A Study of Aripiprazole (Abilify) in Patients With Bipolar Mania

This study has been completed.
Sponsor:
Collaborator:
Otsuka America Pharmaceutical
Information provided by:
Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:
NCT00261443
First received: December 1, 2005
Last updated: November 7, 2013
Last verified: April 2011
  Purpose

The purpose of this clinical research study is to learn if outpatients with bipolar mania who are partially nonresponsive to lithium or valproate monotherapy can achieve stable symptoms on a combination treatment of aripiprazole plus lithium or valproate.


Condition Intervention Phase
Bipolar Disorder
Drug: Lithium or Valproate with placebo (PBO)
Drug: Lithium or Valproate with Aripiprazole
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Efficacy of Aripiprazole in Combination With Lithium or Valproate in the Long-Term Maintenance Treatment of Bipolar I Disorder in Outpatients Partially Nonresponsive to Lithium or Valproate Monotherapy

Resource links provided by NLM:


Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:
  • Proportion of Participants Not Experiencing Relapse to Any Mood Episode Through Week 52, Phase 3 [ Time Frame: Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 of Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Kaplan-Meier estimated survival rate. Criteria for relapse include one or more of the following: hospitalization for a manic, mixed or depressive episode; serious adverse event of worsening disease under study accompanied by a Y-MRS > 16 and/or a MADRS > 16; discontinuation due to lack of efficacy as determined by the investigator accompanied by a Y-MRS > 16 and/or a MADRS > 16.


Secondary Outcome Measures:
  • Baseline and Adjusted Mean Change From Baseline in Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) Severity of Illness Score (Mania) Through Phase 3 [ Time Frame: Baseline (end of Phase 2), 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Proportion of Participants Not Experiencing Relapse of Manic Episode Through Phase 3 [ Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 of phase 3 ] [ Designated as safety issue: No ]
    Kaplan-Meier estimated survival rate. Criteria for relapse include one or more of the following: relapse is defined as any of the following events accompanied by a Young-Mania Rating Scale (Y-MRS) >16 and/or a Montgomery Åsberg Depression Rating Scale (MADRS) >16; serious adverse event of worsening disease, or discontinuation by the investigator for lack of efficacy. A hospitalization for a manic, mixed, or depressive episode does meet the criteria for relapse, however does not require an accompanying Y-MRS and/or MADRS score >16.

  • Proportion of Participants Not Experiencing Relapse of Depressive Episode Through Week 52 During Phase 3 [ Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 of phase 3 ] [ Designated as safety issue: No ]
    Kaplan Meier estimated survival rate. Relapse is defined as any of the following events accompanied by a YMRS > 16 and/or a MADRS > 16; serious adverse event of worsening disease, or discontinuation by the investigator for lack of efficacy. A hospitalization for a manic, mixed, or depressive episode does meet the criteria for relapse, however does not require an accompanying Y-MRS and/or MADRS score > 16.

  • Mean Baseline and Unadjusted Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Total Score Through Phase 2 [ Time Frame: Baseline (end of ph 1), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 (Ph2) Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, + Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    The Y-MRS consists of 11 items: 1) Elevated Mood, 2) Increased Motor Activity -Energy, 3) Sexual Interest, 4) Sleep, 5) Irritability, 6) Speech (Rate and Amount), 7) Language -Thought Disorder, 8) Content, 9) Disruptive-Aggressive Behavior, 10) Appearance, 11) Insight. Seven items are rated on a 0 to 4 scale, while 4 items (items 5, 6, 8 and 9) are rated on a 0 to 8 scale (twice the weight of the other items.) For all items, 0 is the "best" rating and 4 or 8 is the "worst" rating. Total Score is the sum of the ratings for all 11 items. The possible Total Scores are from 0 (best) to 60 (worst).

  • Mean Baseline and Adjusted Mean Change From Baseline in Young-Mania Rating Scale (Y-MRS) Total Score Through Phase 3 [ Time Frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 of Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    The Y-MRS consists of 11 items: 1) Elevated Mood, 2) Increased Motor Activity -Energy, 3) Sexual Interest, 4) Sleep, 5) Irritability, 6) Speech (Rate and Amount), 7) Language -Thought Disorder, 8) Content, 9) Disruptive-Aggressive Behavior, 10) Appearance, 11) Insight. 7 items are rated on a 0 to 4 scale, while 4 items (items 5, 6, 8 and 9) are rated on a 0 to 8 scale (twice the weight of the other items.) For all items, 0 is the "best" rating and 4 or 8 is the "worst" rating. Total Score is the sum of the ratings for all 11 items. The possible Total Scores are from 0 (best) to 60 (worst).

  • Mean Baseline and Unadjusted Mean Change From Baseline in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score Through Phase 2 and at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 (Ph2) Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. MADRS total score, a 10-item, ordinal rating scale (0=no symptoms; 60=most severe symptoms). Change from baseline=postbaseline score - baseline score. A negative change score indicates improvement.

  • Mean Baseline and Adjusted Mean Change From Baseline in Montgomery Åsberg Depression Rating Scale (MADRS) Total Score Through Phase 3 [ Time Frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. MADRS total score, a 10-item, ordinal rating scale (0=no symptoms; 60=most severe symptoms). Change from baseline=postbaseline score - baseline score. A negative change score indicates improvement.

  • Unadjusted Mean Change Baseline and Mean Change From Baseline in the CGI-BP Severity of Illness (Overall) Through Phase 2 [ Time Frame: Baseline (end of Ph 1), Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Baseline and Adjusted Mean Change From Baseline in the CGI-BP Severity of Illness (Overall) Through Phase 3 [ Time Frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Unadjusted Mean Change Baseline and Mean Change From Baseline in the CGI-BP Severity of Illness (Depression) Through Phase 2 [ Time Frame: Baseline (end of Ph 1), Weeks 1, 2, 4,6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from baseline (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Baseline and Adjusted Mean Change From Baseline in CGI-BP Severity of Illness (Depression) Score Through Phase 3 [ Time Frame: Baseline (end of Ph 2), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Unadjusted Mean Change From Preceding Phase in the CGI-BP (Mania) Through Phase 2 [ Time Frame: Weeks 1, 2, 4,6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall change from preceding phase items on a 7-point scale [1 to 7], with 1 being very much improved and 7 being very much worse).

  • Unadjusted Mean Baseline and Mean Change From Baseline in the CGI-BP Severity of Illness (Mania) Through Phase 2 [ Time Frame: Baseline (end of Ph 1), Weeks 1, 2, 4,6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from baseline (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Adjusted Mean Change in CGI-BP From Preceding Phase (Mania) Through Phase 3 [ Time Frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Unadjusted Mean Change From Preceding Phase in the CGI-BP (Depression) Through Phase 2 [ Time Frame: Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being very much improved and 7 being very much worse).

  • Adjusted Mean Change in CGI-BP From Preceding Phase (Depression) Through Phase 3 [ Time Frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline (in this case, preceding phase) in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being very much improved and 7 being very much worse).

  • Unadjusted Mean Change From Preceding Phase in the CGI-BP (Overall) Through Phase 2 [ Time Frame: Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, and Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline (in this case, preceding phase) in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being very much improved and 7 being very much worse).

  • Adjusted Mean Change in CGI-BP From Preceding Phase (Overall) Through Phase 3 [ Time Frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change from baseline (in this case, preceding phase) in patients with bipolar disorder. Patients are rated on mania, depression and overall bipolar illness items on a 7-point scale [1 to 7], with 1 being very much improved and 7 being very much worse).

  • Number of Participants Maintaining Remission During Phase 3 [ Time Frame: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52. Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Remission is defined as Y-MRS Total Score <=12 and MADRS Total Score <=12.

  • Proportion of Participants Discontinuing For Any Reason Through Week 52 (During Phase 3) [ Time Frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
  • Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuations Due to AEs During Phase 2 [ Time Frame: During Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
    Participants with Adverse Events (AEs), Deaths, Serious AEs (SAEs), and AEs leading to study discontinuation. AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

  • Treatment-Emergent Adverse Events in >=5 Percent of Participants, by Severity, During Phase 2 [ Time Frame: During Phase 2. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
    AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. By Common Terminology Criteria Version 3.0 (CTC v3) Grade (Gr): Gr 1 (mild); Gr 2 (moderate); Gr 3 (severe); Gr 4 (life-threatening); Gr 5 (death).

  • Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities During Phase 2 [ Time Frame: Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Sinus Tachycardia: ≥120bpm+↑≥15bpm+no current diagnosis of supraventricular (SV) or ventricular tachycardia or atrial fibrillation (AF) or flutter or other rhythm abnormality (RA). Sinus Bradycardia:≥50bpm+↓≥15bpm+no current diagnosis of AF or flutter or other RA. AF:not present→present or present at rate <100bpm pretreatment to present with rate ≥100bpm+increase of ≥15bpm. AV=atrioventricular; PR=PR interval. Other Intraventricular Block: QRS wave ≥0.12 sec+↑≥0.02 sec+no current diagnosis of left or right bundle branch block. Old Infarction not present→present at ≥12 weeks post study entry.

  • Number of Participants With Potentially Clinically Relevant Vital Sign Abnormalities During Phase 2 [ Time Frame: Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    Heart Rate: increase, ≥120 beats per minute (bpm) and ≥15 relative to baseline (RBL); decrease, ≤50 bpm and ≥15 RBL. Systolic BP: increase, ≥180 mmHg and ≥20 RBL; decrease, ≤90 mmHg and ≥20 RBL. Diastolic BP: increase, ≥105 mmHg and ≥15 RBL; decrease, ≤50 mmHg and ≥15 RBL. For patients missing a baseline value, an on-treatment value was considered potentially clinically relevant if the value meets the criterion value.

  • Number of Participants With Potentially Clinically Relevant Laboratory Abnormalities During Phase 2 [ Time Frame: Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    ULN=upper limit of normal; HDL=high density lipoprotein; LDL=low density lipoprotein. Values for ULN are provided by the lab in the database and could be different for each individual patient based on characteristics such as age, gender, or other patient attributes.

  • Median Baseline and Change From Baseline in ECG Measurements During Phase 2 [ Time Frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline and Change From Baseline in Heart Rate Vital Sign Measurements During Phase 2 [ Time Frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline and Change From Baseline in Blood Pressure (BP) Vital Sign Measurements During Phase 2 [ Time Frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline and Change From Baseline in Weight Vital Sign Measurements At Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline and Change From Baseline in Body Mass Index (BMI) Vital Sign Measurements at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), and Lactate Dehydrogenase (LD), Phase 2 Safety Sample [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase (CK), and Lactate Dehydrogenase (LD) at the End of Phase 2 [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline and Change From Baseline in Heart Rate Measurements During Phase 2 [ Time Frame: Baseline (end of Ph 1), Phase 2 (a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Blood Urea Nitrogen (BUN), Total Cholesterol-Fasting (TC), Creatine, Glucose, High Density Lipoprotein Cholesterol-Fasting (HDL-C), Low Density Lipoprotein Cholesterol-Fasting (LDL-C), Bilirubin-Total, Triglycerides, and Uric Acid [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in BUN, TC, Creatine, Glucose, HDL-C, LDL-C, Bilirubin-Total, Triglycerides, and Uric Acid at the End of Phase 2 [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Eosinophils (Relative) and Neutrophils (Relative) [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in Eosinophils (Relative) and Neutrophils (Relative) [ Time Frame: Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Hemoglobin [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in Hemoglobin [ Time Frame: Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Hematocrit [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in Hematocrit [ Time Frame: Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Homeostasis Model Assessment 2 (HOMA2)-Percent Beta [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
    HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses beta-cell function (HOMA2-%β) relative to expected normal function (indexed to 100% for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-%Beta is a percentage of 'normal function.'

  • Median Baseline Homeostasis Model Assessment 2 HOMA2-Insulin Resistance (IR) [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
    HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses insulin resistance (HOMA2-IR) relative to expected normal function (indexed to 1.0 for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-IR is a proportion of 'normal function.'

  • Median Change From Baseline in Homeostasis Model Assessment 2(HOMA2)-Percent Beta at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint (endpoint of a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
    HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses beta-cell function (HOMA2-%β) relative to expected normal function (indexed to 100% for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-%Beta is a percentage of 'normal function.'

  • Median Change From Baseline in HOMA2 Model Assesses Insulin Resistance (HOMA2-IR) at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint (endpoint of a 13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
    HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses insulin resistance (HOMA2-IR) relative to expected normal function (indexed to 1.0 for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-IR is a proportion of 'normal function.'

  • Median Baseline Platelet Count [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in Platelet Count at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Prolactin [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in Prolactin at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Median Baseline Leukocytes [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]
  • Median Change From Baseline in Leukocytes at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: Yes ]
  • Baseline Abnormal Involuntary Movement Scale (AIMS) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction.

  • Unadjusted Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction.

  • Baseline in Simpson-Angus Scale (SAS) Total Score [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50.(lower score=less severe). Negative change scores indicate improvement.

  • Unadjusted Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50(lower score=less severe). Negative change scores indicate improvement.

  • Baseline in Barnes Akathisia Global Clinical Assessment [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.

  • Unadjusted Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment at Phase 2 Endpoint [ Time Frame: Baseline (end of Ph 1), Phase 2 Endpoint. Phase 2 (13- to 24-week Stability and Maintenance of Stability Phase, which followed a 2- to 8-week Screening, Washout, and Confirmation of Partial Nonresponse Phase) ] [ Designated as safety issue: No ]
    The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.

  • Deaths, Treatment-Emergent Serious Adverse Events (SAEs), Adverse Events (AEs) in >=2% of Participants, and AEs Leading to Discontinuation During Phase 3 [ Time Frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    Participants with Adverse Events (AEs), Deaths, Serious AEs (SAEs), and AEs leading to study discontinuation. AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

  • Treatment-Emergent AEs in >=5% of Participants During Phase 3, by Age, Gender, Race, and Maximum Intensity [ Time Frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. By Common Terminology Criteria Version 3.0 (CTC v3) Grade (Gr): Gr 1 (mild); Gr 2 (moderate); Gr 3 (severe); Gr 4 (life-threatening); Gr 5 (death).

  • Participants With Potentially Clinically Relevant Vital Sign Abnormalities During Phase 3 [ Time Frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    Heart Rate: increase, ≥120 beats per minute (bpm) and ≥15 relative to baseline (RBL); decrease, ≤50 bpm and ≥15 RBL. Systolic BP: increase, ≥180 mmHg and ≥20 RBL; decrease, ≤90 mmHg and ≥20 RBL. Diastolic BP: increase, ≥105 mmHg and ≥15 RBL; decrease, ≤50 mmHg and ≥15 RBL. For patients missing a baseline value, an on-treatment value was considered potentially clinically relevant if the value meets the criterion value.

  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Supine Systolic BP During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Supine Diastolic BP During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Supine Heart Rate During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Sitting Systolic BP During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Sitting Diastolic BP During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Sitting Heart Rate During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Standing Systolic BP During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Standing Diastolic BP During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Values in Standing Heart Rate During Phase 3 [ Time Frame: Baseline, During Phase 3 (for highest/lowest values), Week 52 ] [ Designated as safety issue: Yes ]
  • Baseline and Adjusted Mean Change From Baseline in Weight [ Time Frame: Baseline, Weeks 12, 24, 36, 52, During Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Number of Participants Showing Relevant Weight Gain During Phase 3 [ Time Frame: Weeks 12, 24, 36, 52, 52 (LOCF), and throughout Phase 3 (for 'at any time' assessment) ] [ Designated as safety issue: Yes ]
    Relevant weight gain: >=7% increase from baseline

  • Number of Participants Showing Relevant Weight Loss During Phase 3 [ Time Frame: Weeks 12, 24, 36, 52, 52 (LOCF), and throughout Phase 3 (for 'at any time' assessment) ] [ Designated as safety issue: Yes ]
    Relevant weight loss: >=7% decrease from baseline

  • Median Baseline and Change From Baseline in Body Mass Index (BMI) During Phase 3 [ Time Frame: Baseline, Week 12, Week 24, Week 36, Week 52, Week 52 (LOCF), During Phase 3 (for lowest/highest values) ] [ Designated as safety issue: Yes ]
  • Number of Participants With Potentially Clinically Relevant Laboratory Abnormalities During Phase 3 [ Time Frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    ULN=upper limit of normal; Hb=hemoglobin

  • Median Baseline, Change From Baseline, and Highest Value of Change in Alkaline Phosphatase (ALP), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in ALT, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in AST, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in BUN, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Total Cholesterol (Fasting), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Creatine Kinase, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Creatinine, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Eosinophils (Relative), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
    The change values reported are the median of (post baseline percentage (of white blood cell count) minus baseline percentage (of white blood cell count).

  • Median Baseline, Change From Baseline, and Highest Value of Change in Glucose (Fasting), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Lowest Value of Change in Hemoglobin, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for lowest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Lowest Value of Change in Hematocrit, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for lowest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Lowest Value of Change in HDL Cholesterol (Fasting), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for lowest value ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in HOMA2-Percent Beta, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value ] [ Designated as safety issue: Yes ]
    HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses beta-cell function (HOMA2-%β) relative to expected normal function (indexed to 100% for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-%Beta is a percentage of 'normal function.'

  • Median Baseline, Change From Baseline, and Highest Value of Change in HOMA2-IR, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value ] [ Designated as safety issue: Yes ]
    HOMA stands for homeostasis model assessment of insulin resistance and beta-cell function. These are model-based calculations that use fasting insulin and glucose concentrations in order to assess pancreatic beta-cell function and insulin resistance. The HOMA2 model assesses insulin resistance (HOMA2-IR) relative to expected normal function (indexed to 1.0 for normal function) and is based on predictions from experimental human data on the relationship between insulin and glucose in a fasted state. HOMA2-IR is a proportion of 'normal function.'

  • Median Baseline, Change From Baseline, and Highest Value of Change in Lactate Dehydrogenase, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Change Value in LDL Cholesterol (Fasting), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Neutrophils (Relative), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Value of Change in Platelet Count, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest/lowest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Prolactin, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Total Bilirubin, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Triglycerides (Fasting), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in Uric Acid, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest and Lowest Value of Change in Leukocytes, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest/lowest value) ] [ Designated as safety issue: Yes ]
  • Number of Participants With Potentially Clinically Relevant Electrocardiogram (ECG) Abnormalities During Phase 3 [ Time Frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Sinus Tachycardia: ≥120bpm+↑≥15bpm+no current diagnosis of supraventricular (SV) or ventricular tachycardia or atrial fibrillation (AF) or flutter or other rhythm abnormality (RA). Sinus Bradycardia:≥50bpm+↓≥15bpm+no current diagnosis of AF or flutter or other RA. AF:not present→present or present at rate <100bpm pretreatment to present with rate ≥100bpm+increase of ≥15bpm. AV=atrioventricular; PR=PR interval. Other Intraventricular Block: QRS wave ≥0.12 sec+↑≥0.02 sec+no current diagnosis of left or right bundle branch block. Old Infarction not present→present at ≥12 weeks post study entry.

  • Median Baseline, Change From Baseline, and Highest Value of Change in QT Interval Corrected for Heart Rate (QTc) Bazett, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in QTc (0.33), Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in PR, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in RR, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Median Baseline, Change From Baseline, and Highest Value of Change in QRS, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Adjusted Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score During Phase 3 [ Time Frame: Baseline, Weeks 4,8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change) ] [ Designated as safety issue: No ]
    The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50(lower scores=less severe). Negative change scores indicate improvement.

  • Median Baseline, Change From Baseline, and Highest Value of Change in Heart Rate, Phase 3 Safety Sample [ Time Frame: Baseline, Week 52 (LOCF), Throughout Phase 3 (for highest value) ] [ Designated as safety issue: Yes ]
  • Adjusted Mean Change From Baseline in AIMS Total Score During Phase 3 [ Time Frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change) ] [ Designated as safety issue: No ]
    The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). The AIMS Total Score has a possible range from 0 to 28. Negative change scores indicate improvement in movement dysfunction.

  • Adjusted Mean Change From Baseline in AIMS Item 8 During Phase 3 [ Time Frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change) ] [ Designated as safety issue: No ]
    The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). AIMS Item 8 Score range from 0 to 4. A negative score signifies improvement.

  • Adjusted Mean Change From Baseline in AIMS Item 9 During Phase 3 [ Time Frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change) ] [ Designated as safety issue: No ]
    The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). AIMS Item 9 Score range from 0 to 4. A negative score signifies improvement.

  • Adjusted Mean Change From Baseline in AIMS Item 10 During Phase 3 [ Time Frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change) ] [ Designated as safety issue: No ]
    The AIMS is an assessment of movement dysfunctions. It is a 12-item instrument assessing abnormal involuntary movements associated with antipsychotic drugs and 'spontaneous' motor disturbance related to the illness itself. Scoring the AIMS consists of rating the severity of movement in 3 main anatomic areas (facial/oral, extremities, and trunk), based on a five-point scale (0=none, 4=severe). AIMS Item 10 Score range from 0 to 4. A negative score signifies improvement.

  • Adjusted Mean Change From Baseline in Barnes Akathisia Global Clinical Assessment During Phase 3 [ Time Frame: Baseline, Weeks 4, 8, 12, 24, 36, 52, throughout Phase 3 (for Highest Value of Change) ] [ Designated as safety issue: No ]
    The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.

  • Number of Participants Taking Concomitant Medications for Potential Treatment of Extrapyramidal Syndrome (EPS) During Phase 3 [ Time Frame: Phase 3 (A 52-Week Assessment of Relapse Phase following Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
  • Extension Phase: Mean Baseline and Mean Change From Baseline in CGI-BP (Mania) [ Time Frame: Baseline, Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72 of LTE Phase. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Extension Phase: Mean Change From Baseline in CGI-BP (Mania) Severity of Illness at Extension Phase Endpoint [ Time Frame: Baseline, Extension Phase Endpoint. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Extension Phase: Mean Change From Baseline in CGI-BP Severity of Illness (Depression) at Extension Phase Endpoint [ Time Frame: Baseline, Extension Phase Endpoint. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Extension Phase: Mean Baseline and Mean Change From Baseline in CGI-BP Severity of Illness (Depression) Through Extension Phase [ Time Frame: Baseline, Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Extension Phase: Mean Baseline and Mean Change From Baseline in CGI-BP Severity of Illness (Overall) Through Extension Phase [ Time Frame: Baseline, Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Extension Phase: Mean Change From Baseline in CGI-BP Severity of Illness (Overall) at Extension Phase Endpoint [ Time Frame: Baseline, Extension Phase Endpoint. LTE Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: No ]
    Clinical Global Impression-Bipolar (CGI-BP) assesses global illness severity and change in patients with bipolar disorder. Patients are rated on Change from Preceding Phase (mania, depression and overall bipolar illness) items (also a 7-point scale [1 to 7], with 1 being normal and 7 being very severely ill). A negative change score signifies improvement.

  • Extension Phase: Deaths, Adverse Events (AES), Serious Adverse Events (SAEs), and Discontinuations [ Time Frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    Participants with Adverse Events (AEs), Deaths, Serious AEs (SAEs), and AEs leading to study discontinuation. AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

  • Extension Phase: Participants With Potentially Clinically Relevant Metabolic Laboratory Abnormalities During Extension Phase [ Time Frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    Metabolic abnormalities considered by the investigator as clinically relevant. (Need normal values for each.)

  • Extension Phase: Participants With Potentially Clinically Relevant Vital Sign Abnormalities [ Time Frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    Vital sign abnormalities considered by the investigator as clinically relevant.

  • Extension Phase: Adverse Events (AEs), by Maximum Intensity [ Time Frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. By Common Terminology Criteria Version 3.0 (CTC v3) Grade (Gr): Gr 1 (mild); Gr 2 (moderate); Gr 3 (severe); Gr 4 (life-threatening); Gr 5 (death).

  • Extension Phase: Participants With Potentially Clinically Relevant Laboratory Abnormalities [ Time Frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    Chemistry, hematology, and urinalysis abnormalities considered by the investigator as clinically relevant. Hematocrit: ≤37%(M)/≤32%(F)+3 percentage pts↓from baseline.

  • Extension Phase: Participants With Potentially Clinically Relevant ECG Abnormalities [ Time Frame: From first day until 30 days after the last dose of double-blind dosing in the Extension Phase (A 72-week Extension Phase [until study unblinding] following Phase 3 [52 weeks], Phase 2 [13 to 24 weeks] and Phase 1 [2 to 8 weeks]) ] [ Designated as safety issue: Yes ]
    ECG abnormalities considered by the investigator as clinically relevant.Left Bundle Branch Block: Not present at Baseline--> present post-baseline.


Enrollment: 1270
Study Start Date: September 2005
Study Completion Date: October 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: A1
/Active Comparator
Drug: Lithium or Valproate with placebo (PBO)

Tablets, Oral, once daily

lithium 250-2100 mg/day

valproate 250-2500mg/day

Placebo once daily

Experimental: A2 Drug: Lithium or Valproate with Aripiprazole

Tablets, Oral, once daily, 52 weeks post randomization (Pre-Randomization Phases 13-24 weeks)

lithium 250-2100 mg/day

valproate 250-2500mg/day

aripiprazole 15-30 mg/day

Other Names:
  • Abilify
  • BMS-337039

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women > or = to 18 years of age meeting Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for bipolar I disorder, currently experiencing a manic or mixed episode with a history of one or more manic or mixed episodes or sufficient severity to require hospitalization and/or treatment with a mood stabilizer or antipsychotic.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00261443

  Hide Study Locations
Locations
United States, Alabama
Tuscaloosa Va Medical Center
Tuscaloosa, Alabama, United States, 35404
United States, California
Pravin Kansagra, M.D.
Anaheim, California, United States, 92801
Psychopharmacology Research Network Of Torrance
Cerritos, California, United States, 90703
Atp Clinical Research, Inc.
Costa Mesa, California, United States, 92626
Us Clinical Research Centers, Llc
Costa Mesa, California, United States, 92627
Va Long Beach Healthcare System
Long Beach, California, United States, 90822
Synergy Clinical Research Center
National City, California, United States, 91950
University Of California, Irvine Medical Center
Orange, California, United States, 92868
United States, Florida
Clinical Neuroscience Solutions, Inc.
Orlando, Florida, United States, 32806
University Of South Florida
Tampa, Florida, United States, 33613
United States, Georgia
Carman Research
Smyrna, Georgia, United States, 30080
United States, Massachusetts
University Of Massachusetts Medical School
Worcester, Massachusetts, United States, 01605
United States, Missouri
Psych Care Consultants Research
St. Louis, Missouri, United States, 63128
United States, New Jersey
Cns Research Institute, P.C.
Clementon, New Jersey, United States, 08021
United States, New York
Neuropsychiatric Research Associates
New York, New York, United States, 10128
Behavioral Medical Research Of Staten Island
Staten Island, New York, United States, 10305
Richmond Behavioral Associates
Staten Island, New York, United States, 10312
United States, North Carolina
Psychiatry And Clinical Research
Raleigh, North Carolina, United States, 27609
United States, Ohio
Rakesh Ranjan, Md & Associates, Inc.
Beachwood, Ohio, United States, 44122
University Of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45267
Metro Health Medical Center
Cleveland, Ohio, United States, 44109
Midwest Clinical Research Center
Dayton, Ohio, United States, 45408
United States, Oregon
Portland Va Medical Center
Portland, Oregon, United States, 97201
United States, Texas
Senior Adults Specialty Research, Inc.
Austin, Texas, United States, 78757
Futuresearch Trials
Dallas, Texas, United States, 75231
Insite Clinical Research
Desoto, Texas, United States, 75115
Red Oak Psychiatry Associates, Pa
Houston, Texas, United States, 77090
United States, Utah
University Of Utah School Of Medicine
Salt Lake City, Utah, United States, 84132
United States, Washington
Northwest Clinical Research Center
Bellevue, Washington, United States, 98004
Brazil
Local Institution
Salvador, Bahia, Brazil, 40325
Local Institution
Aparecida De Goinia, Goias, Brazil, 74922
Local Institution
Pelotas, Rio Grande Do Sul, Brazil, 96030 003
Local Institution
Rio De Janeiro, Brazil, 21020
Local Institution
Sao Paulo, Brazil, 05403
Local Institution
Sao Paulo, Brazil, 02340
Bulgaria
Local Institution
Bourgas, Bulgaria, 8000
Local Institution
Rousse, Bulgaria, 7002
Croatia
Local Institution
Rijeka, Croatia, 51-000
Local Institution
Split, Croatia, 21000
Local Institution
Zadar, Croatia, 23000
Local Institution
Zagreb, Croatia, 10 090
Czech Republic
Local Institution
Brno, Czech Republic, 610 00
Local Institution
Brno, Czech Republic, 625 00
Local Institution
Havirov, Czech Republic, 736 01
Local Institution
Litomerice, Czech Republic, 412 01
Local Institution
Prague 2, Czech Republic, 120 00
Local Institution
Praha 6, Czech Republic, 160 00
Local Institution
Prerov, Czech Republic, 75002
France
Local Institution
Nantes, Cedex 01, France, 44035
Local Institution
Dole, France, 39100
Local Institution
Henin Beaumont, France, 62251
Local Institution
Jonzac Cedex, France, 175003
Local Institution
La Seyne Sur Mer, France, 83500
Local Institution
Marseille, France, 13009
Local Institution
Nantes, France, 44000
Local Institution
Nimes, France, 30900
Local Institution
Rennes, France, 35000
India
Local Institution
Hyderabad, Andhra Pradesh, India, 500 034
Local Institution
Ahmedabad, Gujarat, India, 6577647
Local Institution
Ahmedabad, Gujarat, India, 380 006
Local Institution
Kalyan (West), Maharashtra, India, 421 301
Local Institution
Nagur, Maharashtra, India, 440010
Local Institution
Pune, Maharashtra, India, 400 001
Local Institution
Mangalore, Manipal, India, 576 104
Local Institution
Mumbai, Sion (W), India, 400 022
Local Institution
Delhi, India, 110 092
Local Institution
Hyderabad, India, 500 038
Local Institution
Mumbai, India, 400 008
Local Institution
Mumbai, India, 400 058
Local Institution
New Delhi, India, 110 065
Local Institution
New Delhi, India, 110 002
Russian Federation
Local Institution
Izhevsk, Russian Federation, 426053
Local Institution
Moscow, Russian Federation, 107258
Local Institution
Nizhny Novgorod, Russian Federation, 603107
Local Institution
Saint-Petersburg, Russian Federation, 191119
Local Institution
Saratov, Russian Federation, 410028
Local Institution
St-Petersburg, Russian Federation, 190000
Local Institution
Tomsk, Russian Federation, 634014
South Africa
Local Institution
Pretoria, Gauteng, South Africa, 0001
Local Institution
Berea, Kwa Zulu Natal, South Africa, 4001
Local Institution
Durban, Kwa Zulu Natal, South Africa, 4001
Local Institution
Cape Town, Western Cape, South Africa, 7708
Local Institution
Paarl, Western Cape, South Africa, 7646
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Otsuka America Pharmaceutical
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided by Otsuka Pharmaceutical Development & Commercialization, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00261443     History of Changes
Other Study ID Numbers: CN138-189
Study First Received: December 1, 2005
Results First Received: January 28, 2011
Last Updated: November 7, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Bipolar I Disorder with a recent manic or mixed episode

Additional relevant MeSH terms:
Bipolar Disorder
Disease
Affective Disorders, Psychotic
Mood Disorders
Mental Disorders
Pathologic Processes
Aripiprazole
Lithium
Lithium Carbonate
Valproic Acid
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Antimanic Agents
Antidepressive Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticonvulsants
GABA Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on September 16, 2014