Study of the Efficacy of a Fixed-dose Regimen of Cariprazine Compared to Placebo for Treatment of the Depressive Episode in Participants With Bipolar I Disorder

Study Overview
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Brief Summary
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This study is designed to prospectively confirm the efficacy of a fixed-dose regimen of cariprazine 1.5 milligrams (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.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Fixed-Dose Clinical Trial Evaluating The Efficacy, Safety And Tolerability Of Cariprazine In Patients With Bipolar I Depression

Conditions
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Depression, Bipolar Disorder

Intervention / Treatment
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* Drug: Cariprazine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 Patient 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 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: Patients with a positive cannabinoid on entry may be retested before randomization. If the patient remains positive, the patient is no longer eligible Patients 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cariprazine 3.0 mg<br>Following a 7 to 14 days screening/washout period, cariprazine 1.5 milligrams (mg) capsule, one per day, orally for 2 weeks increased to cariprazine 3.0 mg capsule, one per day orally beginning on Day 15 for 4 weeks. | Drug: Cariprazine<br>* Cariprazine capsule one per day orally.<br>* Other names: Vraylar;|
| Experimental: Cariprazine 1.5 mg<br>Following a 7 to 14 days screening/washout period, cariprazine 1.5 mg capsule, one per day, orally for 6 weeks. | Drug: Cariprazine<br>* Cariprazine capsule one per day orally.<br>* Other names: Vraylar;|
| Placebo Comparator: Placebo<br>Following a 7 to 14 days screening/washout period, matching placebo capsule, one per day, orally for 6 weeks. | Drug: Placebo<br>* Matching placebo capsule one per day orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) | MADRS is a 10-item, clinician-rated scale that evaluates the participants 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. Mixed-effects Model for Repeated Measures (MMRM) with fixed factors (treatment group, pooled study center, and visit), baseline (a covariate), and interactions (treatment group by visit, baseline by visit). | Baseline (Week 0) to Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinical Global Impressions-Severity (CGI-S) Score | CGI-S is a clinician-rated scale that measures the overall severity of a participant's illness in comparison with the severity of other patients 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 patients. A negative change from Baseline indicates improvement. MMRM with fixed factors (treatment group, pooled study center, and visit), baseline (a covariate), and interactions (treatment group by visit, baseline by visit). | Baseline (Week 0) to Week 6 |