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

• Proportion of subjects meeting criteria for recurrence of any mood episode(manic, mixed, depressive) [ Time Frame: Up to 52 weeks from randomization ] [ Designated as safety issue: No ]
• Mean change from randomization to endpoint in the CGI-BP-S (mania) score [ Time Frame: Up to 52 weeks from randomization ] [ Designated as safety issue: No ]
• Time from randomization to recurrence defined by hospitalization for a mood episode. [ Time Frame: Up to 52 weeks from randomization ] [ Designated as safety issue: No ]

• Proportion of subjects meeting criteria for recurrence of any mood episode(manic, mixed, depressive) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
• Mean change from randomization to endpoint in the CGI-BP-S (mania) score [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
• Time from randomization to recurrence defined by hospitalization for a mood episode. [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]

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.

• Drug: Intramuscular (IM) Depot Aripiprazole
  Formulation: Intramuscular (IM) Depot Aripiprazole Formulation 400 mg or 300 mg, once a month injection
• Drug: Intramuscular (IM) Depot Placebo
  Formulation: Intramuscular (IM) Depot Placebo 400 mg or 300 mg, once a month injection

• Active Comparator: 1
  Active Comparator: Treatment of Aripiprazole IM Depot
  Intervention: Drug: Intramuscular (IM) Depot Aripiprazole
• Placebo Comparator: 2
  Placebo Comparator: Treatment of IM Depot Placebo
  Intervention: Drug: Intramuscular (IM) Depot Placebo

Key Inclusion Criteria:

1. Male and female subjects 18 to 65 years of age, inclusive, at time of informed consent.
2. Subjects with a current diagnosis of bipolar I disorder, as defined by DSM-IV-TR criteria and confirmed by the MINI, who have experienced at least 1 previous manic episode of sufficient severity to require hospitalization and/or treatment with a mood stabilizer or antipsychotic agent, in addition to their most recent episode. Rapid cyclers with 8 or less episodes in the previous year will be included.
3. Subjects currently experiencing a manic episode with a YMRS total score of ≥20 at the Screening Visit.
4. Subjects can have an inpatient or outpatient status prior to entry into Phase C (IM depot stabilization).
5. 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:

1. Subjects with a current Axis I (DSM-IV-TR) diagnosis other than bipolar I disorder.
2. Subjects who have not experienced at least 1 previous manic episode of sufficient severity to require hospitalization in their lifetime and/or treatment with a mood stabilizer or antipsychotic agent, excluding their current manic episode.
3. Subjects with bipolar I disorder who are considered resistant/refractory to treatment for manic symptoms by history.
4. Subjects who are unresponsive to clozapine or those who only respond to clozapine for treatment of mania.
5. 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).
6. Subjects who have a current manic episode with duration of > 2 years.
7. Subjects who currently 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.
8. 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.
9. Subjects who are currently experiencing a mixed or a depressive episode (per DSM-IV-TR criteria).
10. Subjects with a history of hypersensitivity to antipsychotic agents.