MRI findings of these four different stages, as we mentioned above, can coexist in the same site. Moreover, the central regions of the BMN were sometimes surrounded by peripheral bands of low intensity, and the peripheral rims became enhanced when gadolinium was administered (16). Although these features are nonspecific, clinicians should take these MRI features into consideration when assessing patients with suspected BMN.
Table a. Classification Based on the Qualitative Assessment of Alterations in MRI Signal Intensity in BMN.
BMN stage Class A Class B Class C Class D Hematological malignancies
T1 weighted Hyperintensity Hyperintensity Hypointensity Hypointensity Hypointensity
T2 weighted Isointensity-mild hyperintensity Hyperintensity Hyperintensity Hypointensity Nonspecific
STIR Hypointensity Unknown Unknown Unknown Hyperintensity
What does this finding mainly reflect? Fatty materials Blood and proteinaceous materials Denaturation of protein Fibrosis tissue
This table was made by the authors based on reference 16-18.
BMN: bone marrow necrosis, MRI: magnetic resonance imaging, STIR: short TI inversion recovery
In our case, MRI was performed after obtaining the BMA and BMB findings, which matched BMN in the bilateral iliac bone. The MRI features of the right iliac bone, the surface side of the left iliac bone, and the central side of the left iliac bone corresponded to classes B, D, and B, respectively (Table b).
Table b. Pathological Features and MRI Findings of Bone Marrow.
Right iliac Left iliac
BMA on day 28 of MEC Muddy and jelly-like specimen (Figure 1b, 3) None
BMA on day 35 of MEC None Dry tap
BMB on day 35 of MEC None Bone marrow space was mostly replaced by eosinophilic debris (Figure 1c, d)
MRI feature on day 45 of MEC Class B Class B (central) Class D (peripheral)
BMA: bone marrow aspiration, BMB: bone marrow biopsy, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MRI: magnetic resonance imaging
Of note, the pathological BMB finding of the left iliac bone showed necrotic tissue without fibrotic tissue, which was in contrast to the MRI findings. BMB from the left iliac bone was performed 10 days before MRI. During that time, the bone marrow fibrosis was considered to have progressed. Thus, clinicians should note that MRI of BMN can differ depending on the location and timing. MRI performed just before a bone marrow examination is very useful, and clinicians could choose the best part for proper evaluation of BMN. Class A (earliest stage) and class D (end stage) mainly show fatty marrow and fibrosis, respectively (Table a, b), and BMA can result in ‘dry tap’ aspiration. Moreover, the disease status of BMN in each of the stages is likely to be less active. Thus, a bone marrow examination from the part containing class B or C findings on MRI may be helpful when assessing BMN.
Second, hematologists have sometimes experienced difficulty when assessing the therapeutic effects in patients with hematological malignancies and BMN because BMN and relapsing hematological malignancies have similar clinical symptoms, including fever and bone pain, as well as laboratory data, such as cytopenia and elevated LDH. Moreover, as mentioned above, MRI is a useful and noninvasive method for assessing the features of BMN, which can differ by stage. However, MRI cannot precisely distinguish BMN from hematological malignancies because the MRI features of hematological malignancies are partially similar to those of BMN. In patients with hematological malignancies, are hypointense signals are observed on T1 images, while the signal characteristics are nonspecific on T2 images (Table a) (17,18). In addition, in some cases, BMA specimens cannot be obtained due to ‘dry tap,’ and even if the specimens are obtained, they may be jelly-like or muddy, which makes it difficult to accurately evaluate the therapeutic effect (2). This diagnostic dilemma caused by necrotic tissue without evaluable cells could be solved by repeated BMA and BMB from not only the bilateral iliac bone but also the sternum, as was performed in our case. However, clinicians are not always able to assess the underlying hematological malignancies by bone marrow examinations from either the bilateral iliac bone or sternum because of the extremely extensive BMN. Miyoshi et al. reported a case of BMN in which an evaluable specimen of underlying ALL could not be obtained, even with repeated bone marrow examinations from both the sternum and iliac bone (5). In view of the severity of the illness of this patient, combination chemotherapy for lymphoid malignancies was immediately started based on the clinical features, which included systemic lymphadenopathy, hepatosplenomegaly, pancytopenia, and high LDH. One month later, leukemia cells appeared in the peripheral blood, leading to a diagnosis of ALL. In addition, Moritake et al. showed that leukemic cell-eliciting Fas-ligand and macrophage-eliciting tumor necrosis factor-alpha could be associated with the molecular mechanism underlying BMN with ALL (19). Thus, because these cytokines from leukemic cells can cause BMN, reducing the tumor burden via chemotherapy, as was reported by Miyoshi et al., could be effective for relieving BMN and may be useful for making a reliable disease assessment.
In conclusion, MRI is helpful for an extensive assessment of the site and status of BMN. Although the disease status is sometimes difficult to assess in the case of hematological malignancies with BMN due ‘dry tap’ or a non-evaluable muddy and jelly-like specimen, a more appropriate examination site could be selected by performing MRI just before a bone marrow examination.
Written informed consent for publication was obtained from the patient's wife.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Dr. Taro Shimono, Clinical Professor, Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine for significant advice.
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Intravenous (not otherwise specified)
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DrugAdministrationRoute
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CC BY-NC-ND
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33116012
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2021-04-01
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What was the dosage of drug 'INOTUZUMAB OZOGAMICIN'?
|
Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.
Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.
Introduction
Bone marrow necrosis (BMN) is an extremely infrequent phenomenon, defined as necrosis of the myeloid tissue and medullary stroma. The prevalence of BMN was reported to be between 0.3% and 2% antemortem of patients eligible for bone marrow examination, and BMN is often detected on autopsy (1,2). The causes of BMN have been identified, including hematological malignancies, solid tumors, infectious disease, chemical exposure, radiation, sickle cell disease, antiphospholipid syndrome, and disseminated intravascular coagulation (2-13). Moreover, acute lymphoblastic leukemia (ALL) accompanied by BMN has been reported to have a poor prognosis (14). The main clinical symptoms of BMN are fever and bone pain. Laboratory findings, such as severe pancytopenia and elevated levels of lactate dehydrogenase (LDH) are generally indicative of BMN (1,2). However, these features can be absent in some cases (15). Magnetic resonance imaging (MRI) findings can be helpful but are nonspecific in the evaluation of bone marrow disorders (16). The morphological assessment of bone marrow aspirate and the pathological findings of bone marrow biopsy (BMB) specimens are most essential for the diagnosis of BMN. Many hematologists report difficulty in assessing the disease status of hematological malignancies by bone marrow aspiration (BMA) because they cannot obtain appropriate samples in cases of extensive BMN and ‘dry tap’, defined as failure to obtain bone marrow on attempted marrow aspiration (6). We herein report a case in which an appropriate disease evaluation was performed using bone marrow aspirate obtained from the sternum of a patient with recurrent ALL accompanied by BMN after re-induction therapy. The MRI features of BMN are also taken into consideration.
Case Report
A 52-year-old male patient received cord blood transplantation for Philadelphia chromosome-positive ALL without T315I mutation. One year later, he was diagnosed with recurrent ALL accompanied by severe bone pain. He was transferred to our institution for re-induction therapy. A BMA specimen could not be obtained due to ‘dry tap’; however, BMB showed numerous blast cells before re-induction therapy, as shown in Fig. 1a. On hospital admission, he had high-grade fever, and a blood culture test was negative; however, a rapid diagnostic test for influenza virus using a nasopharyngeal swab specimen was positive for influenza A. Thus, the patient was treated with mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy and intravenous peramivir (300 mg, once daily). His high-grade fever temporarily improved after treatment; however, his severe fever symptom was exacerbated again on day 16 of MEC therapy. At the time, Aspergillus fumigatus invasion was detected and intravenous voriconazole (VRCZ) was initiated (Fig. 2). His high-grade fever did not improve, despite the antifungal treatment, even after almost recovering from pancytopenia during the nadir period (white blood cell count, 6.8×103/μL with 0% blast cells; hemoglobin, 8.7 g/dL; and platelet count, 14.8×103/μL).
Figure 1. Pathological findings of bone marrow biopsy (BMB) and bone marrow aspiration (BMA). (a) Pathological findings of BMB on admission. Hematoxylin and Eosin (H&E) staining (×400). (b) Pathological findings of BMA on day 28 of mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy. May-Giemsa staining (×400). (c) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×200). (d) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×400).
Figure 2. The clinical course. BMA: bone marrow aspiration, BMB: bone marrow biopsy, CPFG: caspofungin, L-AMB: liposomal amphotericin B, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MEPM: meropenem, MRI: magnetic resonance imaging, PIPC/TAZ: piperacillin/tazobactam, TEIC: teicoplanin, VRCZ: voriconazole, WBC: white blood cell
To estimate the disease status, a BMA test was performed from the right iliac bone on day 28 of MEC therapy, but we only obtained a muddy and jelly-like specimen. When this sample was centrifuged, a cloudy pink precipitate was obtained (Fig. 3). A BMA smear from the specimen showed irregular and indistinct margins, and the cytoplasm appeared fused, as shown in Fig. 1b. In addition, a peripheral blood analysis revealed a high LDH level of 551 IU/L. Subsequently, both BMA and BMB tests were performed from the left iliac bone on day 35 of MEC therapy. We could not obtain sufficient BMA specimens because of ‘dry tap’ aspiration. The findings of the BMB tests showed that most of the bone marrow space was replaced by eosinophilic debris. Although a very small number of blast cells remained, an accurate evaluation was difficult, as shown in Fig. 1c, d. We switched the antifungal agent from VRCZ to liposomal amphotericin B (L-AMB; 3 mg/kg, daily) on day 35 of MEC therapy because his high-grade fever had not improved. On day 45 of MEC therapy, the patient's lower back and lower limb pain gradually worsened. MRI showed heterogeneous patchy areas of high signal intensity at the right iliac bone and sacrum on T1-weighted and T2-weighted imaging. In contrast, MRI showed heterogeneous patchy areas of signal intensity at the left iliac bone on T1-weighted and T2-weighted imaging. In addition, high short T1 inversion recovery imaging of both the bilateral iliac bone and sacrum showed partially high signal intensity, as shown in Fig. 4. These findings appeared to reflect a bone marrow abnormality, including BMN, however a further qualitative evaluation was difficult. On day 50 of MEC therapy, his bone pain drastically deteriorated. On day 51 of MEC therapy, BMA from the sternum revealed 59% blast cells, and ALL induction failure with T315I mutation was confirmed (Fig. 2). The patient was treated with inotuzumab ozogamicin, which was ineffective. Furthermore, invasive pulmonary aspergillosis was also refractory, although we added micafungin to L-AMB on day 50 of MEC therapy. The patient did not desire further treatment and was transferred to a nearby hospital to receive the best supportive care.
Figure 3. Centrifuged bone marrow sample. (a) A centrifuged sample of the present patient with bone marrow necrosis (BMN). (b) A centrifuged sample of another patient with acute lymphoblastic leukemia, without BMN.
Figure 4. Magnetic resonance images showing different abnormal signals in the bilateral iliac bone marrow (arrow). (a) Axial T1-weighted magnetic resonance image. (b) Axial T2-weighted magnetic resonance image. (c) Coronal high short T1 inversion recovery image.
Discussion
We detected two important clinical issues. The first is that the MRI features of BMN can vary depending on the location and stage. The second is that severe BMN can hinder the assessment of underlying hematological malignancies.
First, MRI of BMN can differ based on the condition. In general, MRI allows clinicians to noninvasively evaluate abnormal bone marrow and is complementary to a bone marrow examination. On MRI, the signal intensity of the bone marrow mainly reflects the proportion of fatty and serous materials. Tang et al. reported that the MRI features of BMN showed slight variation, depending on the stage. They categorized the different stages of BMN into four classes (Table a) (16). In an earlier BMN stage (class A or B), fatty cells remained in the bone marrow. Thus, T1-weighted MRI showed hyperintensity. The signal on T1-weighted MRI became hypointense as the fatty material was gradually lost. The characteristic MRI features of BMN include extensive, diffuse, geographic patterns of signal abnormalities, and the MRI findings of these four different stages, as we mentioned above, can coexist in the same site. Moreover, the central regions of the BMN were sometimes surrounded by peripheral bands of low intensity, and the peripheral rims became enhanced when gadolinium was administered (16). Although these features are nonspecific, clinicians should take these MRI features into consideration when assessing patients with suspected BMN.
Table a. Classification Based on the Qualitative Assessment of Alterations in MRI Signal Intensity in BMN.
BMN stage Class A Class B Class C Class D Hematological malignancies
T1 weighted Hyperintensity Hyperintensity Hypointensity Hypointensity Hypointensity
T2 weighted Isointensity-mild hyperintensity Hyperintensity Hyperintensity Hypointensity Nonspecific
STIR Hypointensity Unknown Unknown Unknown Hyperintensity
What does this finding mainly reflect? Fatty materials Blood and proteinaceous materials Denaturation of protein Fibrosis tissue
This table was made by the authors based on reference 16-18.
BMN: bone marrow necrosis, MRI: magnetic resonance imaging, STIR: short TI inversion recovery
In our case, MRI was performed after obtaining the BMA and BMB findings, which matched BMN in the bilateral iliac bone. The MRI features of the right iliac bone, the surface side of the left iliac bone, and the central side of the left iliac bone corresponded to classes B, D, and B, respectively (Table b).
Table b. Pathological Features and MRI Findings of Bone Marrow.
Right iliac Left iliac
BMA on day 28 of MEC Muddy and jelly-like specimen (Figure 1b, 3) None
BMA on day 35 of MEC None Dry tap
BMB on day 35 of MEC None Bone marrow space was mostly replaced by eosinophilic debris (Figure 1c, d)
MRI feature on day 45 of MEC Class B Class B (central) Class D (peripheral)
BMA: bone marrow aspiration, BMB: bone marrow biopsy, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MRI: magnetic resonance imaging
Of note, the pathological BMB finding of the left iliac bone showed necrotic tissue without fibrotic tissue, which was in contrast to the MRI findings. BMB from the left iliac bone was performed 10 days before MRI. During that time, the bone marrow fibrosis was considered to have progressed. Thus, clinicians should note that MRI of BMN can differ depending on the location and timing. MRI performed just before a bone marrow examination is very useful, and clinicians could choose the best part for proper evaluation of BMN. Class A (earliest stage) and class D (end stage) mainly show fatty marrow and fibrosis, respectively (Table a, b), and BMA can result in ‘dry tap’ aspiration. Moreover, the disease status of BMN in each of the stages is likely to be less active. Thus, a bone marrow examination from the part containing class B or C findings on MRI may be helpful when assessing BMN.
Second, hematologists have sometimes experienced difficulty when assessing the therapeutic effects in patients with hematological malignancies and BMN because BMN and relapsing hematological malignancies have similar clinical symptoms, including fever and bone pain, as well as laboratory data, such as cytopenia and elevated LDH. Moreover, as mentioned above, MRI is a useful and noninvasive method for assessing the features of BMN, which can differ by stage. However, MRI cannot precisely distinguish BMN from hematological malignancies because the MRI features of hematological malignancies are partially similar to those of BMN. In patients with hematological malignancies, are hypointense signals are observed on T1 images, while the signal characteristics are nonspecific on T2 images (Table a) (17,18). In addition, in some cases, BMA specimens cannot be obtained due to ‘dry tap,’ and even if the specimens are obtained, they may be jelly-like or muddy, which makes it difficult to accurately evaluate the therapeutic effect (2). This diagnostic dilemma caused by necrotic tissue without evaluable cells could be solved by repeated BMA and BMB from not only the bilateral iliac bone but also the sternum, as was performed in our case. However, clinicians are not always able to assess the underlying hematological malignancies by bone marrow examinations from either the bilateral iliac bone or sternum because of the extremely extensive BMN. Miyoshi et al. reported a case of BMN in which an evaluable specimen of underlying ALL could not be obtained, even with repeated bone marrow examinations from both the sternum and iliac bone (5). In view of the severity of the illness of this patient, combination chemotherapy for lymphoid malignancies was immediately started based on the clinical features, which included systemic lymphadenopathy, hepatosplenomegaly, pancytopenia, and high LDH. One month later, leukemia cells appeared in the peripheral blood, leading to a diagnosis of ALL. In addition, Moritake et al. showed that leukemic cell-eliciting Fas-ligand and macrophage-eliciting tumor necrosis factor-alpha could be associated with the molecular mechanism underlying BMN with ALL (19). Thus, because these cytokines from leukemic cells can cause BMN, reducing the tumor burden via chemotherapy, as was reported by Miyoshi et al., could be effective for relieving BMN and may be useful for making a reliable disease assessment.
In conclusion, MRI is helpful for an extensive assessment of the site and status of BMN. Although the disease status is sometimes difficult to assess in the case of hematological malignancies with BMN due ‘dry tap’ or a non-evaluable muddy and jelly-like specimen, a more appropriate examination site could be selected by performing MRI just before a bone marrow examination.
Written informed consent for publication was obtained from the patient's wife.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Dr. Taro Shimono, Clinical Professor, Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine for significant advice.
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UNK UNK, UNKNOWN FREQ.
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DrugDosageText
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CC BY-NC-ND
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33116012
| 20,073,058
|
2021-04-01
|
What was the dosage of drug 'MICAFUNGIN'?
|
Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.
Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.
Introduction
Bone marrow necrosis (BMN) is an extremely infrequent phenomenon, defined as necrosis of the myeloid tissue and medullary stroma. The prevalence of BMN was reported to be between 0.3% and 2% antemortem of patients eligible for bone marrow examination, and BMN is often detected on autopsy (1,2). The causes of BMN have been identified, including hematological malignancies, solid tumors, infectious disease, chemical exposure, radiation, sickle cell disease, antiphospholipid syndrome, and disseminated intravascular coagulation (2-13). Moreover, acute lymphoblastic leukemia (ALL) accompanied by BMN has been reported to have a poor prognosis (14). The main clinical symptoms of BMN are fever and bone pain. Laboratory findings, such as severe pancytopenia and elevated levels of lactate dehydrogenase (LDH) are generally indicative of BMN (1,2). However, these features can be absent in some cases (15). Magnetic resonance imaging (MRI) findings can be helpful but are nonspecific in the evaluation of bone marrow disorders (16). The morphological assessment of bone marrow aspirate and the pathological findings of bone marrow biopsy (BMB) specimens are most essential for the diagnosis of BMN. Many hematologists report difficulty in assessing the disease status of hematological malignancies by bone marrow aspiration (BMA) because they cannot obtain appropriate samples in cases of extensive BMN and ‘dry tap’, defined as failure to obtain bone marrow on attempted marrow aspiration (6). We herein report a case in which an appropriate disease evaluation was performed using bone marrow aspirate obtained from the sternum of a patient with recurrent ALL accompanied by BMN after re-induction therapy. The MRI features of BMN are also taken into consideration.
Case Report
A 52-year-old male patient received cord blood transplantation for Philadelphia chromosome-positive ALL without T315I mutation. One year later, he was diagnosed with recurrent ALL accompanied by severe bone pain. He was transferred to our institution for re-induction therapy. A BMA specimen could not be obtained due to ‘dry tap’; however, BMB showed numerous blast cells before re-induction therapy, as shown in Fig. 1a. On hospital admission, he had high-grade fever, and a blood culture test was negative; however, a rapid diagnostic test for influenza virus using a nasopharyngeal swab specimen was positive for influenza A. Thus, the patient was treated with mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy and intravenous peramivir (300 mg, once daily). His high-grade fever temporarily improved after treatment; however, his severe fever symptom was exacerbated again on day 16 of MEC therapy. At the time, Aspergillus fumigatus invasion was detected and intravenous voriconazole (VRCZ) was initiated (Fig. 2). His high-grade fever did not improve, despite the antifungal treatment, even after almost recovering from pancytopenia during the nadir period (white blood cell count, 6.8×103/μL with 0% blast cells; hemoglobin, 8.7 g/dL; and platelet count, 14.8×103/μL).
Figure 1. Pathological findings of bone marrow biopsy (BMB) and bone marrow aspiration (BMA). (a) Pathological findings of BMB on admission. Hematoxylin and Eosin (H&E) staining (×400). (b) Pathological findings of BMA on day 28 of mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy. May-Giemsa staining (×400). (c) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×200). (d) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×400).
Figure 2. The clinical course. BMA: bone marrow aspiration, BMB: bone marrow biopsy, CPFG: caspofungin, L-AMB: liposomal amphotericin B, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MEPM: meropenem, MRI: magnetic resonance imaging, PIPC/TAZ: piperacillin/tazobactam, TEIC: teicoplanin, VRCZ: voriconazole, WBC: white blood cell
To estimate the disease status, a BMA test was performed from the right iliac bone on day 28 of MEC therapy, but we only obtained a muddy and jelly-like specimen. When this sample was centrifuged, a cloudy pink precipitate was obtained (Fig. 3). A BMA smear from the specimen showed irregular and indistinct margins, and the cytoplasm appeared fused, as shown in Fig. 1b. In addition, a peripheral blood analysis revealed a high LDH level of 551 IU/L. Subsequently, both BMA and BMB tests were performed from the left iliac bone on day 35 of MEC therapy. We could not obtain sufficient BMA specimens because of ‘dry tap’ aspiration. The findings of the BMB tests showed that most of the bone marrow space was replaced by eosinophilic debris. Although a very small number of blast cells remained, an accurate evaluation was difficult, as shown in Fig. 1c, d. We switched the antifungal agent from VRCZ to liposomal amphotericin B (L-AMB; 3 mg/kg, daily) on day 35 of MEC therapy because his high-grade fever had not improved. On day 45 of MEC therapy, the patient's lower back and lower limb pain gradually worsened. MRI showed heterogeneous patchy areas of high signal intensity at the right iliac bone and sacrum on T1-weighted and T2-weighted imaging. In contrast, MRI showed heterogeneous patchy areas of signal intensity at the left iliac bone on T1-weighted and T2-weighted imaging. In addition, high short T1 inversion recovery imaging of both the bilateral iliac bone and sacrum showed partially high signal intensity, as shown in Fig. 4. These findings appeared to reflect a bone marrow abnormality, including BMN, however a further qualitative evaluation was difficult. On day 50 of MEC therapy, his bone pain drastically deteriorated. On day 51 of MEC therapy, BMA from the sternum revealed 59% blast cells, and ALL induction failure with T315I mutation was confirmed (Fig. 2). The patient was treated with inotuzumab ozogamicin, which was ineffective. Furthermore, invasive pulmonary aspergillosis was also refractory, although we added micafungin to L-AMB on day 50 of MEC therapy. The patient did not desire further treatment and was transferred to a nearby hospital to receive the best supportive care.
Figure 3. Centrifuged bone marrow sample. (a) A centrifuged sample of the present patient with bone marrow necrosis (BMN). (b) A centrifuged sample of another patient with acute lymphoblastic leukemia, without BMN.
Figure 4. Magnetic resonance images showing different abnormal signals in the bilateral iliac bone marrow (arrow). (a) Axial T1-weighted magnetic resonance image. (b) Axial T2-weighted magnetic resonance image. (c) Coronal high short T1 inversion recovery image.
Discussion
We detected two important clinical issues. The first is that the MRI features of BMN can vary depending on the location and stage. The second is that severe BMN can hinder the assessment of underlying hematological malignancies.
First, MRI of BMN can differ based on the condition. In general, MRI allows clinicians to noninvasively evaluate abnormal bone marrow and is complementary to a bone marrow examination. On MRI, the signal intensity of the bone marrow mainly reflects the proportion of fatty and serous materials. Tang et al. reported that the MRI features of BMN showed slight variation, depending on the stage. They categorized the different stages of BMN into four classes (Table a) (16). In an earlier BMN stage (class A or B), fatty cells remained in the bone marrow. Thus, T1-weighted MRI showed hyperintensity. The signal on T1-weighted MRI became hypointense as the fatty material was gradually lost. The characteristic MRI features of BMN include extensive, diffuse, geographic patterns of signal abnormalities, and the MRI findings of these four different stages, as we mentioned above, can coexist in the same site. Moreover, the central regions of the BMN were sometimes surrounded by peripheral bands of low intensity, and the peripheral rims became enhanced when gadolinium was administered (16). Although these features are nonspecific, clinicians should take these MRI features into consideration when assessing patients with suspected BMN.
Table a. Classification Based on the Qualitative Assessment of Alterations in MRI Signal Intensity in BMN.
BMN stage Class A Class B Class C Class D Hematological malignancies
T1 weighted Hyperintensity Hyperintensity Hypointensity Hypointensity Hypointensity
T2 weighted Isointensity-mild hyperintensity Hyperintensity Hyperintensity Hypointensity Nonspecific
STIR Hypointensity Unknown Unknown Unknown Hyperintensity
What does this finding mainly reflect? Fatty materials Blood and proteinaceous materials Denaturation of protein Fibrosis tissue
This table was made by the authors based on reference 16-18.
BMN: bone marrow necrosis, MRI: magnetic resonance imaging, STIR: short TI inversion recovery
In our case, MRI was performed after obtaining the BMA and BMB findings, which matched BMN in the bilateral iliac bone. The MRI features of the right iliac bone, the surface side of the left iliac bone, and the central side of the left iliac bone corresponded to classes B, D, and B, respectively (Table b).
Table b. Pathological Features and MRI Findings of Bone Marrow.
Right iliac Left iliac
BMA on day 28 of MEC Muddy and jelly-like specimen (Figure 1b, 3) None
BMA on day 35 of MEC None Dry tap
BMB on day 35 of MEC None Bone marrow space was mostly replaced by eosinophilic debris (Figure 1c, d)
MRI feature on day 45 of MEC Class B Class B (central) Class D (peripheral)
BMA: bone marrow aspiration, BMB: bone marrow biopsy, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MRI: magnetic resonance imaging
Of note, the pathological BMB finding of the left iliac bone showed necrotic tissue without fibrotic tissue, which was in contrast to the MRI findings. BMB from the left iliac bone was performed 10 days before MRI. During that time, the bone marrow fibrosis was considered to have progressed. Thus, clinicians should note that MRI of BMN can differ depending on the location and timing. MRI performed just before a bone marrow examination is very useful, and clinicians could choose the best part for proper evaluation of BMN. Class A (earliest stage) and class D (end stage) mainly show fatty marrow and fibrosis, respectively (Table a, b), and BMA can result in ‘dry tap’ aspiration. Moreover, the disease status of BMN in each of the stages is likely to be less active. Thus, a bone marrow examination from the part containing class B or C findings on MRI may be helpful when assessing BMN.
Second, hematologists have sometimes experienced difficulty when assessing the therapeutic effects in patients with hematological malignancies and BMN because BMN and relapsing hematological malignancies have similar clinical symptoms, including fever and bone pain, as well as laboratory data, such as cytopenia and elevated LDH. Moreover, as mentioned above, MRI is a useful and noninvasive method for assessing the features of BMN, which can differ by stage. However, MRI cannot precisely distinguish BMN from hematological malignancies because the MRI features of hematological malignancies are partially similar to those of BMN. In patients with hematological malignancies, are hypointense signals are observed on T1 images, while the signal characteristics are nonspecific on T2 images (Table a) (17,18). In addition, in some cases, BMA specimens cannot be obtained due to ‘dry tap,’ and even if the specimens are obtained, they may be jelly-like or muddy, which makes it difficult to accurately evaluate the therapeutic effect (2). This diagnostic dilemma caused by necrotic tissue without evaluable cells could be solved by repeated BMA and BMB from not only the bilateral iliac bone but also the sternum, as was performed in our case. However, clinicians are not always able to assess the underlying hematological malignancies by bone marrow examinations from either the bilateral iliac bone or sternum because of the extremely extensive BMN. Miyoshi et al. reported a case of BMN in which an evaluable specimen of underlying ALL could not be obtained, even with repeated bone marrow examinations from both the sternum and iliac bone (5). In view of the severity of the illness of this patient, combination chemotherapy for lymphoid malignancies was immediately started based on the clinical features, which included systemic lymphadenopathy, hepatosplenomegaly, pancytopenia, and high LDH. One month later, leukemia cells appeared in the peripheral blood, leading to a diagnosis of ALL. In addition, Moritake et al. showed that leukemic cell-eliciting Fas-ligand and macrophage-eliciting tumor necrosis factor-alpha could be associated with the molecular mechanism underlying BMN with ALL (19). Thus, because these cytokines from leukemic cells can cause BMN, reducing the tumor burden via chemotherapy, as was reported by Miyoshi et al., could be effective for relieving BMN and may be useful for making a reliable disease assessment.
In conclusion, MRI is helpful for an extensive assessment of the site and status of BMN. Although the disease status is sometimes difficult to assess in the case of hematological malignancies with BMN due ‘dry tap’ or a non-evaluable muddy and jelly-like specimen, a more appropriate examination site could be selected by performing MRI just before a bone marrow examination.
Written informed consent for publication was obtained from the patient's wife.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Dr. Taro Shimono, Clinical Professor, Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine for significant advice.
|
UNK UNK, UNKNOWN FREQ.
|
DrugDosageText
|
CC BY-NC-ND
|
33116012
| 20,073,058
|
2021-04-01
|
What was the dosage of drug 'PERAMIVIR'?
|
Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.
Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.
Introduction
Bone marrow necrosis (BMN) is an extremely infrequent phenomenon, defined as necrosis of the myeloid tissue and medullary stroma. The prevalence of BMN was reported to be between 0.3% and 2% antemortem of patients eligible for bone marrow examination, and BMN is often detected on autopsy (1,2). The causes of BMN have been identified, including hematological malignancies, solid tumors, infectious disease, chemical exposure, radiation, sickle cell disease, antiphospholipid syndrome, and disseminated intravascular coagulation (2-13). Moreover, acute lymphoblastic leukemia (ALL) accompanied by BMN has been reported to have a poor prognosis (14). The main clinical symptoms of BMN are fever and bone pain. Laboratory findings, such as severe pancytopenia and elevated levels of lactate dehydrogenase (LDH) are generally indicative of BMN (1,2). However, these features can be absent in some cases (15). Magnetic resonance imaging (MRI) findings can be helpful but are nonspecific in the evaluation of bone marrow disorders (16). The morphological assessment of bone marrow aspirate and the pathological findings of bone marrow biopsy (BMB) specimens are most essential for the diagnosis of BMN. Many hematologists report difficulty in assessing the disease status of hematological malignancies by bone marrow aspiration (BMA) because they cannot obtain appropriate samples in cases of extensive BMN and ‘dry tap’, defined as failure to obtain bone marrow on attempted marrow aspiration (6). We herein report a case in which an appropriate disease evaluation was performed using bone marrow aspirate obtained from the sternum of a patient with recurrent ALL accompanied by BMN after re-induction therapy. The MRI features of BMN are also taken into consideration.
Case Report
A 52-year-old male patient received cord blood transplantation for Philadelphia chromosome-positive ALL without T315I mutation. One year later, he was diagnosed with recurrent ALL accompanied by severe bone pain. He was transferred to our institution for re-induction therapy. A BMA specimen could not be obtained due to ‘dry tap’; however, BMB showed numerous blast cells before re-induction therapy, as shown in Fig. 1a. On hospital admission, he had high-grade fever, and a blood culture test was negative; however, a rapid diagnostic test for influenza virus using a nasopharyngeal swab specimen was positive for influenza A. Thus, the patient was treated with mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy and intravenous peramivir (300 mg, once daily). His high-grade fever temporarily improved after treatment; however, his severe fever symptom was exacerbated again on day 16 of MEC therapy. At the time, Aspergillus fumigatus invasion was detected and intravenous voriconazole (VRCZ) was initiated (Fig. 2). His high-grade fever did not improve, despite the antifungal treatment, even after almost recovering from pancytopenia during the nadir period (white blood cell count, 6.8×103/μL with 0% blast cells; hemoglobin, 8.7 g/dL; and platelet count, 14.8×103/μL).
Figure 1. Pathological findings of bone marrow biopsy (BMB) and bone marrow aspiration (BMA). (a) Pathological findings of BMB on admission. Hematoxylin and Eosin (H&E) staining (×400). (b) Pathological findings of BMA on day 28 of mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy. May-Giemsa staining (×400). (c) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×200). (d) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×400).
Figure 2. The clinical course. BMA: bone marrow aspiration, BMB: bone marrow biopsy, CPFG: caspofungin, L-AMB: liposomal amphotericin B, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MEPM: meropenem, MRI: magnetic resonance imaging, PIPC/TAZ: piperacillin/tazobactam, TEIC: teicoplanin, VRCZ: voriconazole, WBC: white blood cell
To estimate the disease status, a BMA test was performed from the right iliac bone on day 28 of MEC therapy, but we only obtained a muddy and jelly-like specimen. When this sample was centrifuged, a cloudy pink precipitate was obtained (Fig. 3). A BMA smear from the specimen showed irregular and indistinct margins, and the cytoplasm appeared fused, as shown in Fig. 1b. In addition, a peripheral blood analysis revealed a high LDH level of 551 IU/L. Subsequently, both BMA and BMB tests were performed from the left iliac bone on day 35 of MEC therapy. We could not obtain sufficient BMA specimens because of ‘dry tap’ aspiration. The findings of the BMB tests showed that most of the bone marrow space was replaced by eosinophilic debris. Although a very small number of blast cells remained, an accurate evaluation was difficult, as shown in Fig. 1c, d. We switched the antifungal agent from VRCZ to liposomal amphotericin B (L-AMB; 3 mg/kg, daily) on day 35 of MEC therapy because his high-grade fever had not improved. On day 45 of MEC therapy, the patient's lower back and lower limb pain gradually worsened. MRI showed heterogeneous patchy areas of high signal intensity at the right iliac bone and sacrum on T1-weighted and T2-weighted imaging. In contrast, MRI showed heterogeneous patchy areas of signal intensity at the left iliac bone on T1-weighted and T2-weighted imaging. In addition, high short T1 inversion recovery imaging of both the bilateral iliac bone and sacrum showed partially high signal intensity, as shown in Fig. 4. These findings appeared to reflect a bone marrow abnormality, including BMN, however a further qualitative evaluation was difficult. On day 50 of MEC therapy, his bone pain drastically deteriorated. On day 51 of MEC therapy, BMA from the sternum revealed 59% blast cells, and ALL induction failure with T315I mutation was confirmed (Fig. 2). The patient was treated with inotuzumab ozogamicin, which was ineffective. Furthermore, invasive pulmonary aspergillosis was also refractory, although we added micafungin to L-AMB on day 50 of MEC therapy. The patient did not desire further treatment and was transferred to a nearby hospital to receive the best supportive care.
Figure 3. Centrifuged bone marrow sample. (a) A centrifuged sample of the present patient with bone marrow necrosis (BMN). (b) A centrifuged sample of another patient with acute lymphoblastic leukemia, without BMN.
Figure 4. Magnetic resonance images showing different abnormal signals in the bilateral iliac bone marrow (arrow). (a) Axial T1-weighted magnetic resonance image. (b) Axial T2-weighted magnetic resonance image. (c) Coronal high short T1 inversion recovery image.
Discussion
We detected two important clinical issues. The first is that the MRI features of BMN can vary depending on the location and stage. The second is that severe BMN can hinder the assessment of underlying hematological malignancies.
First, MRI of BMN can differ based on the condition. In general, MRI allows clinicians to noninvasively evaluate abnormal bone marrow and is complementary to a bone marrow examination. On MRI, the signal intensity of the bone marrow mainly reflects the proportion of fatty and serous materials. Tang et al. reported that the MRI features of BMN showed slight variation, depending on the stage. They categorized the different stages of BMN into four classes (Table a) (16). In an earlier BMN stage (class A or B), fatty cells remained in the bone marrow. Thus, T1-weighted MRI showed hyperintensity. The signal on T1-weighted MRI became hypointense as the fatty material was gradually lost. The characteristic MRI features of BMN include extensive, diffuse, geographic patterns of signal abnormalities, and the MRI findings of these four different stages, as we mentioned above, can coexist in the same site. Moreover, the central regions of the BMN were sometimes surrounded by peripheral bands of low intensity, and the peripheral rims became enhanced when gadolinium was administered (16). Although these features are nonspecific, clinicians should take these MRI features into consideration when assessing patients with suspected BMN.
Table a. Classification Based on the Qualitative Assessment of Alterations in MRI Signal Intensity in BMN.
BMN stage Class A Class B Class C Class D Hematological malignancies
T1 weighted Hyperintensity Hyperintensity Hypointensity Hypointensity Hypointensity
T2 weighted Isointensity-mild hyperintensity Hyperintensity Hyperintensity Hypointensity Nonspecific
STIR Hypointensity Unknown Unknown Unknown Hyperintensity
What does this finding mainly reflect? Fatty materials Blood and proteinaceous materials Denaturation of protein Fibrosis tissue
This table was made by the authors based on reference 16-18.
BMN: bone marrow necrosis, MRI: magnetic resonance imaging, STIR: short TI inversion recovery
In our case, MRI was performed after obtaining the BMA and BMB findings, which matched BMN in the bilateral iliac bone. The MRI features of the right iliac bone, the surface side of the left iliac bone, and the central side of the left iliac bone corresponded to classes B, D, and B, respectively (Table b).
Table b. Pathological Features and MRI Findings of Bone Marrow.
Right iliac Left iliac
BMA on day 28 of MEC Muddy and jelly-like specimen (Figure 1b, 3) None
BMA on day 35 of MEC None Dry tap
BMB on day 35 of MEC None Bone marrow space was mostly replaced by eosinophilic debris (Figure 1c, d)
MRI feature on day 45 of MEC Class B Class B (central) Class D (peripheral)
BMA: bone marrow aspiration, BMB: bone marrow biopsy, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MRI: magnetic resonance imaging
Of note, the pathological BMB finding of the left iliac bone showed necrotic tissue without fibrotic tissue, which was in contrast to the MRI findings. BMB from the left iliac bone was performed 10 days before MRI. During that time, the bone marrow fibrosis was considered to have progressed. Thus, clinicians should note that MRI of BMN can differ depending on the location and timing. MRI performed just before a bone marrow examination is very useful, and clinicians could choose the best part for proper evaluation of BMN. Class A (earliest stage) and class D (end stage) mainly show fatty marrow and fibrosis, respectively (Table a, b), and BMA can result in ‘dry tap’ aspiration. Moreover, the disease status of BMN in each of the stages is likely to be less active. Thus, a bone marrow examination from the part containing class B or C findings on MRI may be helpful when assessing BMN.
Second, hematologists have sometimes experienced difficulty when assessing the therapeutic effects in patients with hematological malignancies and BMN because BMN and relapsing hematological malignancies have similar clinical symptoms, including fever and bone pain, as well as laboratory data, such as cytopenia and elevated LDH. Moreover, as mentioned above, MRI is a useful and noninvasive method for assessing the features of BMN, which can differ by stage. However, MRI cannot precisely distinguish BMN from hematological malignancies because the MRI features of hematological malignancies are partially similar to those of BMN. In patients with hematological malignancies, are hypointense signals are observed on T1 images, while the signal characteristics are nonspecific on T2 images (Table a) (17,18). In addition, in some cases, BMA specimens cannot be obtained due to ‘dry tap,’ and even if the specimens are obtained, they may be jelly-like or muddy, which makes it difficult to accurately evaluate the therapeutic effect (2). This diagnostic dilemma caused by necrotic tissue without evaluable cells could be solved by repeated BMA and BMB from not only the bilateral iliac bone but also the sternum, as was performed in our case. However, clinicians are not always able to assess the underlying hematological malignancies by bone marrow examinations from either the bilateral iliac bone or sternum because of the extremely extensive BMN. Miyoshi et al. reported a case of BMN in which an evaluable specimen of underlying ALL could not be obtained, even with repeated bone marrow examinations from both the sternum and iliac bone (5). In view of the severity of the illness of this patient, combination chemotherapy for lymphoid malignancies was immediately started based on the clinical features, which included systemic lymphadenopathy, hepatosplenomegaly, pancytopenia, and high LDH. One month later, leukemia cells appeared in the peripheral blood, leading to a diagnosis of ALL. In addition, Moritake et al. showed that leukemic cell-eliciting Fas-ligand and macrophage-eliciting tumor necrosis factor-alpha could be associated with the molecular mechanism underlying BMN with ALL (19). Thus, because these cytokines from leukemic cells can cause BMN, reducing the tumor burden via chemotherapy, as was reported by Miyoshi et al., could be effective for relieving BMN and may be useful for making a reliable disease assessment.
In conclusion, MRI is helpful for an extensive assessment of the site and status of BMN. Although the disease status is sometimes difficult to assess in the case of hematological malignancies with BMN due ‘dry tap’ or a non-evaluable muddy and jelly-like specimen, a more appropriate examination site could be selected by performing MRI just before a bone marrow examination.
Written informed consent for publication was obtained from the patient's wife.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Dr. Taro Shimono, Clinical Professor, Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine for significant advice.
|
300 MG, QD
|
DrugDosageText
|
CC BY-NC-ND
|
33116012
| 20,408,999
|
2021-04-01
|
What was the dosage of drug 'VORICONAZOLE'?
|
Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.
Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.
Introduction
Bone marrow necrosis (BMN) is an extremely infrequent phenomenon, defined as necrosis of the myeloid tissue and medullary stroma. The prevalence of BMN was reported to be between 0.3% and 2% antemortem of patients eligible for bone marrow examination, and BMN is often detected on autopsy (1,2). The causes of BMN have been identified, including hematological malignancies, solid tumors, infectious disease, chemical exposure, radiation, sickle cell disease, antiphospholipid syndrome, and disseminated intravascular coagulation (2-13). Moreover, acute lymphoblastic leukemia (ALL) accompanied by BMN has been reported to have a poor prognosis (14). The main clinical symptoms of BMN are fever and bone pain. Laboratory findings, such as severe pancytopenia and elevated levels of lactate dehydrogenase (LDH) are generally indicative of BMN (1,2). However, these features can be absent in some cases (15). Magnetic resonance imaging (MRI) findings can be helpful but are nonspecific in the evaluation of bone marrow disorders (16). The morphological assessment of bone marrow aspirate and the pathological findings of bone marrow biopsy (BMB) specimens are most essential for the diagnosis of BMN. Many hematologists report difficulty in assessing the disease status of hematological malignancies by bone marrow aspiration (BMA) because they cannot obtain appropriate samples in cases of extensive BMN and ‘dry tap’, defined as failure to obtain bone marrow on attempted marrow aspiration (6). We herein report a case in which an appropriate disease evaluation was performed using bone marrow aspirate obtained from the sternum of a patient with recurrent ALL accompanied by BMN after re-induction therapy. The MRI features of BMN are also taken into consideration.
Case Report
A 52-year-old male patient received cord blood transplantation for Philadelphia chromosome-positive ALL without T315I mutation. One year later, he was diagnosed with recurrent ALL accompanied by severe bone pain. He was transferred to our institution for re-induction therapy. A BMA specimen could not be obtained due to ‘dry tap’; however, BMB showed numerous blast cells before re-induction therapy, as shown in Fig. 1a. On hospital admission, he had high-grade fever, and a blood culture test was negative; however, a rapid diagnostic test for influenza virus using a nasopharyngeal swab specimen was positive for influenza A. Thus, the patient was treated with mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy and intravenous peramivir (300 mg, once daily). His high-grade fever temporarily improved after treatment; however, his severe fever symptom was exacerbated again on day 16 of MEC therapy. At the time, Aspergillus fumigatus invasion was detected and intravenous voriconazole (VRCZ) was initiated (Fig. 2). His high-grade fever did not improve, despite the antifungal treatment, even after almost recovering from pancytopenia during the nadir period (white blood cell count, 6.8×103/μL with 0% blast cells; hemoglobin, 8.7 g/dL; and platelet count, 14.8×103/μL).
Figure 1. Pathological findings of bone marrow biopsy (BMB) and bone marrow aspiration (BMA). (a) Pathological findings of BMB on admission. Hematoxylin and Eosin (H&E) staining (×400). (b) Pathological findings of BMA on day 28 of mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC) therapy. May-Giemsa staining (×400). (c) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×200). (d) Pathological findings of BMB on day 35 of MEC therapy. H&E staining (×400).
Figure 2. The clinical course. BMA: bone marrow aspiration, BMB: bone marrow biopsy, CPFG: caspofungin, L-AMB: liposomal amphotericin B, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MEPM: meropenem, MRI: magnetic resonance imaging, PIPC/TAZ: piperacillin/tazobactam, TEIC: teicoplanin, VRCZ: voriconazole, WBC: white blood cell
To estimate the disease status, a BMA test was performed from the right iliac bone on day 28 of MEC therapy, but we only obtained a muddy and jelly-like specimen. When this sample was centrifuged, a cloudy pink precipitate was obtained (Fig. 3). A BMA smear from the specimen showed irregular and indistinct margins, and the cytoplasm appeared fused, as shown in Fig. 1b. In addition, a peripheral blood analysis revealed a high LDH level of 551 IU/L. Subsequently, both BMA and BMB tests were performed from the left iliac bone on day 35 of MEC therapy. We could not obtain sufficient BMA specimens because of ‘dry tap’ aspiration. The findings of the BMB tests showed that most of the bone marrow space was replaced by eosinophilic debris. Although a very small number of blast cells remained, an accurate evaluation was difficult, as shown in Fig. 1c, d. We switched the antifungal agent from VRCZ to liposomal amphotericin B (L-AMB; 3 mg/kg, daily) on day 35 of MEC therapy because his high-grade fever had not improved. On day 45 of MEC therapy, the patient's lower back and lower limb pain gradually worsened. MRI showed heterogeneous patchy areas of high signal intensity at the right iliac bone and sacrum on T1-weighted and T2-weighted imaging. In contrast, MRI showed heterogeneous patchy areas of signal intensity at the left iliac bone on T1-weighted and T2-weighted imaging. In addition, high short T1 inversion recovery imaging of both the bilateral iliac bone and sacrum showed partially high signal intensity, as shown in Fig. 4. These findings appeared to reflect a bone marrow abnormality, including BMN, however a further qualitative evaluation was difficult. On day 50 of MEC therapy, his bone pain drastically deteriorated. On day 51 of MEC therapy, BMA from the sternum revealed 59% blast cells, and ALL induction failure with T315I mutation was confirmed (Fig. 2). The patient was treated with inotuzumab ozogamicin, which was ineffective. Furthermore, invasive pulmonary aspergillosis was also refractory, although we added micafungin to L-AMB on day 50 of MEC therapy. The patient did not desire further treatment and was transferred to a nearby hospital to receive the best supportive care.
Figure 3. Centrifuged bone marrow sample. (a) A centrifuged sample of the present patient with bone marrow necrosis (BMN). (b) A centrifuged sample of another patient with acute lymphoblastic leukemia, without BMN.
Figure 4. Magnetic resonance images showing different abnormal signals in the bilateral iliac bone marrow (arrow). (a) Axial T1-weighted magnetic resonance image. (b) Axial T2-weighted magnetic resonance image. (c) Coronal high short T1 inversion recovery image.
Discussion
We detected two important clinical issues. The first is that the MRI features of BMN can vary depending on the location and stage. The second is that severe BMN can hinder the assessment of underlying hematological malignancies.
First, MRI of BMN can differ based on the condition. In general, MRI allows clinicians to noninvasively evaluate abnormal bone marrow and is complementary to a bone marrow examination. On MRI, the signal intensity of the bone marrow mainly reflects the proportion of fatty and serous materials. Tang et al. reported that the MRI features of BMN showed slight variation, depending on the stage. They categorized the different stages of BMN into four classes (Table a) (16). In an earlier BMN stage (class A or B), fatty cells remained in the bone marrow. Thus, T1-weighted MRI showed hyperintensity. The signal on T1-weighted MRI became hypointense as the fatty material was gradually lost. The characteristic MRI features of BMN include extensive, diffuse, geographic patterns of signal abnormalities, and the MRI findings of these four different stages, as we mentioned above, can coexist in the same site. Moreover, the central regions of the BMN were sometimes surrounded by peripheral bands of low intensity, and the peripheral rims became enhanced when gadolinium was administered (16). Although these features are nonspecific, clinicians should take these MRI features into consideration when assessing patients with suspected BMN.
Table a. Classification Based on the Qualitative Assessment of Alterations in MRI Signal Intensity in BMN.
BMN stage Class A Class B Class C Class D Hematological malignancies
T1 weighted Hyperintensity Hyperintensity Hypointensity Hypointensity Hypointensity
T2 weighted Isointensity-mild hyperintensity Hyperintensity Hyperintensity Hypointensity Nonspecific
STIR Hypointensity Unknown Unknown Unknown Hyperintensity
What does this finding mainly reflect? Fatty materials Blood and proteinaceous materials Denaturation of protein Fibrosis tissue
This table was made by the authors based on reference 16-18.
BMN: bone marrow necrosis, MRI: magnetic resonance imaging, STIR: short TI inversion recovery
In our case, MRI was performed after obtaining the BMA and BMB findings, which matched BMN in the bilateral iliac bone. The MRI features of the right iliac bone, the surface side of the left iliac bone, and the central side of the left iliac bone corresponded to classes B, D, and B, respectively (Table b).
Table b. Pathological Features and MRI Findings of Bone Marrow.
Right iliac Left iliac
BMA on day 28 of MEC Muddy and jelly-like specimen (Figure 1b, 3) None
BMA on day 35 of MEC None Dry tap
BMB on day 35 of MEC None Bone marrow space was mostly replaced by eosinophilic debris (Figure 1c, d)
MRI feature on day 45 of MEC Class B Class B (central) Class D (peripheral)
BMA: bone marrow aspiration, BMB: bone marrow biopsy, MEC: mitoxantrone, etoposide, and intermediate-dose cytarabine, MRI: magnetic resonance imaging
Of note, the pathological BMB finding of the left iliac bone showed necrotic tissue without fibrotic tissue, which was in contrast to the MRI findings. BMB from the left iliac bone was performed 10 days before MRI. During that time, the bone marrow fibrosis was considered to have progressed. Thus, clinicians should note that MRI of BMN can differ depending on the location and timing. MRI performed just before a bone marrow examination is very useful, and clinicians could choose the best part for proper evaluation of BMN. Class A (earliest stage) and class D (end stage) mainly show fatty marrow and fibrosis, respectively (Table a, b), and BMA can result in ‘dry tap’ aspiration. Moreover, the disease status of BMN in each of the stages is likely to be less active. Thus, a bone marrow examination from the part containing class B or C findings on MRI may be helpful when assessing BMN.
Second, hematologists have sometimes experienced difficulty when assessing the therapeutic effects in patients with hematological malignancies and BMN because BMN and relapsing hematological malignancies have similar clinical symptoms, including fever and bone pain, as well as laboratory data, such as cytopenia and elevated LDH. Moreover, as mentioned above, MRI is a useful and noninvasive method for assessing the features of BMN, which can differ by stage. However, MRI cannot precisely distinguish BMN from hematological malignancies because the MRI features of hematological malignancies are partially similar to those of BMN. In patients with hematological malignancies, are hypointense signals are observed on T1 images, while the signal characteristics are nonspecific on T2 images (Table a) (17,18). In addition, in some cases, BMA specimens cannot be obtained due to ‘dry tap,’ and even if the specimens are obtained, they may be jelly-like or muddy, which makes it difficult to accurately evaluate the therapeutic effect (2). This diagnostic dilemma caused by necrotic tissue without evaluable cells could be solved by repeated BMA and BMB from not only the bilateral iliac bone but also the sternum, as was performed in our case. However, clinicians are not always able to assess the underlying hematological malignancies by bone marrow examinations from either the bilateral iliac bone or sternum because of the extremely extensive BMN. Miyoshi et al. reported a case of BMN in which an evaluable specimen of underlying ALL could not be obtained, even with repeated bone marrow examinations from both the sternum and iliac bone (5). In view of the severity of the illness of this patient, combination chemotherapy for lymphoid malignancies was immediately started based on the clinical features, which included systemic lymphadenopathy, hepatosplenomegaly, pancytopenia, and high LDH. One month later, leukemia cells appeared in the peripheral blood, leading to a diagnosis of ALL. In addition, Moritake et al. showed that leukemic cell-eliciting Fas-ligand and macrophage-eliciting tumor necrosis factor-alpha could be associated with the molecular mechanism underlying BMN with ALL (19). Thus, because these cytokines from leukemic cells can cause BMN, reducing the tumor burden via chemotherapy, as was reported by Miyoshi et al., could be effective for relieving BMN and may be useful for making a reliable disease assessment.
In conclusion, MRI is helpful for an extensive assessment of the site and status of BMN. Although the disease status is sometimes difficult to assess in the case of hematological malignancies with BMN due ‘dry tap’ or a non-evaluable muddy and jelly-like specimen, a more appropriate examination site could be selected by performing MRI just before a bone marrow examination.
Written informed consent for publication was obtained from the patient's wife.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank Dr. Taro Shimono, Clinical Professor, Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine for significant advice.
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UNK UNK, UNKNOWN FREQ.
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DrugDosageText
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CC BY-NC-ND
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33116012
| 20,073,058
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2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastric polyps'.
|
Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the "Gastrin Link Theory".
We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.
Introduction
Esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia (GAVE) are common and characteristic findings observed by endoscopic examinations in patients with liver cirrhosis (1-6). They are the cause of anemia and acute or chronic gastrointestinal bleeding in patients with liver cirrhosis (1-6).
Although GAVE was first described in 1953 by Rider et al. as a cause of massive gastric bleeding (7), its etiology is not fully understood. Treatment includes conservative measures, such as acid suppression agents, blood transfusion, and endoscopic therapy. Endoscopic therapy, especially coagulation with argon plasma coagulation (APC), has become increasingly popular for the treatment of GAVE (8-10). In general, complications of APC for GAVE such as perforation and bleeding, are rare because of the superficial coagulation effect (11-13). However, rare cases of gastric polyps developing after APC therapy for GAVE have been reported (14-20) and termed “portal hypertension-associated polyps” or “portal hypertensive polyps” (21-24). The pathogenesis of gastric hyperplastic polyps is still unknown, but it is thought that the exaggerated repair of mucosal damage (25,26) or hypergastrinemia may play a role in the development of the polyps (27-29).
We herein report a rare case of gastric hyperplastic polyps following APC of GAVE. In this case, hypergastrinemia was caused by the prolonged use of a proton pump inhibitor (PPI) at the time of the diagnosis of gastric hyperplastic polyps. The discontinuance of PPIs and change to an H2-receptor antagonist with rebamipide normalized the level of serum gastrin and promoted the natural disappearance of gastric polyps with a good prognosis of GAVE.
Case Report
A 65-year-old man with liver cirrhosis and portal hypertension associated with hepatitis C virus was referred to us from an outside facility for the further evaluation of refractory iron deficiency anemia (Hb, 9.1 g/mL). He had a history of long-term use of PPIs because of suspicion of gastrointestinal bleeding.
Initial upper gastrointestinal endoscopy revealed mild esophageal varix in the lower esophagus and multiple red spots in the antrum with multiple low polyploid lesions, which were diagnosed as GAVE associated with portal hypertension and raised type-erosive gastritis. No atrophy and no polyps were found in the stomach, and APC therapy was performed for GAVE (Fig. 1). After APC therapy, a PPI (esomeprazole 20 mg/day) was subsequently readministered. Repeated endoscopies (second and third) showed multiple ulcers in the antrum at one week after APC (Fig. 2a, b), as well as multiple scars and reddish small polypoid lesions in the antrum at two months after APC (Fig. 2c, d). PPI treatment was continued for the patient, and the clinical course was good except for moderate iron deficiency anemia (Hb, 11.0 g/mL).
Figure 1. Initial endoscopic findings. Endoscopy revealed mild esophageal varix in the lower esophagus (a) and multiple red spots in the antrum with multiple low polyploid lesions (b). No atrophy or polyps were present (c). Multiple erosions after APC therapy (d). APC: argon plasma coagulation
Figure 2. Repeated endoscopies (second and third). Multiple ulcers in the antrum at one week after APC (a, b) and multiple scars and reddish small polypoid lesions in the antrum at two months after APC (c, d). APC: argon plasma coagulation
Five months after APC therapy, he was diagnosed with hepatocellular carcinoma (HCC) (size 1×1 cm) and treated with radiofrequency ablation without recurrence. Eight months later, he was treated for hepatitis C using direct acting antivirals and went into remission. Two years and six months after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach (Fig. 3). Biopsy specimens from gastric polyps in the antrum and angle indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Fig. 4), and the lesions were diagnosed as gastric hyperplastic polyps. The level of fasting serum gastrin was 817 pg/mL (normal range: 50-150 pg/mL), and serum Helicobacter pylori antibody was negative on the day of endoscopy. Therefore, we considered the cause of gastric hyperplastic polyps to be hypergastrinemia induced by PPIs and switched from a PPI to an H2 blocker antagonist (famotidine 40 mg/day) and a mucoprotective agent (rebamipide 300 mg/day).
Figure 3. Two years after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach. APC: argon plasma coagulation
Figure 4. Biopsy specimens from gastric polyps of the antrum (a) and angle (b) indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Hematoxylin and Eosin staining, ×100).
One year later, a fifth endoscopy revealed that all polyps had completely disappeared, and GAVE was not present (Fig. 5). The fasting level of serum gastrin was in the normal range (121 pg/mL). In addition, a complete improvement in iron deficiency anemia was found (Hb, 15.4 g/mL). Four and five years after APC therapy, the sixth and seventh endoscopic examinations were performed, respectively, and no polyps or GAVE were observed. The clinical course of liver cirrhosis was stable during the follow-up period (Fig. 6).
Figure 5. One year after the fourth endoscopy, a fifth endoscopy revealed that all polyps and the remaining GAVE had completely disappeared (a-d). GAVE: gastric antral vascular ectasia
Figure 6. Four and five years after APC therapy, the sixth (a, b) and seventh (c, d) endoscopic examinations, respectively, indicated the polyps and GAVE had not reappeared. Esophageal varix was not markedly different from that at the initial endoscopy (a). APC: argon plasma coagulation, GAVE: gastric antral vascular ectasia
Discussion
Hyperplastic gastric polyps developing after electrocoagulation therapy for GAVE were first reported after endoscopic laser therapy by Geller et al. in 1996 (14). In 1998, Dohmen et al. reported the first Japanese case of gastric hyperplastic polyps at four months after heater probe therapy in a patient with liver cirrhosis (15). Subsequent reports described the development of gastric polyps as a complication of endoscopic therapy, especially APC, for the treatment of GAVE (16-20). This is the first reported case whereby switching from a PPI to an H2 blocker antagonist led to the disappearance of gastric polyps that appeared after endoscopic therapy for GAVE.
The histological findings of gastric polyps after the endoscopic treatment of GAVE indicated hyperplastic foveolar epithelium with the dilation and increase of capillaries, similar to common gastric hyperplastic polyps (14-20). The gastric polyps in our case showed a similar histology. Previous studies of gastric polyps in patients with portal hypertension used the terms “portal hypertensive polyp,” “gastric polyps in patients with portal hypertension,” or “portal hypertension-associated gastric polyp” (21-24).
The pathogenic mechanism of gastric hyperplastic polyps in patients with liver cirrhosis or portal hypertension is currently unclear, but several previous studies have suggested that congestion caused by elevated portal pressure might have an important role in inducing mucosal proliferation and angiogenesis (14-20). Furthermore, mucosal and vascular structural damage induced by APC might be involved in the pathogenesis rather than the superficial inflammation of the mucosa. In general, common gastric hyperplastic polyps arise from atrophic gastric mucosa caused by H. pylori infection (25-27) or autoimmune gastritis (27,30,31). In our case, H. pylori infection was negative, and no atrophy of the gastric mucosa evaluated by endoscopy was found. Moreover, previous studies of the pathogenesis of gastric hyperplastic polyps have shown that hypergastrinemia induced by severe atrophic gastritis of the corpus (25-29) or prolonged use of PPIs might induce the development of gastric hyperplastic polys (28,32,33). Gastrin has trophic effects on the gastrointestinal mucosa (34) and may repair gastric mucosal damage caused by APC. When gastric hyperplastic polyps were diagnosed in the present case, hypergastrinemia (817 pg/mL) caused by PPIs was found, and the gastrin level was normalized (121 pg/mL) by changing the treatment to an H2 blocker antagonist and rebamipide, with all gastric polyps and iron deficiency anemia completely disappearing. Rebamipide was used because it decreases gastrin levels in the blood and repairs damaged gastric mucosal tissues (35-37). PPIs were reported to be related to iron deficiency anemia (38,39); therefore, the discontinuation of PPIs might have been involved in the improvement of anemia in this case.
Recently, Okazaki et al. reported gastric hyperplastic polyps in a patient with gastroesophageal reflux disease, which might have been caused by the prolonged use of PPIs, disappeared one year after switching from a PPI to an H2 receptor antagonist (40). PPIs were suspected to have caused the development of gastric hyperplastic polyps because H. pylori infection was negative and atrophic gastritis was not found. In general, common gastric hyperplastic polyps develop from atrophic gastritis induced by H. pylori infection (25-27) or autoimmune gastritis with hypergastrinemia (30,31). Unfortunately, the level of serum gastrin was not described in that case study. Anjiki et al. reported a case of multiple hyperplastic polyps with adenocarcinoma in which hypergastrinemia was induced by the long-term use of PPIs; however, the gastric polyps disappeared and gastrin levels normalized after the discontinuation of PPIs (41). That case was H. pylori-positive, and H. pylori eradication therapy was performed in addition to the discontinuation of PPIs. H. pylori eradication therapy was reported to normalize serum gastrin levels (42,43) and reduce gastric hyperplastic polyps (43,44). In our case, which was negative for H. pylori and atrophic gastritis, the gastric hyperplastic polyps disappeared completely with the normalization of gastrin levels.
Our patient had liver cirrhosis with hepatocellular carcinoma, and various factors might have been involved in the disappearance of the polyps over a long period; however, such polyps do not disappear spontaneously. PPIs are useful for treating reflux esophagitis and peptic ulcer diseases as well as for H. pylori eradication therapy and the prevention of peptic ulcer diseases. Furthermore, they are often used long-term in general practice. When hyperplastic polyps are diagnosed after APC treatment of GAVE, hypergastrinemia induced by PPIs should be considered, as in the present case, and treatment by decreasing the PPI dose or switching from a PPI to an H2 receptor antagonist with rebamipide might be suitable.
Informed consent was obtained from the patient.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank J. Ludovic Croxford, PhD for editing a draft of this manuscript.
|
ESOMEPRAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33116013
| 20,089,064
|
2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypergastrinaemia'.
|
Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the "Gastrin Link Theory".
We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.
Introduction
Esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia (GAVE) are common and characteristic findings observed by endoscopic examinations in patients with liver cirrhosis (1-6). They are the cause of anemia and acute or chronic gastrointestinal bleeding in patients with liver cirrhosis (1-6).
Although GAVE was first described in 1953 by Rider et al. as a cause of massive gastric bleeding (7), its etiology is not fully understood. Treatment includes conservative measures, such as acid suppression agents, blood transfusion, and endoscopic therapy. Endoscopic therapy, especially coagulation with argon plasma coagulation (APC), has become increasingly popular for the treatment of GAVE (8-10). In general, complications of APC for GAVE such as perforation and bleeding, are rare because of the superficial coagulation effect (11-13). However, rare cases of gastric polyps developing after APC therapy for GAVE have been reported (14-20) and termed “portal hypertension-associated polyps” or “portal hypertensive polyps” (21-24). The pathogenesis of gastric hyperplastic polyps is still unknown, but it is thought that the exaggerated repair of mucosal damage (25,26) or hypergastrinemia may play a role in the development of the polyps (27-29).
We herein report a rare case of gastric hyperplastic polyps following APC of GAVE. In this case, hypergastrinemia was caused by the prolonged use of a proton pump inhibitor (PPI) at the time of the diagnosis of gastric hyperplastic polyps. The discontinuance of PPIs and change to an H2-receptor antagonist with rebamipide normalized the level of serum gastrin and promoted the natural disappearance of gastric polyps with a good prognosis of GAVE.
Case Report
A 65-year-old man with liver cirrhosis and portal hypertension associated with hepatitis C virus was referred to us from an outside facility for the further evaluation of refractory iron deficiency anemia (Hb, 9.1 g/mL). He had a history of long-term use of PPIs because of suspicion of gastrointestinal bleeding.
Initial upper gastrointestinal endoscopy revealed mild esophageal varix in the lower esophagus and multiple red spots in the antrum with multiple low polyploid lesions, which were diagnosed as GAVE associated with portal hypertension and raised type-erosive gastritis. No atrophy and no polyps were found in the stomach, and APC therapy was performed for GAVE (Fig. 1). After APC therapy, a PPI (esomeprazole 20 mg/day) was subsequently readministered. Repeated endoscopies (second and third) showed multiple ulcers in the antrum at one week after APC (Fig. 2a, b), as well as multiple scars and reddish small polypoid lesions in the antrum at two months after APC (Fig. 2c, d). PPI treatment was continued for the patient, and the clinical course was good except for moderate iron deficiency anemia (Hb, 11.0 g/mL).
Figure 1. Initial endoscopic findings. Endoscopy revealed mild esophageal varix in the lower esophagus (a) and multiple red spots in the antrum with multiple low polyploid lesions (b). No atrophy or polyps were present (c). Multiple erosions after APC therapy (d). APC: argon plasma coagulation
Figure 2. Repeated endoscopies (second and third). Multiple ulcers in the antrum at one week after APC (a, b) and multiple scars and reddish small polypoid lesions in the antrum at two months after APC (c, d). APC: argon plasma coagulation
Five months after APC therapy, he was diagnosed with hepatocellular carcinoma (HCC) (size 1×1 cm) and treated with radiofrequency ablation without recurrence. Eight months later, he was treated for hepatitis C using direct acting antivirals and went into remission. Two years and six months after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach (Fig. 3). Biopsy specimens from gastric polyps in the antrum and angle indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Fig. 4), and the lesions were diagnosed as gastric hyperplastic polyps. The level of fasting serum gastrin was 817 pg/mL (normal range: 50-150 pg/mL), and serum Helicobacter pylori antibody was negative on the day of endoscopy. Therefore, we considered the cause of gastric hyperplastic polyps to be hypergastrinemia induced by PPIs and switched from a PPI to an H2 blocker antagonist (famotidine 40 mg/day) and a mucoprotective agent (rebamipide 300 mg/day).
Figure 3. Two years after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach. APC: argon plasma coagulation
Figure 4. Biopsy specimens from gastric polyps of the antrum (a) and angle (b) indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Hematoxylin and Eosin staining, ×100).
One year later, a fifth endoscopy revealed that all polyps had completely disappeared, and GAVE was not present (Fig. 5). The fasting level of serum gastrin was in the normal range (121 pg/mL). In addition, a complete improvement in iron deficiency anemia was found (Hb, 15.4 g/mL). Four and five years after APC therapy, the sixth and seventh endoscopic examinations were performed, respectively, and no polyps or GAVE were observed. The clinical course of liver cirrhosis was stable during the follow-up period (Fig. 6).
Figure 5. One year after the fourth endoscopy, a fifth endoscopy revealed that all polyps and the remaining GAVE had completely disappeared (a-d). GAVE: gastric antral vascular ectasia
Figure 6. Four and five years after APC therapy, the sixth (a, b) and seventh (c, d) endoscopic examinations, respectively, indicated the polyps and GAVE had not reappeared. Esophageal varix was not markedly different from that at the initial endoscopy (a). APC: argon plasma coagulation, GAVE: gastric antral vascular ectasia
Discussion
Hyperplastic gastric polyps developing after electrocoagulation therapy for GAVE were first reported after endoscopic laser therapy by Geller et al. in 1996 (14). In 1998, Dohmen et al. reported the first Japanese case of gastric hyperplastic polyps at four months after heater probe therapy in a patient with liver cirrhosis (15). Subsequent reports described the development of gastric polyps as a complication of endoscopic therapy, especially APC, for the treatment of GAVE (16-20). This is the first reported case whereby switching from a PPI to an H2 blocker antagonist led to the disappearance of gastric polyps that appeared after endoscopic therapy for GAVE.
The histological findings of gastric polyps after the endoscopic treatment of GAVE indicated hyperplastic foveolar epithelium with the dilation and increase of capillaries, similar to common gastric hyperplastic polyps (14-20). The gastric polyps in our case showed a similar histology. Previous studies of gastric polyps in patients with portal hypertension used the terms “portal hypertensive polyp,” “gastric polyps in patients with portal hypertension,” or “portal hypertension-associated gastric polyp” (21-24).
The pathogenic mechanism of gastric hyperplastic polyps in patients with liver cirrhosis or portal hypertension is currently unclear, but several previous studies have suggested that congestion caused by elevated portal pressure might have an important role in inducing mucosal proliferation and angiogenesis (14-20). Furthermore, mucosal and vascular structural damage induced by APC might be involved in the pathogenesis rather than the superficial inflammation of the mucosa. In general, common gastric hyperplastic polyps arise from atrophic gastric mucosa caused by H. pylori infection (25-27) or autoimmune gastritis (27,30,31). In our case, H. pylori infection was negative, and no atrophy of the gastric mucosa evaluated by endoscopy was found. Moreover, previous studies of the pathogenesis of gastric hyperplastic polyps have shown that hypergastrinemia induced by severe atrophic gastritis of the corpus (25-29) or prolonged use of PPIs might induce the development of gastric hyperplastic polys (28,32,33). Gastrin has trophic effects on the gastrointestinal mucosa (34) and may repair gastric mucosal damage caused by APC. When gastric hyperplastic polyps were diagnosed in the present case, hypergastrinemia (817 pg/mL) caused by PPIs was found, and the gastrin level was normalized (121 pg/mL) by changing the treatment to an H2 blocker antagonist and rebamipide, with all gastric polyps and iron deficiency anemia completely disappearing. Rebamipide was used because it decreases gastrin levels in the blood and repairs damaged gastric mucosal tissues (35-37). PPIs were reported to be related to iron deficiency anemia (38,39); therefore, the discontinuation of PPIs might have been involved in the improvement of anemia in this case.
Recently, Okazaki et al. reported gastric hyperplastic polyps in a patient with gastroesophageal reflux disease, which might have been caused by the prolonged use of PPIs, disappeared one year after switching from a PPI to an H2 receptor antagonist (40). PPIs were suspected to have caused the development of gastric hyperplastic polyps because H. pylori infection was negative and atrophic gastritis was not found. In general, common gastric hyperplastic polyps develop from atrophic gastritis induced by H. pylori infection (25-27) or autoimmune gastritis with hypergastrinemia (30,31). Unfortunately, the level of serum gastrin was not described in that case study. Anjiki et al. reported a case of multiple hyperplastic polyps with adenocarcinoma in which hypergastrinemia was induced by the long-term use of PPIs; however, the gastric polyps disappeared and gastrin levels normalized after the discontinuation of PPIs (41). That case was H. pylori-positive, and H. pylori eradication therapy was performed in addition to the discontinuation of PPIs. H. pylori eradication therapy was reported to normalize serum gastrin levels (42,43) and reduce gastric hyperplastic polyps (43,44). In our case, which was negative for H. pylori and atrophic gastritis, the gastric hyperplastic polyps disappeared completely with the normalization of gastrin levels.
Our patient had liver cirrhosis with hepatocellular carcinoma, and various factors might have been involved in the disappearance of the polyps over a long period; however, such polyps do not disappear spontaneously. PPIs are useful for treating reflux esophagitis and peptic ulcer diseases as well as for H. pylori eradication therapy and the prevention of peptic ulcer diseases. Furthermore, they are often used long-term in general practice. When hyperplastic polyps are diagnosed after APC treatment of GAVE, hypergastrinemia induced by PPIs should be considered, as in the present case, and treatment by decreasing the PPI dose or switching from a PPI to an H2 receptor antagonist with rebamipide might be suitable.
Informed consent was obtained from the patient.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank J. Ludovic Croxford, PhD for editing a draft of this manuscript.
|
ESOMEPRAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33116013
| 20,089,064
|
2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Iron deficiency anaemia'.
|
Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the "Gastrin Link Theory".
We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.
Introduction
Esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia (GAVE) are common and characteristic findings observed by endoscopic examinations in patients with liver cirrhosis (1-6). They are the cause of anemia and acute or chronic gastrointestinal bleeding in patients with liver cirrhosis (1-6).
Although GAVE was first described in 1953 by Rider et al. as a cause of massive gastric bleeding (7), its etiology is not fully understood. Treatment includes conservative measures, such as acid suppression agents, blood transfusion, and endoscopic therapy. Endoscopic therapy, especially coagulation with argon plasma coagulation (APC), has become increasingly popular for the treatment of GAVE (8-10). In general, complications of APC for GAVE such as perforation and bleeding, are rare because of the superficial coagulation effect (11-13). However, rare cases of gastric polyps developing after APC therapy for GAVE have been reported (14-20) and termed “portal hypertension-associated polyps” or “portal hypertensive polyps” (21-24). The pathogenesis of gastric hyperplastic polyps is still unknown, but it is thought that the exaggerated repair of mucosal damage (25,26) or hypergastrinemia may play a role in the development of the polyps (27-29).
We herein report a rare case of gastric hyperplastic polyps following APC of GAVE. In this case, hypergastrinemia was caused by the prolonged use of a proton pump inhibitor (PPI) at the time of the diagnosis of gastric hyperplastic polyps. The discontinuance of PPIs and change to an H2-receptor antagonist with rebamipide normalized the level of serum gastrin and promoted the natural disappearance of gastric polyps with a good prognosis of GAVE.
Case Report
A 65-year-old man with liver cirrhosis and portal hypertension associated with hepatitis C virus was referred to us from an outside facility for the further evaluation of refractory iron deficiency anemia (Hb, 9.1 g/mL). He had a history of long-term use of PPIs because of suspicion of gastrointestinal bleeding.
Initial upper gastrointestinal endoscopy revealed mild esophageal varix in the lower esophagus and multiple red spots in the antrum with multiple low polyploid lesions, which were diagnosed as GAVE associated with portal hypertension and raised type-erosive gastritis. No atrophy and no polyps were found in the stomach, and APC therapy was performed for GAVE (Fig. 1). After APC therapy, a PPI (esomeprazole 20 mg/day) was subsequently readministered. Repeated endoscopies (second and third) showed multiple ulcers in the antrum at one week after APC (Fig. 2a, b), as well as multiple scars and reddish small polypoid lesions in the antrum at two months after APC (Fig. 2c, d). PPI treatment was continued for the patient, and the clinical course was good except for moderate iron deficiency anemia (Hb, 11.0 g/mL).
Figure 1. Initial endoscopic findings. Endoscopy revealed mild esophageal varix in the lower esophagus (a) and multiple red spots in the antrum with multiple low polyploid lesions (b). No atrophy or polyps were present (c). Multiple erosions after APC therapy (d). APC: argon plasma coagulation
Figure 2. Repeated endoscopies (second and third). Multiple ulcers in the antrum at one week after APC (a, b) and multiple scars and reddish small polypoid lesions in the antrum at two months after APC (c, d). APC: argon plasma coagulation
Five months after APC therapy, he was diagnosed with hepatocellular carcinoma (HCC) (size 1×1 cm) and treated with radiofrequency ablation without recurrence. Eight months later, he was treated for hepatitis C using direct acting antivirals and went into remission. Two years and six months after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach (Fig. 3). Biopsy specimens from gastric polyps in the antrum and angle indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Fig. 4), and the lesions were diagnosed as gastric hyperplastic polyps. The level of fasting serum gastrin was 817 pg/mL (normal range: 50-150 pg/mL), and serum Helicobacter pylori antibody was negative on the day of endoscopy. Therefore, we considered the cause of gastric hyperplastic polyps to be hypergastrinemia induced by PPIs and switched from a PPI to an H2 blocker antagonist (famotidine 40 mg/day) and a mucoprotective agent (rebamipide 300 mg/day).
Figure 3. Two years after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach. APC: argon plasma coagulation
Figure 4. Biopsy specimens from gastric polyps of the antrum (a) and angle (b) indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Hematoxylin and Eosin staining, ×100).
One year later, a fifth endoscopy revealed that all polyps had completely disappeared, and GAVE was not present (Fig. 5). The fasting level of serum gastrin was in the normal range (121 pg/mL). In addition, a complete improvement in iron deficiency anemia was found (Hb, 15.4 g/mL). Four and five years after APC therapy, the sixth and seventh endoscopic examinations were performed, respectively, and no polyps or GAVE were observed. The clinical course of liver cirrhosis was stable during the follow-up period (Fig. 6).
Figure 5. One year after the fourth endoscopy, a fifth endoscopy revealed that all polyps and the remaining GAVE had completely disappeared (a-d). GAVE: gastric antral vascular ectasia
Figure 6. Four and five years after APC therapy, the sixth (a, b) and seventh (c, d) endoscopic examinations, respectively, indicated the polyps and GAVE had not reappeared. Esophageal varix was not markedly different from that at the initial endoscopy (a). APC: argon plasma coagulation, GAVE: gastric antral vascular ectasia
Discussion
Hyperplastic gastric polyps developing after electrocoagulation therapy for GAVE were first reported after endoscopic laser therapy by Geller et al. in 1996 (14). In 1998, Dohmen et al. reported the first Japanese case of gastric hyperplastic polyps at four months after heater probe therapy in a patient with liver cirrhosis (15). Subsequent reports described the development of gastric polyps as a complication of endoscopic therapy, especially APC, for the treatment of GAVE (16-20). This is the first reported case whereby switching from a PPI to an H2 blocker antagonist led to the disappearance of gastric polyps that appeared after endoscopic therapy for GAVE.
The histological findings of gastric polyps after the endoscopic treatment of GAVE indicated hyperplastic foveolar epithelium with the dilation and increase of capillaries, similar to common gastric hyperplastic polyps (14-20). The gastric polyps in our case showed a similar histology. Previous studies of gastric polyps in patients with portal hypertension used the terms “portal hypertensive polyp,” “gastric polyps in patients with portal hypertension,” or “portal hypertension-associated gastric polyp” (21-24).
The pathogenic mechanism of gastric hyperplastic polyps in patients with liver cirrhosis or portal hypertension is currently unclear, but several previous studies have suggested that congestion caused by elevated portal pressure might have an important role in inducing mucosal proliferation and angiogenesis (14-20). Furthermore, mucosal and vascular structural damage induced by APC might be involved in the pathogenesis rather than the superficial inflammation of the mucosa. In general, common gastric hyperplastic polyps arise from atrophic gastric mucosa caused by H. pylori infection (25-27) or autoimmune gastritis (27,30,31). In our case, H. pylori infection was negative, and no atrophy of the gastric mucosa evaluated by endoscopy was found. Moreover, previous studies of the pathogenesis of gastric hyperplastic polyps have shown that hypergastrinemia induced by severe atrophic gastritis of the corpus (25-29) or prolonged use of PPIs might induce the development of gastric hyperplastic polys (28,32,33). Gastrin has trophic effects on the gastrointestinal mucosa (34) and may repair gastric mucosal damage caused by APC. When gastric hyperplastic polyps were diagnosed in the present case, hypergastrinemia (817 pg/mL) caused by PPIs was found, and the gastrin level was normalized (121 pg/mL) by changing the treatment to an H2 blocker antagonist and rebamipide, with all gastric polyps and iron deficiency anemia completely disappearing. Rebamipide was used because it decreases gastrin levels in the blood and repairs damaged gastric mucosal tissues (35-37). PPIs were reported to be related to iron deficiency anemia (38,39); therefore, the discontinuation of PPIs might have been involved in the improvement of anemia in this case.
Recently, Okazaki et al. reported gastric hyperplastic polyps in a patient with gastroesophageal reflux disease, which might have been caused by the prolonged use of PPIs, disappeared one year after switching from a PPI to an H2 receptor antagonist (40). PPIs were suspected to have caused the development of gastric hyperplastic polyps because H. pylori infection was negative and atrophic gastritis was not found. In general, common gastric hyperplastic polyps develop from atrophic gastritis induced by H. pylori infection (25-27) or autoimmune gastritis with hypergastrinemia (30,31). Unfortunately, the level of serum gastrin was not described in that case study. Anjiki et al. reported a case of multiple hyperplastic polyps with adenocarcinoma in which hypergastrinemia was induced by the long-term use of PPIs; however, the gastric polyps disappeared and gastrin levels normalized after the discontinuation of PPIs (41). That case was H. pylori-positive, and H. pylori eradication therapy was performed in addition to the discontinuation of PPIs. H. pylori eradication therapy was reported to normalize serum gastrin levels (42,43) and reduce gastric hyperplastic polyps (43,44). In our case, which was negative for H. pylori and atrophic gastritis, the gastric hyperplastic polyps disappeared completely with the normalization of gastrin levels.
Our patient had liver cirrhosis with hepatocellular carcinoma, and various factors might have been involved in the disappearance of the polyps over a long period; however, such polyps do not disappear spontaneously. PPIs are useful for treating reflux esophagitis and peptic ulcer diseases as well as for H. pylori eradication therapy and the prevention of peptic ulcer diseases. Furthermore, they are often used long-term in general practice. When hyperplastic polyps are diagnosed after APC treatment of GAVE, hypergastrinemia induced by PPIs should be considered, as in the present case, and treatment by decreasing the PPI dose or switching from a PPI to an H2 receptor antagonist with rebamipide might be suitable.
Informed consent was obtained from the patient.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank J. Ludovic Croxford, PhD for editing a draft of this manuscript.
|
ESOMEPRAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33116013
| 20,089,064
|
2021-04-01
|
What was the outcome of reaction 'Gastric polyps'?
|
Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the "Gastrin Link Theory".
We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.
Introduction
Esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia (GAVE) are common and characteristic findings observed by endoscopic examinations in patients with liver cirrhosis (1-6). They are the cause of anemia and acute or chronic gastrointestinal bleeding in patients with liver cirrhosis (1-6).
Although GAVE was first described in 1953 by Rider et al. as a cause of massive gastric bleeding (7), its etiology is not fully understood. Treatment includes conservative measures, such as acid suppression agents, blood transfusion, and endoscopic therapy. Endoscopic therapy, especially coagulation with argon plasma coagulation (APC), has become increasingly popular for the treatment of GAVE (8-10). In general, complications of APC for GAVE such as perforation and bleeding, are rare because of the superficial coagulation effect (11-13). However, rare cases of gastric polyps developing after APC therapy for GAVE have been reported (14-20) and termed “portal hypertension-associated polyps” or “portal hypertensive polyps” (21-24). The pathogenesis of gastric hyperplastic polyps is still unknown, but it is thought that the exaggerated repair of mucosal damage (25,26) or hypergastrinemia may play a role in the development of the polyps (27-29).
We herein report a rare case of gastric hyperplastic polyps following APC of GAVE. In this case, hypergastrinemia was caused by the prolonged use of a proton pump inhibitor (PPI) at the time of the diagnosis of gastric hyperplastic polyps. The discontinuance of PPIs and change to an H2-receptor antagonist with rebamipide normalized the level of serum gastrin and promoted the natural disappearance of gastric polyps with a good prognosis of GAVE.
Case Report
A 65-year-old man with liver cirrhosis and portal hypertension associated with hepatitis C virus was referred to us from an outside facility for the further evaluation of refractory iron deficiency anemia (Hb, 9.1 g/mL). He had a history of long-term use of PPIs because of suspicion of gastrointestinal bleeding.
Initial upper gastrointestinal endoscopy revealed mild esophageal varix in the lower esophagus and multiple red spots in the antrum with multiple low polyploid lesions, which were diagnosed as GAVE associated with portal hypertension and raised type-erosive gastritis. No atrophy and no polyps were found in the stomach, and APC therapy was performed for GAVE (Fig. 1). After APC therapy, a PPI (esomeprazole 20 mg/day) was subsequently readministered. Repeated endoscopies (second and third) showed multiple ulcers in the antrum at one week after APC (Fig. 2a, b), as well as multiple scars and reddish small polypoid lesions in the antrum at two months after APC (Fig. 2c, d). PPI treatment was continued for the patient, and the clinical course was good except for moderate iron deficiency anemia (Hb, 11.0 g/mL).
Figure 1. Initial endoscopic findings. Endoscopy revealed mild esophageal varix in the lower esophagus (a) and multiple red spots in the antrum with multiple low polyploid lesions (b). No atrophy or polyps were present (c). Multiple erosions after APC therapy (d). APC: argon plasma coagulation
Figure 2. Repeated endoscopies (second and third). Multiple ulcers in the antrum at one week after APC (a, b) and multiple scars and reddish small polypoid lesions in the antrum at two months after APC (c, d). APC: argon plasma coagulation
Five months after APC therapy, he was diagnosed with hepatocellular carcinoma (HCC) (size 1×1 cm) and treated with radiofrequency ablation without recurrence. Eight months later, he was treated for hepatitis C using direct acting antivirals and went into remission. Two years and six months after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach (Fig. 3). Biopsy specimens from gastric polyps in the antrum and angle indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Fig. 4), and the lesions were diagnosed as gastric hyperplastic polyps. The level of fasting serum gastrin was 817 pg/mL (normal range: 50-150 pg/mL), and serum Helicobacter pylori antibody was negative on the day of endoscopy. Therefore, we considered the cause of gastric hyperplastic polyps to be hypergastrinemia induced by PPIs and switched from a PPI to an H2 blocker antagonist (famotidine 40 mg/day) and a mucoprotective agent (rebamipide 300 mg/day).
Figure 3. Two years after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach. APC: argon plasma coagulation
Figure 4. Biopsy specimens from gastric polyps of the antrum (a) and angle (b) indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Hematoxylin and Eosin staining, ×100).
One year later, a fifth endoscopy revealed that all polyps had completely disappeared, and GAVE was not present (Fig. 5). The fasting level of serum gastrin was in the normal range (121 pg/mL). In addition, a complete improvement in iron deficiency anemia was found (Hb, 15.4 g/mL). Four and five years after APC therapy, the sixth and seventh endoscopic examinations were performed, respectively, and no polyps or GAVE were observed. The clinical course of liver cirrhosis was stable during the follow-up period (Fig. 6).
Figure 5. One year after the fourth endoscopy, a fifth endoscopy revealed that all polyps and the remaining GAVE had completely disappeared (a-d). GAVE: gastric antral vascular ectasia
Figure 6. Four and five years after APC therapy, the sixth (a, b) and seventh (c, d) endoscopic examinations, respectively, indicated the polyps and GAVE had not reappeared. Esophageal varix was not markedly different from that at the initial endoscopy (a). APC: argon plasma coagulation, GAVE: gastric antral vascular ectasia
Discussion
Hyperplastic gastric polyps developing after electrocoagulation therapy for GAVE were first reported after endoscopic laser therapy by Geller et al. in 1996 (14). In 1998, Dohmen et al. reported the first Japanese case of gastric hyperplastic polyps at four months after heater probe therapy in a patient with liver cirrhosis (15). Subsequent reports described the development of gastric polyps as a complication of endoscopic therapy, especially APC, for the treatment of GAVE (16-20). This is the first reported case whereby switching from a PPI to an H2 blocker antagonist led to the disappearance of gastric polyps that appeared after endoscopic therapy for GAVE.
The histological findings of gastric polyps after the endoscopic treatment of GAVE indicated hyperplastic foveolar epithelium with the dilation and increase of capillaries, similar to common gastric hyperplastic polyps (14-20). The gastric polyps in our case showed a similar histology. Previous studies of gastric polyps in patients with portal hypertension used the terms “portal hypertensive polyp,” “gastric polyps in patients with portal hypertension,” or “portal hypertension-associated gastric polyp” (21-24).
The pathogenic mechanism of gastric hyperplastic polyps in patients with liver cirrhosis or portal hypertension is currently unclear, but several previous studies have suggested that congestion caused by elevated portal pressure might have an important role in inducing mucosal proliferation and angiogenesis (14-20). Furthermore, mucosal and vascular structural damage induced by APC might be involved in the pathogenesis rather than the superficial inflammation of the mucosa. In general, common gastric hyperplastic polyps arise from atrophic gastric mucosa caused by H. pylori infection (25-27) or autoimmune gastritis (27,30,31). In our case, H. pylori infection was negative, and no atrophy of the gastric mucosa evaluated by endoscopy was found. Moreover, previous studies of the pathogenesis of gastric hyperplastic polyps have shown that hypergastrinemia induced by severe atrophic gastritis of the corpus (25-29) or prolonged use of PPIs might induce the development of gastric hyperplastic polys (28,32,33). Gastrin has trophic effects on the gastrointestinal mucosa (34) and may repair gastric mucosal damage caused by APC. When gastric hyperplastic polyps were diagnosed in the present case, hypergastrinemia (817 pg/mL) caused by PPIs was found, and the gastrin level was normalized (121 pg/mL) by changing the treatment to an H2 blocker antagonist and rebamipide, with all gastric polyps and iron deficiency anemia completely disappearing. Rebamipide was used because it decreases gastrin levels in the blood and repairs damaged gastric mucosal tissues (35-37). PPIs were reported to be related to iron deficiency anemia (38,39); therefore, the discontinuation of PPIs might have been involved in the improvement of anemia in this case.
Recently, Okazaki et al. reported gastric hyperplastic polyps in a patient with gastroesophageal reflux disease, which might have been caused by the prolonged use of PPIs, disappeared one year after switching from a PPI to an H2 receptor antagonist (40). PPIs were suspected to have caused the development of gastric hyperplastic polyps because H. pylori infection was negative and atrophic gastritis was not found. In general, common gastric hyperplastic polyps develop from atrophic gastritis induced by H. pylori infection (25-27) or autoimmune gastritis with hypergastrinemia (30,31). Unfortunately, the level of serum gastrin was not described in that case study. Anjiki et al. reported a case of multiple hyperplastic polyps with adenocarcinoma in which hypergastrinemia was induced by the long-term use of PPIs; however, the gastric polyps disappeared and gastrin levels normalized after the discontinuation of PPIs (41). That case was H. pylori-positive, and H. pylori eradication therapy was performed in addition to the discontinuation of PPIs. H. pylori eradication therapy was reported to normalize serum gastrin levels (42,43) and reduce gastric hyperplastic polyps (43,44). In our case, which was negative for H. pylori and atrophic gastritis, the gastric hyperplastic polyps disappeared completely with the normalization of gastrin levels.
Our patient had liver cirrhosis with hepatocellular carcinoma, and various factors might have been involved in the disappearance of the polyps over a long period; however, such polyps do not disappear spontaneously. PPIs are useful for treating reflux esophagitis and peptic ulcer diseases as well as for H. pylori eradication therapy and the prevention of peptic ulcer diseases. Furthermore, they are often used long-term in general practice. When hyperplastic polyps are diagnosed after APC treatment of GAVE, hypergastrinemia induced by PPIs should be considered, as in the present case, and treatment by decreasing the PPI dose or switching from a PPI to an H2 receptor antagonist with rebamipide might be suitable.
Informed consent was obtained from the patient.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank J. Ludovic Croxford, PhD for editing a draft of this manuscript.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33116013
| 20,089,064
|
2021-04-01
|
What was the outcome of reaction 'Hypergastrinaemia'?
|
Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the "Gastrin Link Theory".
We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.
Introduction
Esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia (GAVE) are common and characteristic findings observed by endoscopic examinations in patients with liver cirrhosis (1-6). They are the cause of anemia and acute or chronic gastrointestinal bleeding in patients with liver cirrhosis (1-6).
Although GAVE was first described in 1953 by Rider et al. as a cause of massive gastric bleeding (7), its etiology is not fully understood. Treatment includes conservative measures, such as acid suppression agents, blood transfusion, and endoscopic therapy. Endoscopic therapy, especially coagulation with argon plasma coagulation (APC), has become increasingly popular for the treatment of GAVE (8-10). In general, complications of APC for GAVE such as perforation and bleeding, are rare because of the superficial coagulation effect (11-13). However, rare cases of gastric polyps developing after APC therapy for GAVE have been reported (14-20) and termed “portal hypertension-associated polyps” or “portal hypertensive polyps” (21-24). The pathogenesis of gastric hyperplastic polyps is still unknown, but it is thought that the exaggerated repair of mucosal damage (25,26) or hypergastrinemia may play a role in the development of the polyps (27-29).
We herein report a rare case of gastric hyperplastic polyps following APC of GAVE. In this case, hypergastrinemia was caused by the prolonged use of a proton pump inhibitor (PPI) at the time of the diagnosis of gastric hyperplastic polyps. The discontinuance of PPIs and change to an H2-receptor antagonist with rebamipide normalized the level of serum gastrin and promoted the natural disappearance of gastric polyps with a good prognosis of GAVE.
Case Report
A 65-year-old man with liver cirrhosis and portal hypertension associated with hepatitis C virus was referred to us from an outside facility for the further evaluation of refractory iron deficiency anemia (Hb, 9.1 g/mL). He had a history of long-term use of PPIs because of suspicion of gastrointestinal bleeding.
Initial upper gastrointestinal endoscopy revealed mild esophageal varix in the lower esophagus and multiple red spots in the antrum with multiple low polyploid lesions, which were diagnosed as GAVE associated with portal hypertension and raised type-erosive gastritis. No atrophy and no polyps were found in the stomach, and APC therapy was performed for GAVE (Fig. 1). After APC therapy, a PPI (esomeprazole 20 mg/day) was subsequently readministered. Repeated endoscopies (second and third) showed multiple ulcers in the antrum at one week after APC (Fig. 2a, b), as well as multiple scars and reddish small polypoid lesions in the antrum at two months after APC (Fig. 2c, d). PPI treatment was continued for the patient, and the clinical course was good except for moderate iron deficiency anemia (Hb, 11.0 g/mL).
Figure 1. Initial endoscopic findings. Endoscopy revealed mild esophageal varix in the lower esophagus (a) and multiple red spots in the antrum with multiple low polyploid lesions (b). No atrophy or polyps were present (c). Multiple erosions after APC therapy (d). APC: argon plasma coagulation
Figure 2. Repeated endoscopies (second and third). Multiple ulcers in the antrum at one week after APC (a, b) and multiple scars and reddish small polypoid lesions in the antrum at two months after APC (c, d). APC: argon plasma coagulation
Five months after APC therapy, he was diagnosed with hepatocellular carcinoma (HCC) (size 1×1 cm) and treated with radiofrequency ablation without recurrence. Eight months later, he was treated for hepatitis C using direct acting antivirals and went into remission. Two years and six months after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach (Fig. 3). Biopsy specimens from gastric polyps in the antrum and angle indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Fig. 4), and the lesions were diagnosed as gastric hyperplastic polyps. The level of fasting serum gastrin was 817 pg/mL (normal range: 50-150 pg/mL), and serum Helicobacter pylori antibody was negative on the day of endoscopy. Therefore, we considered the cause of gastric hyperplastic polyps to be hypergastrinemia induced by PPIs and switched from a PPI to an H2 blocker antagonist (famotidine 40 mg/day) and a mucoprotective agent (rebamipide 300 mg/day).
Figure 3. Two years after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach. APC: argon plasma coagulation
Figure 4. Biopsy specimens from gastric polyps of the antrum (a) and angle (b) indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Hematoxylin and Eosin staining, ×100).
One year later, a fifth endoscopy revealed that all polyps had completely disappeared, and GAVE was not present (Fig. 5). The fasting level of serum gastrin was in the normal range (121 pg/mL). In addition, a complete improvement in iron deficiency anemia was found (Hb, 15.4 g/mL). Four and five years after APC therapy, the sixth and seventh endoscopic examinations were performed, respectively, and no polyps or GAVE were observed. The clinical course of liver cirrhosis was stable during the follow-up period (Fig. 6).
Figure 5. One year after the fourth endoscopy, a fifth endoscopy revealed that all polyps and the remaining GAVE had completely disappeared (a-d). GAVE: gastric antral vascular ectasia
Figure 6. Four and five years after APC therapy, the sixth (a, b) and seventh (c, d) endoscopic examinations, respectively, indicated the polyps and GAVE had not reappeared. Esophageal varix was not markedly different from that at the initial endoscopy (a). APC: argon plasma coagulation, GAVE: gastric antral vascular ectasia
Discussion
Hyperplastic gastric polyps developing after electrocoagulation therapy for GAVE were first reported after endoscopic laser therapy by Geller et al. in 1996 (14). In 1998, Dohmen et al. reported the first Japanese case of gastric hyperplastic polyps at four months after heater probe therapy in a patient with liver cirrhosis (15). Subsequent reports described the development of gastric polyps as a complication of endoscopic therapy, especially APC, for the treatment of GAVE (16-20). This is the first reported case whereby switching from a PPI to an H2 blocker antagonist led to the disappearance of gastric polyps that appeared after endoscopic therapy for GAVE.
The histological findings of gastric polyps after the endoscopic treatment of GAVE indicated hyperplastic foveolar epithelium with the dilation and increase of capillaries, similar to common gastric hyperplastic polyps (14-20). The gastric polyps in our case showed a similar histology. Previous studies of gastric polyps in patients with portal hypertension used the terms “portal hypertensive polyp,” “gastric polyps in patients with portal hypertension,” or “portal hypertension-associated gastric polyp” (21-24).
The pathogenic mechanism of gastric hyperplastic polyps in patients with liver cirrhosis or portal hypertension is currently unclear, but several previous studies have suggested that congestion caused by elevated portal pressure might have an important role in inducing mucosal proliferation and angiogenesis (14-20). Furthermore, mucosal and vascular structural damage induced by APC might be involved in the pathogenesis rather than the superficial inflammation of the mucosa. In general, common gastric hyperplastic polyps arise from atrophic gastric mucosa caused by H. pylori infection (25-27) or autoimmune gastritis (27,30,31). In our case, H. pylori infection was negative, and no atrophy of the gastric mucosa evaluated by endoscopy was found. Moreover, previous studies of the pathogenesis of gastric hyperplastic polyps have shown that hypergastrinemia induced by severe atrophic gastritis of the corpus (25-29) or prolonged use of PPIs might induce the development of gastric hyperplastic polys (28,32,33). Gastrin has trophic effects on the gastrointestinal mucosa (34) and may repair gastric mucosal damage caused by APC. When gastric hyperplastic polyps were diagnosed in the present case, hypergastrinemia (817 pg/mL) caused by PPIs was found, and the gastrin level was normalized (121 pg/mL) by changing the treatment to an H2 blocker antagonist and rebamipide, with all gastric polyps and iron deficiency anemia completely disappearing. Rebamipide was used because it decreases gastrin levels in the blood and repairs damaged gastric mucosal tissues (35-37). PPIs were reported to be related to iron deficiency anemia (38,39); therefore, the discontinuation of PPIs might have been involved in the improvement of anemia in this case.
Recently, Okazaki et al. reported gastric hyperplastic polyps in a patient with gastroesophageal reflux disease, which might have been caused by the prolonged use of PPIs, disappeared one year after switching from a PPI to an H2 receptor antagonist (40). PPIs were suspected to have caused the development of gastric hyperplastic polyps because H. pylori infection was negative and atrophic gastritis was not found. In general, common gastric hyperplastic polyps develop from atrophic gastritis induced by H. pylori infection (25-27) or autoimmune gastritis with hypergastrinemia (30,31). Unfortunately, the level of serum gastrin was not described in that case study. Anjiki et al. reported a case of multiple hyperplastic polyps with adenocarcinoma in which hypergastrinemia was induced by the long-term use of PPIs; however, the gastric polyps disappeared and gastrin levels normalized after the discontinuation of PPIs (41). That case was H. pylori-positive, and H. pylori eradication therapy was performed in addition to the discontinuation of PPIs. H. pylori eradication therapy was reported to normalize serum gastrin levels (42,43) and reduce gastric hyperplastic polyps (43,44). In our case, which was negative for H. pylori and atrophic gastritis, the gastric hyperplastic polyps disappeared completely with the normalization of gastrin levels.
Our patient had liver cirrhosis with hepatocellular carcinoma, and various factors might have been involved in the disappearance of the polyps over a long period; however, such polyps do not disappear spontaneously. PPIs are useful for treating reflux esophagitis and peptic ulcer diseases as well as for H. pylori eradication therapy and the prevention of peptic ulcer diseases. Furthermore, they are often used long-term in general practice. When hyperplastic polyps are diagnosed after APC treatment of GAVE, hypergastrinemia induced by PPIs should be considered, as in the present case, and treatment by decreasing the PPI dose or switching from a PPI to an H2 receptor antagonist with rebamipide might be suitable.
Informed consent was obtained from the patient.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank J. Ludovic Croxford, PhD for editing a draft of this manuscript.
|
Recovering
|
ReactionOutcome
|
CC BY-NC-ND
|
33116013
| 20,089,064
|
2021-04-01
|
What was the outcome of reaction 'Iron deficiency anaemia'?
|
Gastric Hyperplastic Polyps after Argon Plasma Coagulation for Gastric Antral Vascular Ectasia in Patients with Liver Cirrhosis: A Case Suggesting the "Gastrin Link Theory".
We herein report a case of gastric hyperplastic polyps after argon plasma coagulation (APC) for gastric antral vascular ectasia (GAVE) in the antrum of a 65-year-old man with liver cirrhosis and hypergastrinemia induced by long-term proton pump inhibitor (PPI) use. Two years after APC therapy, endoscopy demonstrated multiple gastric polyps in the antrum and angle. A gastric polyp biopsy indicated foveolar epithelium hyperplasia, which was diagnosed as gastric hyperplastic polyps. One year after switching to an H2 blocker antagonist, endoscopy revealed that the polyps and GAVE had disappeared, with normal gastrin levels suggesting that PPI-induced hypergastrinemia had caused gastric hyperplastic polyps after APC therapy, and the polyps had disappeared after discontinuing PPIs.
Introduction
Esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia (GAVE) are common and characteristic findings observed by endoscopic examinations in patients with liver cirrhosis (1-6). They are the cause of anemia and acute or chronic gastrointestinal bleeding in patients with liver cirrhosis (1-6).
Although GAVE was first described in 1953 by Rider et al. as a cause of massive gastric bleeding (7), its etiology is not fully understood. Treatment includes conservative measures, such as acid suppression agents, blood transfusion, and endoscopic therapy. Endoscopic therapy, especially coagulation with argon plasma coagulation (APC), has become increasingly popular for the treatment of GAVE (8-10). In general, complications of APC for GAVE such as perforation and bleeding, are rare because of the superficial coagulation effect (11-13). However, rare cases of gastric polyps developing after APC therapy for GAVE have been reported (14-20) and termed “portal hypertension-associated polyps” or “portal hypertensive polyps” (21-24). The pathogenesis of gastric hyperplastic polyps is still unknown, but it is thought that the exaggerated repair of mucosal damage (25,26) or hypergastrinemia may play a role in the development of the polyps (27-29).
We herein report a rare case of gastric hyperplastic polyps following APC of GAVE. In this case, hypergastrinemia was caused by the prolonged use of a proton pump inhibitor (PPI) at the time of the diagnosis of gastric hyperplastic polyps. The discontinuance of PPIs and change to an H2-receptor antagonist with rebamipide normalized the level of serum gastrin and promoted the natural disappearance of gastric polyps with a good prognosis of GAVE.
Case Report
A 65-year-old man with liver cirrhosis and portal hypertension associated with hepatitis C virus was referred to us from an outside facility for the further evaluation of refractory iron deficiency anemia (Hb, 9.1 g/mL). He had a history of long-term use of PPIs because of suspicion of gastrointestinal bleeding.
Initial upper gastrointestinal endoscopy revealed mild esophageal varix in the lower esophagus and multiple red spots in the antrum with multiple low polyploid lesions, which were diagnosed as GAVE associated with portal hypertension and raised type-erosive gastritis. No atrophy and no polyps were found in the stomach, and APC therapy was performed for GAVE (Fig. 1). After APC therapy, a PPI (esomeprazole 20 mg/day) was subsequently readministered. Repeated endoscopies (second and third) showed multiple ulcers in the antrum at one week after APC (Fig. 2a, b), as well as multiple scars and reddish small polypoid lesions in the antrum at two months after APC (Fig. 2c, d). PPI treatment was continued for the patient, and the clinical course was good except for moderate iron deficiency anemia (Hb, 11.0 g/mL).
Figure 1. Initial endoscopic findings. Endoscopy revealed mild esophageal varix in the lower esophagus (a) and multiple red spots in the antrum with multiple low polyploid lesions (b). No atrophy or polyps were present (c). Multiple erosions after APC therapy (d). APC: argon plasma coagulation
Figure 2. Repeated endoscopies (second and third). Multiple ulcers in the antrum at one week after APC (a, b) and multiple scars and reddish small polypoid lesions in the antrum at two months after APC (c, d). APC: argon plasma coagulation
Five months after APC therapy, he was diagnosed with hepatocellular carcinoma (HCC) (size 1×1 cm) and treated with radiofrequency ablation without recurrence. Eight months later, he was treated for hepatitis C using direct acting antivirals and went into remission. Two years and six months after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach (Fig. 3). Biopsy specimens from gastric polyps in the antrum and angle indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Fig. 4), and the lesions were diagnosed as gastric hyperplastic polyps. The level of fasting serum gastrin was 817 pg/mL (normal range: 50-150 pg/mL), and serum Helicobacter pylori antibody was negative on the day of endoscopy. Therefore, we considered the cause of gastric hyperplastic polyps to be hypergastrinemia induced by PPIs and switched from a PPI to an H2 blocker antagonist (famotidine 40 mg/day) and a mucoprotective agent (rebamipide 300 mg/day).
Figure 3. Two years after APC therapy, a fourth endoscopy demonstrated multiple reddish polypoid lesions in the anterior of the antrum and greater curvature of the stomach. APC: argon plasma coagulation
Figure 4. Biopsy specimens from gastric polyps of the antrum (a) and angle (b) indicated hyperplasia of the foveolar epithelium with edema and capillary dilation (Hematoxylin and Eosin staining, ×100).
One year later, a fifth endoscopy revealed that all polyps had completely disappeared, and GAVE was not present (Fig. 5). The fasting level of serum gastrin was in the normal range (121 pg/mL). In addition, a complete improvement in iron deficiency anemia was found (Hb, 15.4 g/mL). Four and five years after APC therapy, the sixth and seventh endoscopic examinations were performed, respectively, and no polyps or GAVE were observed. The clinical course of liver cirrhosis was stable during the follow-up period (Fig. 6).
Figure 5. One year after the fourth endoscopy, a fifth endoscopy revealed that all polyps and the remaining GAVE had completely disappeared (a-d). GAVE: gastric antral vascular ectasia
Figure 6. Four and five years after APC therapy, the sixth (a, b) and seventh (c, d) endoscopic examinations, respectively, indicated the polyps and GAVE had not reappeared. Esophageal varix was not markedly different from that at the initial endoscopy (a). APC: argon plasma coagulation, GAVE: gastric antral vascular ectasia
Discussion
Hyperplastic gastric polyps developing after electrocoagulation therapy for GAVE were first reported after endoscopic laser therapy by Geller et al. in 1996 (14). In 1998, Dohmen et al. reported the first Japanese case of gastric hyperplastic polyps at four months after heater probe therapy in a patient with liver cirrhosis (15). Subsequent reports described the development of gastric polyps as a complication of endoscopic therapy, especially APC, for the treatment of GAVE (16-20). This is the first reported case whereby switching from a PPI to an H2 blocker antagonist led to the disappearance of gastric polyps that appeared after endoscopic therapy for GAVE.
The histological findings of gastric polyps after the endoscopic treatment of GAVE indicated hyperplastic foveolar epithelium with the dilation and increase of capillaries, similar to common gastric hyperplastic polyps (14-20). The gastric polyps in our case showed a similar histology. Previous studies of gastric polyps in patients with portal hypertension used the terms “portal hypertensive polyp,” “gastric polyps in patients with portal hypertension,” or “portal hypertension-associated gastric polyp” (21-24).
The pathogenic mechanism of gastric hyperplastic polyps in patients with liver cirrhosis or portal hypertension is currently unclear, but several previous studies have suggested that congestion caused by elevated portal pressure might have an important role in inducing mucosal proliferation and angiogenesis (14-20). Furthermore, mucosal and vascular structural damage induced by APC might be involved in the pathogenesis rather than the superficial inflammation of the mucosa. In general, common gastric hyperplastic polyps arise from atrophic gastric mucosa caused by H. pylori infection (25-27) or autoimmune gastritis (27,30,31). In our case, H. pylori infection was negative, and no atrophy of the gastric mucosa evaluated by endoscopy was found. Moreover, previous studies of the pathogenesis of gastric hyperplastic polyps have shown that hypergastrinemia induced by severe atrophic gastritis of the corpus (25-29) or prolonged use of PPIs might induce the development of gastric hyperplastic polys (28,32,33). Gastrin has trophic effects on the gastrointestinal mucosa (34) and may repair gastric mucosal damage caused by APC. When gastric hyperplastic polyps were diagnosed in the present case, hypergastrinemia (817 pg/mL) caused by PPIs was found, and the gastrin level was normalized (121 pg/mL) by changing the treatment to an H2 blocker antagonist and rebamipide, with all gastric polyps and iron deficiency anemia completely disappearing. Rebamipide was used because it decreases gastrin levels in the blood and repairs damaged gastric mucosal tissues (35-37). PPIs were reported to be related to iron deficiency anemia (38,39); therefore, the discontinuation of PPIs might have been involved in the improvement of anemia in this case.
Recently, Okazaki et al. reported gastric hyperplastic polyps in a patient with gastroesophageal reflux disease, which might have been caused by the prolonged use of PPIs, disappeared one year after switching from a PPI to an H2 receptor antagonist (40). PPIs were suspected to have caused the development of gastric hyperplastic polyps because H. pylori infection was negative and atrophic gastritis was not found. In general, common gastric hyperplastic polyps develop from atrophic gastritis induced by H. pylori infection (25-27) or autoimmune gastritis with hypergastrinemia (30,31). Unfortunately, the level of serum gastrin was not described in that case study. Anjiki et al. reported a case of multiple hyperplastic polyps with adenocarcinoma in which hypergastrinemia was induced by the long-term use of PPIs; however, the gastric polyps disappeared and gastrin levels normalized after the discontinuation of PPIs (41). That case was H. pylori-positive, and H. pylori eradication therapy was performed in addition to the discontinuation of PPIs. H. pylori eradication therapy was reported to normalize serum gastrin levels (42,43) and reduce gastric hyperplastic polyps (43,44). In our case, which was negative for H. pylori and atrophic gastritis, the gastric hyperplastic polyps disappeared completely with the normalization of gastrin levels.
Our patient had liver cirrhosis with hepatocellular carcinoma, and various factors might have been involved in the disappearance of the polyps over a long period; however, such polyps do not disappear spontaneously. PPIs are useful for treating reflux esophagitis and peptic ulcer diseases as well as for H. pylori eradication therapy and the prevention of peptic ulcer diseases. Furthermore, they are often used long-term in general practice. When hyperplastic polyps are diagnosed after APC treatment of GAVE, hypergastrinemia induced by PPIs should be considered, as in the present case, and treatment by decreasing the PPI dose or switching from a PPI to an H2 receptor antagonist with rebamipide might be suitable.
Informed consent was obtained from the patient.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We thank J. Ludovic Croxford, PhD for editing a draft of this manuscript.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33116013
| 20,089,064
|
2021-04-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
DOCETAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,485,283
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung squamous cell carcinoma metastatic'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
ACYCLOVIR, CARBOPLATIN, GIMERACIL\OTERACIL\TEGAFUR, RADIATION THERAPY
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,760,944
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
CARBOPLATIN, DOCETAXEL, DURVALUMAB, GIMERACIL\OTERACIL\TEGAFUR, PACLITAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,516,222
|
2021-01
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to central nervous system'.
|
Generalized herpes zoster and cutaneous metastasis during chemotherapy for non-small cell lung cancer: A case report.
Although herpes zoster is known to occur in some patients with lung cancer, generalized (disseminated) herpes zoster is an uncommon form whereby hematogenous dissemination of the virus occurs and leads to the development of widespread cutaneous lesions. Similarly, skin is an uncommon site of metastasis in patients with lung cancer. Here, we report a clinical case of a 53-year-old male patient who developed generalized herpes zoster during chemotherapy for non-small cell lung cancer (squamous cell carcinoma) and subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured by treatment with intravenous aciclovir. The coincidence of these two conditions, generalized herpes zoster and cutaneous metastasis, in the patient during lung cancer treatment might be associated with an impaired or dysregulated immune system partly due to repeated chemotherapy, indicating a poor prognosis. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Introduction
Herpes zoster, which is caused by reactivation of the varicella‐zoster virus (VZV), occurs in immunocompromised patients such as cancer patients and is related to their disease or treatments.
1
,
2
Herpes zoster has been previously reported in some patients with lung cancer.
1
,
2
,
3
Reactivated virus spreads along the sensory nerve to the dermatome; however, generalized (disseminated) herpes zoster, in which the virus disseminates hematogenously to widespread cutaneous lesions, occurs in only about 2%–5% of herpes zoster cases.
4
,
5
The skin is an uncommon site of metastasis from internal malignancies. The overall incidence of cutaneous involvement is approximately 5% and may indicate advanced disease and a poor prognosis.
6
Cutaneous metastasis of lung cancer is also rare.
7
,
8
Here, we report a patient who developed generalized herpes zoster during chemotherapy for non‐small cell lung cancer (NSCLC) and who subsequently developed cutaneous metastasis of lung cancer after generalized herpes zoster was cured. Herpes zoster is associated with cancer risk.
9
,
10
,
11
The occurrence of two rare conditions, generalized herpes zoster and cutaneous metastasis, in the same patient should not be considered a chance finding, as it might be indicative of immunosuppression.
Case report
A previously healthy 53‐year‐old man was admitted to our respiratory department with a history of exertional dyspnea and left shoulder pain for eight weeks. He had no underlying disease, no surgical history and no regular medications, but had smoked two packs a day between the ages of 14–40 years. Chest computed tomography (CT) revealed a 36 mm mass in the left S3 area. Bronchoscopy was performed, and he was diagnosed with non‐small cell lung cancer (squamous cell carcinoma) (cT2aN2M0, cStage IIIA). After first‐line chemotherapy with weekly carboplatin and paclitaxel plus radiation therapy (60 Gy), 14 cycles of second‐line chemotherapy with durvalumab were performed. However, because the lung cancer indicated progressive disease (PD), the third‐line chemotherapy was changed to docetaxel. F18‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET)/CT indicated increased primary tumor, left pleural effusion and left subclavian lymphadenopathy. Biopsy of left subclavian lymphadenopathy was performed with a subsequent diagnosis of metastasis of squamous cell carcinoma, indicating a PD.
The patient was hospitalized for the fourth‐line chemotherapy. During the first to fourth‐line chemotherapy, he was hospitalized for 7 to 14 days and then discharged for 7 to 14 days, for each chemotherapy course. The total length of his hospital stay before the fourth‐line chemotherapy was 203 days. During that period, the only adverse event was grade 1 radiation pulmonary inflammation (CTCAE 4.0) after the first‐line chemotherapy plus radiation therapy. Chest X‐ray showed extensive opacification in the left lung with massive pleural effusion indicated by chest CT (Fig 1a–c). Results of the blood test at this time were as follows; white blood cells 8150/μL; hemoglobin 13.2 g/dL; lactate dehydrogenase (LDH) 197 g/dL; total protein (TP) 6.9 g/dL; albumin 3.6 g/dL; globulin 3.2 g/dL; cholinesterase 297 U/L; and creatinine 0.75 mg/dL. Pale yellow exudative pleural effusion was observed (LDH 129 g/dL; TP 4.9 g/dL; albumin 2.7 g/dL; glucose 96 mg/dL; and lymphocytes 74.4%).
Figure 1 (a) Chest X‐ray showed decreased permeability in the lower left lung field and unaffected trachea; and (b–c) chest computed tomography (CT) scan showed a massive left pleural effusion and pericardial effusion.
On the night of the day of hospitalization, exanthema with vesicles was evident on the left lateral region of his chest (Fig 2a). Because herpes zoster was suspected, we administered valaciclovir hydrochloride 3000 mg orally daily. However, three days later, the exanthema with vesicles worsened (Fig 2b, c), and also appeared on his right wrist. Because the Tzanck smear test for the exanthema was positive, he was diagnosed as having generalized herpes zoster. Valaciclovir hydrochloride was stopped and aciclovir 750 mg intravenously daily was administered. The exanthema improved and we withdrew aciclovir eight days later. Then, he was discharged.
Figure 2 Exanthema with vesicles present in the left lateral region of the chest of the patient. (a) At diagnosis and (b) and (c) three days later.
However, two weeks later, he was rehospitalized suffering from the effects of the chemotherapy. A 3 mm subcutaneous nodule was observed in the left sternal clavicle (bone) (Fig 3a–c). Ultrasonography indicated a hypoechoic mass in the dermis and subcutaneous tissue. The boundaries were unclear, the contours were irregular, and blood flow signals were abundant (Fig 3d). A biopsy indicated a diagnosis of cutaneous metastasis of squamous cell carcinoma (Fig 3e). This was surgically removed because the patient felt pain there.
Figure 3 (a–c) A 3 mm subcutaneous nodule was present in the left sternal clavicle (bone); and (d) ultrasonography revealed cutaneous metastasis of lung cancer. (e) Histopathology indicated the nodule was formed mainly in the dermis to the subcutaneous tissue, with atypical cells forming solid alveolar nests (H&E). In addition, there was some continuity with the epidermis, with cancer pearls present in the alveolar nest.
About three weeks later, during the fourth‐line chemotherapy, he died of respiratory failure due to progressive lung cancer and massive pleural effusion. The clinical course of this patient is summarized in Fig 4.
Figure 4 The clinical course of the patient () WBC () Lym () TP () Alb.
Discussion
Associations between the incidence of herpes zoster and malignancies have been reported.
1
,
2
Hata et al.
2
reported that among 1410 patients with lung cancer, 35 (2.5%) developed herpes zoster. The incidence of herpes zoster in solid tumors is lower than hematological cancer.
1
,
12
Moreover, generalized herpes zoster, where VZV disseminates hematogenously from dorsal root ganglia cells to distant parts of the body, is uncommon.
4
Its risk is increased in immunosuppressed patients. Our patient received repeated chemotherapy plus radiation therapy and chest drainage to treat pleural effusion. Physical trauma is a common cause of herpes zoster,
13
indicating chest drainage or thoracentesis might have affected the incidence.
As with other internal malignancies, cutaneous metastasis from lung cancer is rare; for example, 1.7% of 1223 cases have been reported in the USA,
14
1.78% of 1292 cases in Taiwan,
7
and 2.8% of 579 cases in Japan.
8
The most common malignancies that metastasize to the skin are lung cancer in men, and breast cancer in women.
6
The estimated mean survival after a diagnosis of cutaneous metastases has been reported to be 50% at six months,
6
and the median survival of 16 Japanese cases of skin metastasis from lung cancer approximately four months,
8
which is compatible with the present case. Cutaneous metastasis is typically located on the thorax, abdomen, head/neck, and scalp.
6
,
15
Some studies have reported that adenocarcinoma was the highest among cutaneous metastases from different histological types of lung cancer.
7
,
15
Clinical suspicion of cutaneous metastasis is highly important.
These two rare conditions of generalized herpes zoster and subsequent cutaneous metastasis might be associated with impaired or dysregulated immunity of the host. Cellular immune function is critical for suppressing VZV replication and carcinogenesis.
16
When the cellular immune function is impaired, it causes an eruption of herpes zoster, which may be generalized. Under these circumstances, tumor immunity also deteriorates, promoting cancer, for example cutaneous metastasis in the present case. Repeated chemotherapy in this patient might have contributed to these conditions. Longitudinal epidemiological studies indicated herpes zoster has been found to be associated with increased risk of some types of cancer
9
,
10
,
11
and that it might be an indicator of occult cancer. Hospitalization for herpes zoster has been reported to be associated with a risk of several types of cancer, indicating a poor prognosis. Thus, based on our experience and previous studies, we suggest the early detection of cancer metastasis or occult cancer is critical when a patient with lung cancer has generalized herpes zoster.
In conclusion, generalized herpes zoster and subsequent cutaneous metastasis during chemotherapy should not be regarded as a coincidence of two rare conditions, but rather as an impaired or dysregulated immune system in the patient. Close observation and accurate diagnosis of changes in the skin of patients with lung cancer are important when evaluating their immune status and considering their therapy and prognosis.
Disclosure
The authors declare that there are no conflicts of interest.
|
CARBOPLATIN, DOCETAXEL, DURVALUMAB, GIMERACIL\OTERACIL\TEGAFUR, PACLITAXEL
|
DrugsGivenReaction
|
CC BY
|
33118287
| 18,516,222
|
2021-01
|
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