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

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Pre-Randomized Participants	Phase 1 (2 to 8 Week Screening, Washout and Confirmation of Partial Nonresponse Phase): lithium: 0.6–1.0 mmol/L or valproate 50–125 µg/ml. Phase 2 (13 to 24 Week Stability and Maintenance of Stability Phase): 10-mg, 15-mg, or 30-mg doses of aripiprazole and lithium: 0.6–1.0 mmol/L or valproate 50–125 µg/ml.
Placebo	Phase 3 (52 Week Assessment of Relapse Phase): matching placebo oral tablets and lithium: 0.6–1.0 mmol/L or valproate 50–125 µg/ml.
Aripiprazole	Phase 3 (52 Week Assessment of Relapse Phase): 10-mg, 15-mg, or 30-mg doses of aripiprazole and lithium: 0.6–1.0 mmol/L or valproate 50–125 µg/ml.

Participant Flow for 4 periods

Period 1:   1: Confirmation of Partial Nonresponse

	Pre-Randomized Participants	Placebo	Aripiprazole
STARTED	1270	0	0
COMPLETED	686	0	0
NOT COMPLETED	584	0	0
Adverse Event	33	0	0
Withdrawal by Subject	93	0	0
Lost to Follow-up	111	0	0
Poor/Noncompliance	23	0	0
Pregnancy	1	0	0
Subject No Longer Met Study Criteria	307	0	0
Other Reasons	16	0	0

Period 2:   2: Stability & Maintenance of Stability

	Pre-Randomized Participants	Placebo	Aripiprazole
STARTED	686	0	0
COMPLETED	346	0	0
NOT COMPLETED	340	0	0
Lack of Efficacy	43	0	0
Adverse Event	93	0	0
Withdrawal by Subject	65	0	0
Lost to Follow-up	59	0	0
Poor/Noncompliance	33	0	0
Pregnancy	1	0	0
subject No Longer Met Study Criteria	32	0	0
Administrative Reason by Sponsor	1	0	0
Other Reasons	13	0	0

Period 3:   3: Assessment of Relapse

	Pre-Randomized Participants	Placebo	Aripiprazole
STARTED	0	169	168
COMPLETED	0	89	103
NOT COMPLETED	0	80	65
Lack of Efficacy	0	31	14
Adverse Event	0	15	19
Withdrawal by Subject	0	14	15
Death	0	0	1
Lost to Follow-up	0	7	6
Poor/Noncompliance	0	5	3
Pregnancy	0	2	1
Subject No Longer Meets Study Criteria	0	2	1
Administrative Reason By Sponsor	0	0	2
Other Reasons	0	4	3

Period 4:   4: Extension Phase

	Pre-Randomized Participants	Placebo	Aripiprazole
STARTED	0	19	23
COMPLETED	0	16	21
NOT COMPLETED	0	3	2
Adverse Event	0	1	0
Withdrawal by Subject	0	1	2
Lost to Follow-up	0	1	0

Reporting Groups

	Description
Placebo	Phase 3 (52 Week Assessment of Relapse Phase): matching placebo oral tablets and 250-mg and 300-mg oral lithium tablets or 250-mg Depakote/valproic acid oral tablets
Aripiprazole	Phase 3 (52 Week Assessment of Relapse Phase): aripiprazole 10-mg and 15-mg oral tablets and 250-mg and 300-mg oral lithium tablets or 250-mg Depakote/valproic acid oral tablets
Total	Total of all reporting groups

Baseline Measures

	Placebo	Aripiprazole	Total
Number of Participants   [units: participants]	169	168	337
Age   [units: years] Mean ± Standard Deviation	38.8  ± 12.29	39.2  ± 12.43	39.0  ± 12.34
Gender   [units: participants]
Female	98	87	185
Male	71	81	152
Race/Ethnicity, Customized   [units: participants]
White	112	118	230
Black/African American	19	12	31
Asian	33	34	67
Other	5	4	9
Race/Ethnicity, Customized   [units: Participants]
Hispanic/Latino	3	5	8
Not Hispanic or Latino	55	56	111
Non-US	111	107	218
Region of Enrollment   [units: participants]
France	8	9	17
United States	58	61	119
Czech Republic	18	14	32
Brazil	28	27	55
Croatia	3	4	7
Russian Federation	17	15	32
South Africa	4	4	8
India	33	34	67
Body Mass Index (BMI) Category [1] [units: Participants]
<18.5 kg/m^2	5	0	5
18.5 kg/m^2 to <25 kg/m^2	58	49	107
25 kg/m^2 to <30 kg/m^2	50	63	113
>= 30 kg/m^2	56	56	112
Body Mass Index (BMI) [1] [units: kg/m^2] Mean ± Standard Deviation	28.7  ± 7.72	28.5  ± 6.00	28.6  ± 6.90
CGI-BP Change from Preceding Phase Score (Depression) [2] [units: units on a scale] Mean ± Standard Deviation	3.0  ± 1.34	3.0  ± 1.31	3.0  ± 1.32
CGI-BP Change from Preceding Phase Score (Mania) [2] [units: units on a scale] Mean ± Standard Deviation	1.6  ± 0.81	1.4  ± 0.63	1.5  ± 0.72
CGI-BP Change from Preceding Phase Score (Overall) [2] [units: units on a scale] Mean ± Standard Deviation	1.6  ± 0.85	1.5  ± 0.69	1.6  ± 0.77
CGI-BP Severity of Illness Score (Depression) [3] [units: units on a scale] Mean ± Standard Deviation	1.3  ± 0.57	1.4  ± 0.70	1.4  ± 0.64
CGI-BP Severity of Illness Score (Mania) [3] [units: units on a scale] Mean ± Standard Deviation	1.5  ± 0.72	1.5  ± 0.72	1.5  ± 0.72
CGI-BP Severity of Illness Score (Overall) [3] [units: units on a scale] Mean ± Standard Deviation	1.6  ± 0.76	1.7  ± 0.83	1.6  ± 0.79
Montgomery Åsberg Depression Rating Scale (MADRS) Total Score [4] [units: units on a scale] Mean ± Standard Deviation	3.7  ± 3.45	4.1  ± 3.82	3.9  ± 3.64
Weight   [units: kg] Mean ± Standard Deviation	81.3  ± 25.11	80.6  ± 18.89	81.0  ± 22.20
Young-Mania Rating Scale (Y-MRS) Total Score [5] [units: units on a scale] Mean ± Standard Deviation	4.1  ± 3.31	4.1  ± 3.56	4.1  ± 3.43

1.  Primary:

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]) ]

2.  Secondary:

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 ]

3.  Secondary:

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 ]

4.  Secondary:

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 ]

5.  Secondary:

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) ]

6.  Secondary:

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]) ]

7.  Secondary:

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) ]

8.  Secondary:

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]) ]

9.  Secondary:

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) ]

10.  Secondary:

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]) ]

11.  Secondary:

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) ]

12.  Secondary:

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]) ]

13.  Secondary:

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) ]

14.  Secondary:

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) ]

15.  Secondary:

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]) ]

16.  Secondary:

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) ]

17.  Secondary:

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]) ]

18.  Secondary:

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) ]

19.  Secondary:

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]) ]

20.  Secondary:

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]) ]

21.  Secondary:

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]) ]

22.  Secondary:

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) ]

23.  Secondary:

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) ]

24.  Secondary:

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) ]

25.  Secondary:

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) ]

26.  Secondary:

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) ]

27.  Secondary:

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) ]

28.  Secondary:

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) ]

29.  Secondary:

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) ]

30.  Secondary:

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) ]

31.  Secondary:

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) ]

32.  Secondary:

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 ]

33.  Secondary:

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) ]

34.  Secondary:

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) ]

35.  Secondary:

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 ]

36.  Secondary:

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) ]

37.  Secondary:

Median Baseline Eosinophils (Relative) and Neutrophils (Relative)   [ Time Frame: Baseline ]

38.  Secondary:

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) ]

39.  Secondary:

Median Baseline Hemoglobin   [ Time Frame: Baseline ]

40.  Secondary:

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) ]

41.  Secondary:

Median Baseline Hematocrit   [ Time Frame: Baseline ]

42.  Secondary:

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) ]

43.  Secondary:

Median Baseline Homeostasis Model Assessment 2 (HOMA2)-Percent Beta   [ Time Frame: Baseline ]

44.  Secondary:

Median Baseline Homeostasis Model Assessment 2 HOMA2-Insulin Resistance (IR)   [ Time Frame: Baseline ]

45.  Secondary:

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) ]

46.  Secondary:

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) ]

47.  Secondary:

Median Baseline Platelet Count   [ Time Frame: Baseline ]

48.  Secondary:

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) ]

49.  Secondary:

Median Baseline Prolactin   [ Time Frame: Baseline ]

50.  Secondary:

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) ]

51.  Secondary:

Median Baseline Leukocytes   [ Time Frame: Baseline ]

52.  Secondary:

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) ]

53.  Secondary:

Baseline Abnormal Involuntary Movement Scale (AIMS)   [ Time Frame: Baseline ]

54.  Secondary:

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) ]

55.  Secondary:

Baseline in Simpson-Angus Scale (SAS) Total Score   [ Time Frame: Baseline ]

56.  Secondary:

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) ]

57.  Secondary:

Baseline in Barnes Akathisia Global Clinical Assessment   [ Time Frame: Baseline ]

58.  Secondary:

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) ]

59.  Secondary:

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]) ]

60.  Secondary:

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]) ]

61.  Secondary:

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]) ]

62.  Secondary:

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 ]

63.  Secondary:

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 ]

64.  Secondary:

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 ]

65.  Secondary:

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 ]

66.  Secondary:

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 ]

67.  Secondary:

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 ]

68.  Secondary:

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 ]

69.  Secondary:

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 ]

70.  Secondary:

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 ]

71.  Secondary:

Baseline and Adjusted Mean Change From Baseline in Weight   [ Time Frame: Baseline, Weeks 12, 24, 36, 52, During Phase 3 (for highest value) ]

72.  Secondary:

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) ]

73.  Secondary:

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) ]

74.  Secondary:

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) ]

75.  Secondary:

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]) ]

76.  Secondary:

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) ]

77.  Secondary:

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) ]

78.  Secondary:

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) ]

79.  Secondary:

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) ]

80.  Secondary:

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) ]

81.  Secondary:

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) ]

82.  Secondary:

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) ]

83.  Secondary:

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) ]

84.  Secondary:

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) ]

85.  Secondary:

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) ]

86.  Secondary:

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) ]

87.  Secondary:

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 ]

88.  Secondary:

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 ]

89.  Secondary:

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 ]

90.  Secondary:

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) ]

91.  Secondary:

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) ]

92.  Secondary:

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) ]

93.  Secondary:

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) ]

94.  Secondary:

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) ]

95.  Secondary:

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) ]

96.  Secondary:

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) ]

97.  Secondary:

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) ]

98.  Secondary:

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) ]

99.  Secondary:

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]) ]

100.  Secondary:

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) ]

101.  Secondary:

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) ]

102.  Secondary:

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) ]

103.  Secondary:

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) ]

104.  Secondary:

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) ]

105.  Secondary:

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) ]

106.  Secondary:

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) ]

107.  Secondary:

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) ]

108.  Secondary:

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) ]

109.  Secondary:

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) ]

110.  Secondary:

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) ]

111.  Secondary:

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) ]

112.  Secondary:

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]) ]

113.  Secondary:

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]) ]

114.  Secondary:

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]) ]

115.  Secondary:

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]) ]

116.  Secondary:

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]) ]

117.  Secondary:

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]) ]

118.  Secondary:

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]) ]

119.  Secondary:

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]) ]

120.  Secondary:

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]) ]

121.  Secondary:

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]) ]

122.  Secondary:

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]) ]

123.  Secondary:

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]) ]

124.  Secondary:

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]) ]