Bipolar Disorder, Depression
Conditions
Brief summary
This study investigates the efficacy of a fixed-dose regimen of cariprazine 1.5 milligram (mg)/day or 3 mg/day compared to placebo for treatment of the depressive episode in participants with bipolar I disorder. The safety and tolerability of the fixed-dose regimens will be evaluated.
Interventions
DRUGCariprazine
DRUGPlacebo
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Currently meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for bipolar I disorder without psychotic features confirmed by the administration of the Mini International Neuropsychiatric Interview (MINI), with a current major depressive episode of at least 4 weeks and not exceeding 12 months in duration * Currently treated as an outpatient at the time of enrollment * A verified previous manic or mixed episode. Verification must include one of the following sources: --Treatment of mania with an anti-manic agent (eg, lithium or divalproate) or antipsychotic medication with an approved indication for mania --Hospital records/Medical records --Participant report corroborated by caretaker or previous or current treating clinician * 17-item Hamilton Depression Rating Scale (HAMD-17) total score ≥ 20 * HAMD-17 item 1 score ≥ 2 * Clinical Global Impressions-Severity (CGI-S) score ≥ 4 * Negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test (women of childbearing potential only) * Normal physical examination, clinical laboratory test results, and electrocardiogram (ECG) results or abnormal findings that are judged not clinically significant by the Principal Investigator (PI)
Exclusion criteria
* Young Mania Rating Scale (YMRS) total score \> 12 * Four or more episodes of a mood disturbance (depression, mania, hypomania, or mixed state) within the 12 months before Visit 1 * Any current axis 1 psychiatric diagnosis other than bipolar disorder with the exception of specific phobias * History of meeting DSM-5 criteria for: ○ Dementia, amnesic, or other cognitive disorder ○ Schizophrenia, schizoaffective, or other psychotic disorder ○ Mental retardation - DSM-5-based diagnosis of borderline or antisocial personality disorder or other axis II disorder of sufficient severity to interfere with participation in this study * History of meeting DSM-5 criteria for alcohol or substance abuse or dependence (other than nicotine or caffeine) within the 6 months before Visit 1 * Positive result on blood alcohol test or urine drug screen for any prohibited medication. Exception: ○ Participants with a positive cannabinoid on entry may be retested before randomization. If the participant remains positive, the participant is no longer eligible ○ Participants positive for opiates on entry, discussion with Study Physician is required. * Electroconvulsive therapy in the 3 months before Visit 1 * Previous lack of response to electroconvulsive therapy * Treatment with a depot antipsychotic drug within 1 treatment cycle before Visit 1 * Treatment with clozapine in a dose of \> 50 mg/day in the past 2 years * Prior participation in any investigational study of RGH-188 or cariprazine within the past 12 months * Previous treatment with vagus nerve stimulation or transcranial magnetic stimulation within 6 months before Visit 1 * Prior participation with any clinical trials, involving experimental or investigational drugs, within 6 months before Visit 1 or during the study * Initiation or termination of psychotherapy for depression within the 3 months preceding Visit 1, or plans to initiate, terminate, or change such therapy during the course of the study. * Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study * Gastric bypass or any condition that would be expected to affect drug absorption (lap band procedures are acceptable if there is no problem with absorption) * Known history of cataracts or retinal detachment * Known human immunodeficiency virus infection * Employee, or immediate relative of an employee, of the Sponsor, any of its affiliates or partners, or the study center
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Week 6 | Baseline (Week 0) to Week 6 | The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants were rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each of the 10 items was scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity for a total possible score of 0 (best) to 60 (worst). A negative change from Baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 6 | Baseline (Week 0) to Week 6 | The Clinical Global Impressions-Severity (CGI-S) is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of other participants the physician has observed. The participant was rated on a scale from 1 to 7, with 1 indicating a normal state and 7 indicating among the most extremely ill participants. A negative change from Baseline indicates improvement. |
Countries
Bulgaria, Estonia, Lithuania, Poland, Puerto Rico, United States
Participant flow
Pre-assignment details
Total 782 participants were screened for eligibility; 488 participants randomized to receive double-blind treatment; 480 participants received at least 1 dose of double-blind treatment (Safety Population) and 474 participants had at least 1 postbaseline Montgomery-Åsberg Depression Rating Scale total score assessment (Intent-to-Treat Population).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Following a 7 to 14 days screening/washout period, placebo-matching cariprazine capsule, one per day, orally for 6 weeks. | 163 |
| Cariprazine 1.5 mg Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligram (mg) capsule, one per day, orally for 6 weeks. | 160 |
| Cariprazine 3.0 mg Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day for 2 weeks followed by cariprazine 3.0 mg capsule, one per day, orally beginning on Day 15 for 4 weeks. | 165 |
| Total | 488 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 7 | 9 |
| Overall Study | Did Not Receive Treatment | 5 | 3 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 3 |
| Overall Study | Lost to Follow-up | 5 | 7 | 6 |
| Overall Study | Noncompliance with study drug | 3 | 3 | 2 |
| Overall Study | Other Miscellaneous Reasons | 2 | 3 | 3 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal of Consent | 6 | 3 | 8 |
Baseline characteristics
| Characteristic | Cariprazine 3.0 mg | Total | Placebo | Cariprazine 1.5 mg |
|---|---|---|---|---|
| Age, Continuous | 41.9 years | 42.8 years | 43.9 years | 42.6 years |
| Clinical Global Impressions-Severity (CGI-S) Score at Baseline | 4.5 score on a scale STANDARD_DEVIATION 0.5 | 4.5 score on a scale STANDARD_DEVIATION 0.5 | 4.5 score on a scale STANDARD_DEVIATION 0.5 | 4.5 score on a scale STANDARD_DEVIATION 0.5 |
| Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Baseline | 31.1 score on a scale STANDARD_DEVIATION 4.8 | 30.7 score on a scale STANDARD_DEVIATION 4.5 | 30.3 score on a scale STANDARD_DEVIATION 4.5 | 30.6 score on a scale STANDARD_DEVIATION 4.2 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 5 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 37 Participants | 105 Participants | 39 Participants | 29 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 14 Participants | 42 Participants | 13 Participants | 15 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 151 Participants | 446 Participants | 150 Participants | 145 Participants |
| Race/Ethnicity, Customized White | 126 Participants | 370 Participants | 118 Participants | 126 Participants |
| Sex: Female, Male Female | 94 Participants | 289 Participants | 94 Participants | 101 Participants |
| Sex: Female, Male Male | 71 Participants | 199 Participants | 69 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 158 | 0 / 157 | 0 / 165 |
| other Total, other adverse events | 43 / 158 | 48 / 157 | 62 / 165 |
| serious Total, serious adverse events | 2 / 158 | 2 / 157 | 2 / 165 |
Outcome results
Primary
Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Week 6
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item, clinician-rated scale that evaluates the participant's depressive symptomatology during the past week. Participants were rated on items assessing feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty in concentration, and lack of interest. Each of the 10 items was scored on a 7-point scale with a score of 0 reflecting no symptoms and a score of 6 reflecting symptoms of maximum severity for a total possible score of 0 (best) to 60 (worst). A negative change from Baseline indicates improvement.
Time frame: Baseline (Week 0) to Week 6
Population: The Intent-to-Treat (ITT) Population included all participants from the safety population who had at least 1 postbaseline assessment of the MADRS total score. Overall number of participants analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Week 6 | -12.6 score on a scale | Standard Error 0.76 |
| Cariprazine 1.5 mg | Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Week 6 | -15.1 score on a scale | Standard Error 0.77 |
| Cariprazine 3.0 mg | Change From Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Score at Week 6 | -15.6 score on a scale | Standard Error 0.76 |
Comparison: To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.p-value: 0.033195% CI: [-4.6, -0.4]Mixed Model Repeated Measures (MMRM)
Comparison: To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.p-value: 0.010395% CI: [-5.1, -0.9]Mixed Model Repeated Measures (MMRM)
Secondary
Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 6
The Clinical Global Impressions-Severity (CGI-S) is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of other participants the physician has observed. The participant was rated on a scale from 1 to 7, with 1 indicating a normal state and 7 indicating among the most extremely ill participants. A negative change from Baseline indicates improvement.
Time frame: Baseline (Week 0) to Week 6
Population: ITT Population included all participants from the safety population who had at least 1 postbaseline assessment of the MADRS total score. Overall number of participants analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 6 | -1.3 score on a scale | Standard Error 0.09 |
| Cariprazine 1.5 mg | Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 6 | -1.6 score on a scale | Standard Error 0.1 |
| Cariprazine 3.0 mg | Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 6 | -1.6 score on a scale | Standard Error 0.09 |
Comparison: To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.p-value: 0.071495% CI: [-0.5, 0]Mixed Model Repeated Measures (MMRM)
Comparison: To control the overall type I error rate for multiple comparisons of 2 active doses versus placebo at Week 6 for the primary and secondary efficacy parameters, the parallel gatekeeping procedure was implemented.p-value: 0.066295% CI: [-0.5, 0]Mixed Model Repeated Measures (MMRM)