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

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

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.

Study Overview

• Status: Completed
• Conditions: Bipolar I Disorder
• Intervention / Treatment: Drug: Intramuscular (IM) Depot Aripiprazole; Drug: Intramuscular (IM) Depot Placebo

• Study Type: Interventional
• Enrollment (Actual): 731
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Chatham, Ontario, Canada
• Japan
  • Fukuoka, Japan
  • Itabashi-bu, Japan
  • Kanzaki-gun, Japan
  • Koriyama-shi, Japan
  • Kumamoto, Japan
  • Okinawa, Japan
  • Shinjuku-ku, Japan
  • Tokyo, Japan
  • Tottori, Japan
  • Toyama, Japan
  • Fukusima
    • Aizu Wakamatsu, Fukusima, Japan
  • Hokkaido
    • Sapporo, Hokkaido, Japan
  • Iwate
    • Morioka, Iwate, Japan
  • Kanagawa
    • Kawasaki-shi, Kanagawa, Japan
    • Yokohama, Kanagawa, Japan
    • Yokohama-shi, Kanagawa, Japan
  • Nara
    • Kashihara, Nara, Japan
  • Osaka
    • Sakai, Osaka, Japan
    • Sakai-shi, Osaka, Japan
• Korea, Republic of
  • Daejeon, Korea, Republic of
  • Jeju-si, Korea, Republic of
  • Seoul, Korea, Republic of
  • Gyeonggi-do
    • Anyang-si, Gyeonggi-do, Korea, Republic of
    • Goyang-si, Gyeonggi-do, Korea, Republic of
• Poland
  • Bydgoszcz, Poland
  • Chelmno, Poland
  • Choroszcz, Poland
  • Pomorskie
    • Gdynia, Pomorskie, Poland
• Romania
  • Bucharest, Romania
  • Judet Lasi, Romania
  • Dyambovita
    • Targoviste, Dyambovita, Romania
• Taiwan
  • Keelung City, Taiwan
  • Taipei, Taiwan
  • Taouyuan County, Taiwan
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arkansas
    • Springdale, Arkansas, United States
  • California
    • Beverly Hills, California, United States
    • Costa Mesa, California, United States
    • Escondido, California, United States
    • Garden Grove, California, United States
    • Los Angeles, California, United States
    • National City, California, United States
    • Oceanside, California, United States
    • Orange, California, United States
    • Pico Rivera, California, United States
    • Riverside, California, United States
    • San Diego, California, United States
    • Temecula, California, United States
    • Torrance, California, United States
  • Florida
    • Lauderhill, Florida, United States
    • Leesburg, Florida, United States
    • Melbourne, Florida, United States
    • Oakland Park, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Decatur, Georgia, United States
    • Smyrna, Georgia, United States
  • Illinois
    • Hoffman Estates, Illinois, United States
  • Louisiana
    • New Orleans, Louisiana, United States
  • Maryland
    • Rockville, Maryland, United States
  • Mississippi
    • Flowood, Mississippi, United States
  • Missouri
    • Saint Charles, Missouri, United States
    • Saint Louis, Missouri, United States
  • Nebraska
    • Lincoln, Nebraska, United States
  • New Jersey
    • Cherry Hill, New Jersey, United States
  • New York
    • Brooklyn, New York, United States
    • Buffalo, New York, United States
    • New York, New York, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Dayton, Ohio, United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
  • Pennsylvania
    • Allentown, Pennsylvania, United States
    • Jenkintown, Pennsylvania, United States
  • Texas
    • Austin, Texas, United States
    • Dallas, Texas, United States
    • Wichita Falls, Texas, United States
  • Virginia
    • Richmond, Virginia, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 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.
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 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.
3. Subjects with bipolar I disorder who are considered resistant/refractory to treatment for manic symptoms by history.
4. Subjects unresponsive 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 with a current manic episode with a duration of > 2 years.
7. 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.
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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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 ORMADRS total score ≥ 15 ORCGI-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).

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborators: H. Lundbeck A/S
• Investigators: Study Director: Stacy Wu, MD, Otsuka Pharmaceutical Development and Commercialization, Inc.

Publications and helpful links

General Publications

• Calabrese JR, Sanchez R, Jin N, Amatniek J, Cox K, Johnson B, Perry P, Hertel P, Such P, Salzman PM, McQuade RD, Nyilas M, Carson WH. Efficacy and Safety of Aripiprazole Once-Monthly in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled, 52-Week Randomized Withdrawal Study. J Clin Psychiatry. 2017 Mar;78(3):324-331. doi: 10.4088/JCP.16m11201.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: March 26, 2012
• First Submitted That Met QC Criteria: March 28, 2012
• First Posted (Estimate): March 30, 2012

Study Record Updates

• Last Update Posted (Actual): August 24, 2018
• Last Update Submitted That Met QC Criteria: July 24, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Aripiprazole; Bipolar; Intramuscular (IM) Depot
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Antidepressive Agents; Dopamine Agonists; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Aripiprazole
• Other Study ID Numbers: 31-08-250