Efficacy, Safety, and Tolerability of an Intramuscular Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Bipolar I Patients

Study Overview
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Brief Summary
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This will be a randomized, double-blind, placebo-controlled trial to assess the time to recurrence of any mood episode in subjects with bipolar I disorder who have maintained stability on aripiprazole IM depot for at least 8 weeks. This trial will include male and female subjects 18 to 65 years of age, inclusive, with a diagnosis of bipolar I disorder, according to DSM-IV-TR criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI), who have experienced at least one previous manic episode of sufficient severity to require hospitalization and/or treatment with a mood stabilizer or antipsychotic agent in addition to their current manic episode. All subjects must be experiencing a manic episode (per DSM-IV-TR criteria) with a YMRS total score ≥ 20 at trial entry. Both inpatients and outpatients are eligible for this trial. This trial will consist of a screening phase followed by 4 treatment phases. Subjects will undergo screening for eligibility, followed by a conversion to oral aripiprazole monotherapy phase, if needed, an oral aripiprazole stabilization phase, a single-blind aripiprazole IM depot stabilization phase, and, a double-blind, placebo-controlled phase.

Official Title
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52-week, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of an Intramuscular Depot Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Patients With Bipolar I Disorder

Conditions
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Bipolar I Disorder

Intervention / Treatment
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* Drug: Intramuscular (IM) Depot Aripiprazole
* Drug: Intramuscular (IM) Depot Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female subjects 18 to 65 years of age, inclusive, at time of informed consent. Subjects with a current diagnosis of bipolar I disorder, as defined by DSM-IV-TR criteria and confirmed by the MINI and a history of at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer, and/or treatment with an antipsychotic agent, in addition to their current manic episode. Require is defined as an intervention that occurred rather than one that was recommended. Rapid cyclers with 8 or fewer episodes in the previous year will be included. Subjects currently experiencing a manic episode with a YMRS total score of ≥20 at the Screening Visit. Subjects can have an inpatient or outpatient status prior to entry into Phase C (IM depot stabilization). In the investigator's opinion, subjects who are able to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, aripiprazole IM depot injection, and discontinuation of prohibited concomitant medications; who can read and understand the written word in order to complete subject-reported outcomes measures; and who can be reliably rated on assessment scales. Key Exclusion Criteria: Subjects with a current Axis I (DSM-IV-TR) diagnosis other than bipolar I disorder. Subjects who have NOT experienced at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer, and /or treatment with an antipsychotic agent, excluding their current manic episode. Require is defined as a intervention that occurred rather than one that was recommended. Subjects with bipolar I disorder who are considered resistant/refractory to treatment for manic symptoms by history. Subjects unresponsive to clozapine for treatment of mania. Subjects with a significant risk of committing suicide based on history, mental status examination, investigator's judgment, or C-SSRS answer of yes to question 4 or 5 (current or within the last 90 days). Subjects with a current manic episode with a duration of > 2 years. Subjects who currently (within the past month) meet DSM-IV-TR criteria for substance abuse or substance dependence; this includes the abuse of alcohol and benzodiazepines, but excludes the use of caffeine and/or nicotine. Subjects who have a history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event (AE) or interfere with assessments of safety or efficacy during the course of the trial, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease as determined by the clinical judgment of the investigator. Subjects who are currently experiencing a mixed or a depressive episode (per DSM-IV-TR criteria). Subjects with a history of hypersensitivity to antipsychotic agents.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Active Comparator: Treatment of Aripiprazole IM Depot | Drug: Intramuscular (IM) Depot Aripiprazole<br>* Formulation: Intramuscular (IM) Depot Aripiprazole Formulation 400 mg or 300 mg, once a month injection<br>|
| Placebo Comparator: 2<br>Placebo Comparator: Treatment of IM Depot Placebo | Drug: Intramuscular (IM) Depot Placebo<br>* Formulation: Intramuscular (IM) Depot Placebo 400 mg or 300 mg, once a month injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Randomization to Recurrence of Any Mood Episode During Double-bind Placebo-controlled Phase. | This endpoint was defined as meeting any of the following criteria: Hospitalization for any mood episode OR Any of the following: YMRS total score ≥ 15 OR MADRS total score ≥ 15 OR CGI-BP-S score > 4 (overall score) OR SAE of worsening disease (bipolar I disorder) OR Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR Clinical worsening with the need for treatment of symptoms of an underlying mood disorder by addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, or increase greater than the allowed benzodiazepine doses, or Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of yes on question 4 or 5 on the C-SSRS. The time to event is presented in the following table. | Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Meeting Criteria for Recurrence of Any Mood Episode. | To assess the proportion of subjects who met criteria for recurrence of any mood episode (manic, mixed or depressive). Hierarchical procedure was used to preserve the overall Type I error at 0.05. | Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52). | 
| Mean Change From Randomization to Endpoint in the CGI-BP-S (Mania) Score. | CGI-BP-S assessed the subject's severity of Illness (mania) based on a 7-point scale ranging from 1 (normal/ not ill at all) to 7 (very severely ill). | Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52). | 
| Time From Randomization to Recurrence Defined by Hospitalization for a Mood Episode. | Analysis of time from randomization to recurrence defined by hospitalization for a mood episode (Double-blind, Placebo-controlled Phase efficacy sample). Time to recurrence is presented in the following table. | Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aripiprazole, Intramuscular (IM) Depot, Bipolar