Study to Evaluate the Efficacy and Safety of Aripiprazole Administered With Lithium or Valproate Over 12 Weeks in the Treatment of Mania in Bipolar I Disorder

Study Overview
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Brief Summary
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The purpose of the study is to determine whether aripiprazole provides additional clinical benefit to patients with Bipolar I disorder when combined with lithium or valproate over 12 weeks.

Official Title
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A 12-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study To Evaluate the Efficacy and Safety of Adjunctive Aripiprazole Therapy in the Treatment of Mania in Bipolar I Disorder Patients Treated on Valproate or Lithium and in Need of Further Clinical Improvement

Conditions
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Bipolar Disorder Mania

Intervention / Treatment
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* Drug: Aripiprazole
* Drug: Placebo
* Drug: Lithium
* Drug: Valproate


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Clinical diagnosis of bipolar I disorder mania, manic or mixed episode, with or without psychotic features Current ongoing lithium or valproate treatment with the possibility of benefiting, based on the investigator's clinical judgment, from adjunctive treatment with aripiprazole Therapeutic serum levels of lithium or valproate and a Young Mania Rating Total Score of 16 or higher at screening and baseline Participants taking current lithium or valproate treatment combined with antipsychotic medication other than aripiprazole are acceptable, provided that the other antipsychotic medication is washed out at least 3 days prior to the blood draw for therapeutic plasma levels of lithium and valproate determination. Long-acting antipsychotics must be washed out prior to entering the double-blind treatment. Key exclusion criteria: Women of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the last dose of investigational product A diagnosis of delirium, dementia, amnesia or other cognitive disorder, or a psychotic disorder Current diagnosis of delirium, dementia, a cognitive disorder (ie, amnesia), or a psychotic disorder (ie, schizophrenia or schizoaffective disorder) Current diagnosis of bipolar II disorder, bipolar disorder not otherwise specified, or any other primary psychiatric disorder other than bipolar I disorder mania Thyroid pathology Demonstrated cocaine abuse or dependence within the past 3 months prior to screening. History of neuroleptic malignant syndrome from antipsychotic agents Manic symptoms that investigator considers refractory to treatment Previous nonresponsive (by investigator judgment) to aripiprazole for manic symptoms Significant risk of suicide based on history, mental status exam, or investigator judgment.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + valproate or lithium<br>Participants randomly received placebo (1:1 to study drug) as adjunctive therapy to current ongoing treatment with valproate or lithium for 12 weeks. | Drug: Placebo<br>* Tablets, Oral, 0 mg, once daily, 12 weeks<br>Drug: Lithium<br>* Participant's ongoing dose<br>Drug: Valproate<br>* Participant's ongoing dose<br>|
| Active Comparator: Aripiprazole + valproate or lithium<br>Participants randomly received aripiprazole as adjunctive therapy to current ongoing treatment with valproate or lithium for 12 weeks. Aripiprazole was provided in 5-, 10-, or 15-mg oral tablets and administered at a starting dose of 5 mg per day for Week 1. For Weeks 2 through 3, the dose was titrated up to 10 mg per day, and for Weeks 4 through 6, the dose increased to 15 mg per day. Flexible doses of either 15 or 30 mg per day were administered for Weeks 7 through 12. If participants were unable to tolerate the dose of 15 mg per day of study drug, the dose was decreased to 10 mg per day for Weeks 7 through 12. | Drug: Aripiprazole<br>* 5-, 10-, or 15-mg oral tablets in titrated doses for 12 weeks<br>* Other names: BMS-337039;Drug: Lithium<br>* Participant's ongoing dose<br>Drug: Valproate<br>* Participant's ongoing dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Score on the Young Mania Rating Scale (YMRS) (LOCF Data Set) | The YMRS is a clinician-administered scale, consisting of 11 multiple choice items, and used to assess a patient's manic symptoms and clinical condition over the previous 48 hours. Total scores range from 0 to 60, with 12 or greater signifying hypomania or mania. Each item is given a severity rating ranging from 0 to 8 or 0 to 4. Items for the scale are based on the core symptoms of mania: elevated mood, increased motor activity, sexual interest, sleep, irritability, speech (rate and amount), language-though disorder, content, disruptive-aggressive behavior, appearance, and insight. Scores for each item reflect the severity of that symptom in the patient. The test is administered during a clinical interview typically lasting 15-30 minutes. LOCF=last observation carried forward. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Score on Clinical Global Impression-Bipolar Version (CGI-BP) Severity of Illness (Mania) Scale (LOCF Data Set) | Adjusted mean change. The CGI-BP is a scale used to assess a clinician's impression of a patient's illness. Each patient is rated at baseline and at subsequent visits on items related to severity of depression, mania, and overall bipolar illness. The CGI-BP is a 7-point scale, with scores ranging from 1=normal/not ill to 7=very severely ill. Higher total score indicates greater severity of illness. LOCF=last observation carried forward. | Baseline to Weeks 3, 6, 9, and 12 | 
| Change From Baseline in Score on Clinical Global Impression-Bipolar Version (CGI-BP) Severity of Illness (Depression) Scale (LOCF Data Set) | Adjusted mean change. The CGI-BP is a scale used to assess a clinician's impression of a patient's illness. Each patient is rated at baseline and at subsequent visits on items related to severity of depression, mania, and overall bipolar illness. The CGI-BP is a 7-point scale, with scores ranging from 1=normal/not ill to 7=very severely ill. Higher total score indicates greater severity of illness. LOCF=last observation carried forward. | Baseline to Weeks 3, 6, 9, and 12 | 
| Change From Baseline in Score on Clinical Global Impression-Bipolar Version (CGI-BP) Severity of Illness (Overall) Scale at Week 12 (LOCF Data Set) | Adjusted mean change. The CGI-BP is scale used to assess a clinician's impression of a patient's illness. Each patient is rated at baseline and at subsequent visits on items related to severity of depression, mania, and overall bipolar illness. The CGI-BP is a 7-point scale, with scores ranging from 1=normal/not ill to 7=very severely ill. Higher total score indicates greater severity of illness. LOCF=last observation carried forward. | Baseline to Week 12 | 
| Change From Baseline in Total and Subscale Scores on the Functional Assessment Short Test (FAST)(LOCF Data Set) | The FAST is an interview-administered instrument used to assess the main functioning problems that patients with bipolar disorder experience. Participants are rated at Baseline, Week 3, Week 6, Week 9, and Week 12/End of Study Visit. The FAST consists of 24 items that assess impairment or disability in 6 specific areas of functioning, categorized as the subscales: autonomy, occupational functioning, cognitive functioning, financial issues, interpersonal (IP) relationships, and leisure time. All items are rated using a 4-point scale, 0=no difficulty, 1=mild difficulty, 2=moderate difficulty, and 3=severe difficulty. The global score is the sum of the scores of all items and ranges from 0 (0*24)to 96 (4*24). The higher the global score, the higher the level of impairment. function=functioning. LOCF=last observation carried forward. | Baseline to Weeks 3, 6, 9, and 12 | 
| Percentage of Participants Showing A Response From Baseline on the Young Mania Rating Scale (YMRS)(OC Data Set) | Response on the YMRS is defined as a 50% or greater improvement from baseline in YMRS total score. The YMRS is clinician-administered and consists of 11 multiple choice items. It is used to assess a patient's manic symptoms and clinical condition over the previous 48 hours. Total scores range from 0 to 60, with 12 or greater signifying hypomania or mania. Each item is given a severity rating ranging from 0 to 8 or 0 to 4. Items for the scale are based on the core symptoms of mania: elevated mood, increased motor activity, sexual interest, sleep, irritability, speech (rate and amount), language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight. Scores for each item reflect the severity of that symptom in the patient. The test is administered during a clinical interview typically lasting 15-30 minutes. OC=observed cases. | Baseline to Weeks 3, 6, 9, and 12 | 
| Percentage of Participants Showing Remission in the Young Mania Rating Scale (YMRS) Score From Baseline (LOCF Data Set) | Remission is defined as a YMRS total score of 12 or less. The YMRS is clinician-administered and consists of 11 multiple choice items. It is used to assess a patient's manic symptoms and clinical condition over the previous 48 hours. Total scores range from 0 to 60, with 12 or greater signifying hypomania or mania. Each item is given a severity rating ranging from 0 to 8 or 0 to 4. Items for the scale are based on the core symptoms of mania: elevated mood, increased motor activity, sexual interest, sleep, irritability, speech (rate and amount), language-thought disorder, disruptive-aggressive behavior, appearance, and insight. Scores for each item reflect the severity of that symptom in the patient. The test is administered during a clinical interview typically lasting 15-30 minutes. LOCF=last observation carried forward. | Baseline to Weeks 3,6, 9, and 12 | 
| Change From Baseline in Total Score on the Longitudinal Interval Follow-up Evaluation-Rating Impaired Functioning Tool (LIFE-RIFT)(OC Data Set and Week 12 LOCF Data Set) | Adjusted mean change. The LIFE-RIFT total score ranges from 4 to 20 and is the sum of scores of 4 items: work, interpersonal relations, satisfaction, and recreation. A negative change score signifies improvement. OC=observed cases; LOCF=last observation carried forward. | Baseline to Weeks 6 and 12 | 
| Participant Scores on Patient Global Impression Improvement (PGI-I) Scale (OC Data Set) | Adjusted Mean Scores. The PGI-I is a self-administered 7-point scale, with scores ranging from 1 (very much improved) to 7 (very much worse), that assesses the improvement or worsening of a patient's illness relative to baseline at the beginning of the intervention. Scores: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. OC=observed cases. | Baseline to Weeks 3, 6, 9, and 12 | 
| Change From Baseline in Participant Weight (OC Data Set and Week 12 LOCF Data Set) | Adjusted mean change.OC=observed cases; LOCF=last observation carried forward. | Baseline to Weeks 3, 6, 9, and 12 | 
| Percentage of Participants With Relevant Weight Gain or Weight Loss From Baseline at Week 12 (LOCF Data Set) | Relevant weight gain=7% or greater increase in weight; relevant weight loss=7% or greater decrease in weight. LOCF=last observation carried forward. | Baseline to Weeks 3, 6, 9, and12 | 
| Change From Baseline to Week 12 in Body Mass Index (BMI) (LOCF Data Set) | BMI=Weight in kilograms /(Height in meters^2). LOCF=last observation carried forward. | Baseline to Week 12 |