Bipolar I Disorder
Conditions
Keywords
Aripiprazole, Intramuscular (IM) Depot, Bipolar
Brief summary
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.
Interventions
DRUGIntramuscular (IM) Depot Aripiprazole
Formulation: Intramuscular (IM) Depot Aripiprazole Formulation 400 mg or 300 mg, once a month injection
DRUGIntramuscular (IM) Depot Placebo
Formulation: Intramuscular (IM) Depot Placebo 400 mg or 300 mg, once a month injection
Sponsors
H. Lundbeck A/S
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Recurrence of Any Mood Episode During Double-bind Placebo-controlled Phase. | Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52). | This endpoint was defined as meeting any of the following criteria: 1. Hospitalization for any mood episode OR 2. Any of the following: 1. YMRS total score ≥ 15 OR 2. MADRS total score ≥ 15 OR 3. CGI-BP-S score \> 4 (overall score) OR 3. SAE of worsening disease (bipolar I disorder) OR 4. Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR 5. 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 6. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Meeting Criteria for Recurrence of Any Mood Episode. | Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52). | 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. |
| Mean Change From Randomization to Endpoint in the CGI-BP-S (Mania) Score. | Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52). | 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). |
| Time From Randomization to Recurrence Defined by Hospitalization for a Mood Episode. | Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52). | 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. |
Countries
Canada, Japan, Poland, Romania, South Korea, Taiwan, United States
Participant flow
Recruitment details
This trial was conducted in 1175 subjects (including 444 screen failures) at 103 trial sites in the following 7 countries: Canada, Japan, Republic of Korea, Poland, Romania, Taiwan, and the United States (US).
Pre-assignment details
The trial consisted of a screening phase and 4 phases. In Conversion, Oral Stabilization and IM Depot Stabilization Phases, there was a single treatment group. In Double-blind, Placebo-controlled Phase, there were 2 treatment groups. All Outcome Measures were assessed in the Double-blind, Placebo-controlled Phase of the study.
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole Depot Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks. | 133 |
| Placebo Subjects received placebo intramuscularly up to 52 weeks. | 133 |
| Total | 266 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Conversion Phase. | Adverse Event | 33 | 0 | 0 | 0 | 0 |
| Conversion Phase. | Lack of Efficacy | 2 | 0 | 0 | 0 | 0 |
| Conversion Phase. | Lost to Follow-up | 16 | 0 | 0 | 0 | 0 |
| Conversion Phase. | Met withdrawal criteria | 10 | 0 | 0 | 0 | 0 |
| Conversion Phase. | Protocol deviation | 3 | 0 | 0 | 0 | 0 |
| Conversion Phase. | Withdrawal by Subject | 32 | 0 | 0 | 0 | 0 |
| Conversion Phase. | Withdrawn by the investigator | 3 | 0 | 0 | 0 | 0 |
| Double-blind, Placebo-controlled Phase | AE without recurrence of any moodepisode | 0 | 0 | 0 | 7 | 1 |
| Double-blind, Placebo-controlled Phase | Lost to Follow-up | 0 | 0 | 0 | 8 | 5 |
| Double-blind, Placebo-controlled Phase | Met withdrawal criteria | 0 | 0 | 0 | 4 | 7 |
| Double-blind, Placebo-controlled Phase | Protocol deviation | 0 | 0 | 0 | 1 | 1 |
| Double-blind, Placebo-controlled Phase | Recurrence of any mood episode with AE | 0 | 0 | 0 | 16 | 33 |
| Double-blind, Placebo-controlled Phase | Recurrence of any mood episode withoutAE | 0 | 0 | 0 | 19 | 35 |
| Double-blind, Placebo-controlled Phase | Sponsor discontinued study | 0 | 0 | 0 | 1 | 3 |
| Double-blind, Placebo-controlled Phase | Withdrawal by Subject | 0 | 0 | 0 | 13 | 10 |
| IM Depot Stabilization. | Adverse Event | 0 | 0 | 37 | 0 | 0 |
| IM Depot Stabilization. | Lack of Efficacy | 0 | 0 | 7 | 0 | 0 |
| IM Depot Stabilization. | Lost to Follow-up | 0 | 0 | 21 | 0 | 0 |
| IM Depot Stabilization. | Met withdrawal criteria | 0 | 0 | 26 | 0 | 0 |
| IM Depot Stabilization. | Protocol deviation | 0 | 0 | 5 | 0 | 0 |
| IM Depot Stabilization. | Sponsor discontinued study | 0 | 0 | 1 | 0 | 0 |
| IM Depot Stabilization. | Withdrawal by Subject | 0 | 0 | 56 | 0 | 0 |
| IM Depot Stabilization. | Withdrawn by the investigator | 0 | 0 | 6 | 0 | 0 |
| Oral Aripiprazole Stabilization Phase. | Adverse Event | 0 | 63 | 0 | 0 | 0 |
| Oral Aripiprazole Stabilization Phase. | Lack of Efficacy | 0 | 12 | 0 | 0 | 0 |
| Oral Aripiprazole Stabilization Phase. | Lost to Follow-up | 0 | 44 | 0 | 0 | 0 |
| Oral Aripiprazole Stabilization Phase. | Met withdrawal criteria | 0 | 41 | 0 | 0 | 0 |
| Oral Aripiprazole Stabilization Phase. | Withdrawal by Subject | 0 | 45 | 0 | 0 | 0 |
| Oral Aripiprazole Stabilization Phase. | Withdrawn by the investigator | 0 | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Aripiprazole Depot | Total | Placebo |
|---|---|---|---|
| Age at first manic episode (years) | 25.2 years STANDARD_DEVIATION 10.3 | 25.0 years STANDARD_DEVIATION 10.1 | 24.8 years STANDARD_DEVIATION 9.9 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 133 Participants | 265 Participants | 132 Participants |
| Age, Continuous | 40.6 years STANDARD_DEVIATION 10.8 | 40.6 years STANDARD_DEVIATION 11 | 40.6 years STANDARD_DEVIATION 11.2 |
| Clinical Global Impressions - Bipolar Version Severity (CGI-BP-S) - Mania | 1.5 Scores on a scale STANDARD_DEVIATION 0.7 | 1.5 Scores on a scale STANDARD_DEVIATION 0.7 | 1.4 Scores on a scale STANDARD_DEVIATION 0.6 |
| Duration of disease prior to enrollment (years) | 12.1 years STANDARD_DEVIATION 9.2 | 12.9 years STANDARD_DEVIATION 9.5 | 13.6 years STANDARD_DEVIATION 9.8 |
| Montgomery Asberg Depression Rating Scale (MADRS) Total Score | 3.0 Scores on a scale STANDARD_DEVIATION 3.4 | 2.7 Scores on a scale STANDARD_DEVIATION 3.4 | 2.4 Scores on a scale STANDARD_DEVIATION 3.4 |
| Number of mood episodes past 12 months | 2.2 Mood episodes STANDARD_DEVIATION 1.2 | 2.2 Mood episodes STANDARD_DEVIATION 1.2 | 2.2 Mood episodes STANDARD_DEVIATION 1.1 |
| Number of prior hospitalizations for a mood episode | 3.5 Prior hospitalization for mood episode STANDARD_DEVIATION 3.9 | 3.5 Prior hospitalization for mood episode STANDARD_DEVIATION 4 | 3.5 Prior hospitalization for mood episode STANDARD_DEVIATION 4.1 |
| Region of Enrollment Canada | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Japan | 9 Participants | 19 Participants | 10 Participants |
| Region of Enrollment Poland | 4 Participants | 5 Participants | 1 Participants |
| Region of Enrollment Romania | 8 Participants | 20 Participants | 12 Participants |
| Region of Enrollment South Korea | 7 Participants | 14 Participants | 7 Participants |
| Region of Enrollment Taiwan | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 101 Participants | 203 Participants | 102 Participants |
| Sex: Female, Male Female | 83 Participants | 153 Participants | 70 Participants |
| Sex: Female, Male Male | 50 Participants | 113 Participants | 63 Participants |
| Young-Mania Rating Scale (YMRS) Total Score | 2.9 Scores on a scale STANDARD_DEVIATION 3.5 | 2.8 Scores on a scale STANDARD_DEVIATION 3.3 | 2.6 Scores on a scale STANDARD_DEVIATION 3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 459 | 1 / 614 | 0 / 425 | 1 / 132 | 0 / 133 |
| other Total, other adverse events | 180 / 459 | 196 / 614 | 194 / 425 | 66 / 132 | 62 / 133 |
| serious Total, serious adverse events | 32 / 459 | 35 / 614 | 36 / 425 | 10 / 132 | 25 / 133 |
Outcome results
Primary
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: 1. Hospitalization for any mood episode OR 2. Any of the following: 1. YMRS total score ≥ 15 OR 2. MADRS total score ≥ 15 OR 3. CGI-BP-S score \> 4 (overall score) OR 3. SAE of worsening disease (bipolar I disorder) OR 4. Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR 5. 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 6. 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.
Time frame: Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).
Population: All randomized subjects who received at least one injection of investigational medicinal product (IMP) and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified intent-to-treat (ITT) population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aripiprazole IM Depot | Time From Randomization to Recurrence of Any Mood Episode During Double-bind Placebo-controlled Phase. | NA Days |
| Placebo | Time From Randomization to Recurrence of Any Mood Episode During Double-bind Placebo-controlled Phase. | 308 Days |
Comparison: Significance level 0.05.p-value: <0.000195% CI: [0.299, 0.678]Log Rank
95% CI: [1.475, 3.34]
Secondary
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).
Time frame: Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).
Population: All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aripiprazole IM Depot | Mean Change From Randomization to Endpoint in the CGI-BP-S (Mania) Score. | -0.16 Units on a scale | Standard Error 0.058 |
| Placebo | Mean Change From Randomization to Endpoint in the CGI-BP-S (Mania) Score. | 0.27 Units on a scale | Standard Error 0.126 |
p-value: =0.001195% CI: [-0.69, -0.17]Mixed model repeated measure analysis
Secondary
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.
Time frame: Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).
Population: All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aripiprazole IM Depot | Number of Subjects Meeting Criteria for Recurrence of Any Mood Episode. | 35 Participants |
| Placebo | Number of Subjects Meeting Criteria for Recurrence of Any Mood Episode. | 68 Participants |
Comparison: Statistical analysis for any mood episodep-value: <0.000195% CI: [-36.7, -12.5]Fisher Exact
Secondary
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.
Time frame: Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).
Population: All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aripiprazole IM Depot | Time From Randomization to Recurrence Defined by Hospitalization for a Mood Episode. | NA Days |
| Placebo | Time From Randomization to Recurrence Defined by Hospitalization for a Mood Episode. | NA Days |
p-value: =0.000295% CI: [0.04, 0.465]Log Rank
95% CI: [2.151, 24.865]