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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01567527
• Collaborator: H. Lundbeck A/S (Industry)
• Enrollment: 731
• Locations: 77
• Arms: 2
• Duration (Months): 44
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This will be a randomized, double-blind, placebo-controlled trial to assess the time to recurrence of any mood episode in subjects with bipolar I disorder who have maintained stability on aripiprazole IM depot for at least 8 weeks. This trial will include male and female subjects 18 to 65 years of age, inclusive, with a diagnosis of bipolar I disorder, according to DSM-IV-TR criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI), who have experienced at least one previous manic episode of sufficient severity to require hospitalization and/or treatment with a mood stabilizer or antipsychotic agent in addition to their current manic episode. All subjects must be experiencing a manic episode (per DSM-IV-TR criteria) with a YMRS total score ≥ 20 at trial entry. Both inpatients and outpatients are eligible for this trial.

This trial will consist of a screening phase followed by 4 treatment phases. Subjects will undergo screening for eligibility, followed by a conversion to oral aripiprazole monotherapy phase, if needed, an oral aripiprazole stabilization phase, a single-blind aripiprazole IM depot stabilization phase, and, a double-blind, placebo-controlled phase.

Condition or Disease	Intervention/Treatment	Phase
Bipolar I Disorder	Drug: Intramuscular (IM) Depot Aripiprazole; Drug: Intramuscular (IM) Depot Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 731 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 52-week, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of an Intramuscular Depot Formulation of Aripiprazole (OPC-14597) as Maintenance Treatment in Patients With Bipolar I Disorder
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Time From Randomization to Recurrence of Any Mood Episode During Double-bind Placebo-controlled Phase. [Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).]

   This endpoint was defined as meeting any of the following criteria: Hospitalization for any mood episode OR Any of the following: YMRS total score ≥ 15 OR MADRS total score ≥ 15 OR CGI-BP-S score > 4 (overall score) OR SAE of worsening disease (bipolar I disorder) OR Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR Clinical worsening with the need for treatment of symptoms of an underlying mood disorder by addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, or increase greater than the allowed benzodiazepine doses, or Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of "yes" on question 4 or 5 on the C-SSRS. The time to event is presented in the following table.

Secondary Outcome Measures

1. Number of Subjects Meeting Criteria for Recurrence of Any Mood Episode. [Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).]

   To assess the proportion of subjects who met criteria for recurrence of any mood episode (manic, mixed or depressive). Hierarchical procedure was used to preserve the overall Type I error at 0.05.

2. Mean Change From Randomization to Endpoint in the CGI-BP-S (Mania) Score. [Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).]

   CGI-BP-S assessed the subject's severity of Illness (mania) based on a 7-point scale ranging from 1 (normal/ not ill at all) to 7 (very severely ill).

3. Time From Randomization to Recurrence Defined by Hospitalization for a Mood Episode. [Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).]

   Analysis of time from randomization to recurrence defined by hospitalization for a mood episode (Double-blind, Placebo-controlled Phase efficacy sample). Time to recurrence is presented in the following table.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Male and female subjects 18 to 65 years of age, inclusive, at time of informed consent.

2. Subjects with a current diagnosis of bipolar I disorder, as defined by DSM-IV-TR criteria and confirmed by the MINI and a history of at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer, and/or treatment with an antipsychotic agent, in addition to their current manic episode. "Require" is defined as an intervention that occurred rather than one that was recommended. Rapid cyclers with 8 or fewer episodes in the previous year will be included.

3. Subjects currently experiencing a manic episode with a YMRS total score of ≥20 at the Screening Visit.

4. Subjects can have an inpatient or outpatient status prior to entry into Phase C (IM depot stabilization).

5. In the investigator's opinion, subjects who are able to understand the nature of the trial and follow protocol requirements, including the prescribed dosage regimens, tablet ingestion, aripiprazole IM depot injection, and discontinuation of prohibited concomitant medications; who can read and understand the written word in order to complete subject-reported outcomes measures; and who can be reliably rated on assessment scales.

Key Exclusion Criteria:

1. Subjects with a current Axis I (DSM-IV-TR) diagnosis other than bipolar I disorder.

2. Subjects who have NOT experienced at least one previous manic or mixed episode with manic symptoms of sufficient severity to require one of the following interventions: hospitalization and/or treatment with a mood stabilizer, and /or treatment with an antipsychotic agent, excluding their current manic episode. "Require" is defined as a intervention that occurred rather than one that was recommended.

3. Subjects with bipolar I disorder who are considered resistant/refractory to treatment for manic symptoms by history.

4. Subjects unresponsive to clozapine for treatment of mania.

5. Subjects with a significant risk of committing suicide based on history, mental status examination, investigator's judgment, or C-SSRS answer of "yes" to question 4 or 5 (current or within the last 90 days).

6. Subjects with a current manic episode with a duration of > 2 years.

7. Subjects who currently (within the past month) meet DSM-IV-TR criteria for substance abuse or substance dependence; this includes the abuse of alcohol and benzodiazepines, but excludes the use of caffeine and/or nicotine.

8. Subjects who have a history or evidence of a medical condition that would expose them to an undue risk of a significant adverse event (AE) or interfere with assessments of safety or efficacy during the course of the trial, including but not limited to hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease as determined by the clinical judgment of the investigator.

9. Subjects who are currently experiencing a mixed or a depressive episode (per DSM-IV-TR criteria).

10. Subjects with a history of hypersensitivity to antipsychotic agents.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Springdale	Arkansas	United States
3		Beverly Hills	California	United States
4		Costa Mesa	California	United States
5		Escondido	California	United States
6		Garden Grove	California	United States
7		Los Angeles	California	United States
8		National City	California	United States
9		Oceanside	California	United States
10		Orange	California	United States
11		Pico Rivera	California	United States
12		Riverside	California	United States
13		San Diego	California	United States
14		Temecula	California	United States
15		Torrance	California	United States
16		Lauderhill	Florida	United States
17		Leesburg	Florida	United States
18		Melbourne	Florida	United States
19		Oakland Park	Florida	United States
20		Atlanta	Georgia	United States
21		Decatur	Georgia	United States
22		Smyrna	Georgia	United States
23		Hoffman Estates	Illinois	United States
24		New Orleans	Louisiana	United States
25		Rockville	Maryland	United States
26		Flowood	Mississippi	United States
27		Saint Charles	Missouri	United States
28		Saint Louis	Missouri	United States
29		Lincoln	Nebraska	United States
30		Cherry Hill	New Jersey	United States
31		Brooklyn	New York	United States
32		Buffalo	New York	United States
33		New York	New York	United States
34		Cincinnati	Ohio	United States
35		Dayton	Ohio	United States
36		Oklahoma City	Oklahoma	United States
37		Allentown	Pennsylvania	United States
38		Jenkintown	Pennsylvania	United States
39		Austin	Texas	United States
40		Dallas	Texas	United States
41		Wichita Falls	Texas	United States
42		Richmond	Virginia	United States
43		Chatham	Ontario	Canada
44		Aizu Wakamatsu	Fukusima	Japan
45		Sapporo	Hokkaido	Japan
46		Morioka	Iwate	Japan
47		Kawasaki-shi	Kanagawa	Japan
48		Yokohama-shi	Kanagawa	Japan
49		Yokohama	Kanagawa	Japan
50		Kashihara	Nara	Japan
51		Sakai-shi	Osaka	Japan
52		Sakai	Osaka	Japan
53		Fukuoka		Japan
54		Itabashi-bu		Japan
55		Kanzaki-gun		Japan
56		Koriyama-shi		Japan
57		Kumamoto		Japan
58		Okinawa		Japan
59		Shinjuku-ku		Japan
60		Tokyo		Japan
61		Tottori		Japan
62		Toyama		Japan
63		Anyang-si	Gyeonggi-do	Korea, Republic of
64		Goyang-si	Gyeonggi-do	Korea, Republic of
65		Daejeon		Korea, Republic of
66		Jeju-si		Korea, Republic of
67		Seoul		Korea, Republic of
68		Gdynia	Pomorskie	Poland
69		Bydgoszcz		Poland
70		Chelmno		Poland
71		Choroszcz		Poland
72		Targoviste	Dyambovita	Romania
73		Bucharest		Romania
74		Judet Lasi		Romania
75		Keelung City		Taiwan
76		Taipei		Taiwan
77		Taouyuan County		Taiwan

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.
• H. Lundbeck A/S

Investigators

• Study Director: Stacy Wu, MD, Otsuka Pharmaceutical Development and Commercialization, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01567527
• Other Study ID Numbers: 31-08-250
• First Posted: Mar 30, 2012
• Last Update Posted: Aug 24, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Aripiprazole; Intramuscular (IM) Depot; Bipolar
• Additional relevant MeSH terms: Aripiprazole

Study Results

Participant Flow

Recruitment Details	This trial was conducted in 1175 subjects (including 444 screen failures) at 103 trial sites in the following 7 countries: Canada, Japan, Republic of Korea, Poland, Romania, Taiwan, and the United States (US).
Pre-assignment Detail	The trial consisted of a screening phase and 4 phases. In Conversion, Oral Stabilization and IM Depot Stabilization Phases, there was a single treatment group. In Double-blind, Placebo-controlled Phase, there were 2 treatment groups. All Outcome Measures were assessed in the Double-blind, Placebo-controlled Phase of the study.

Arm/Group Title	Conversion Phase.	Oral Aripiprazole Stabilization Phase.	Intramuscular (IM) Depot Stabilization Phase.	Double-blind Placebo-controlled Phase - Aripiprazole IM Depot.	Double-blind Placebo-controlled Phase - Placebo.
Arm/Group Description	During the Oral Conversion Phase, subjects were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy.	During the Oral Stabilization Phase, subjects were stabilized on an oral dose of aripiprazole. 632 subjects entered the Oral Stabilization Phase (367 subjects entered from the Conversation Phase and 265 subjects entered the Oral Stabilization Phase directly).	During the Depot Stabilization Phase, subjects were stabilized on aripiprazole IM depot. The subjects were assigned to aripiprazole IM depot in the IM Depot Stabilization Phase for a minimum of 12 weeks and a maximum of 28 weeks. To proceed to the Double-blind, Placebo-controlled Phase, subjects were required to meet all the protocol-defined stability criteria for a minimum of 8 consecutive weeks (4 consecutive biweekly visits).	Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks. A total of 266 subjects entered Double-blind Placebo-controlled phase. Of the 266 subjects, 133 were randomized to aripiprazole IM depot treatment. Since one subject withdrew consent to participate prior to receiving an injection, only 132 subjects received aripiprazole IM depot treatment.	Subjects received placebo intramuscularly up to 52 weeks. A total of 266 subjects entered double-blind placebo-controlled Phase. Of the 266 subjects, 133 were randomized to placebo treatment.
Period Title: Conversion Phase.
STARTED	466	0	0	0	0
COMPLETED	367	0	0	0	0
NOT COMPLETED	99	0	0	0	0
Period Title: Conversion Phase.
STARTED	0	632	0	0	0
COMPLETED	0	425	0	0	0
NOT COMPLETED	0	207	0	0	0
Period Title: Conversion Phase.
STARTED	0	0	425	0	0
COMPLETED	0	0	266	0	0
NOT COMPLETED	0	0	159	0	0
Period Title: Conversion Phase.
STARTED	0	0	0	133	133
COMPLETED	0	0	0	64	38
NOT COMPLETED	0	0	0	69	95

Baseline Characteristics

Arm/Group Title	Aripiprazole Depot	Placebo	Total
Arm/Group Description	Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Subjects received placebo intramuscularly up to 52 weeks.	Total of all reporting groups
Overall Participants	133	133	266
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	133 100%	132 99.2%	265 99.6%
>=65 years	0 0%	1 0.8%	1 0.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.6 (10.8)	40.6 (11.2)	40.6 (11.0)
Sex: Female, Male (Count of Participants)
Female	83 62.4%	70 52.6%	153 57.5%
Male	50 37.6%	63 47.4%	113 42.5%
Region of Enrollment (Count of Participants)
Canada	2 1.5%	0 0%	2 0.8%
South Korea	7 5.3%	7 5.3%	14 5.3%
Romania	8 6%	12 9%	20 7.5%
United States	101 75.9%	102 76.7%	203 76.3%
Japan	9 6.8%	10 7.5%	19 7.1%
Taiwan	2 1.5%	1 0.8%	3 1.1%
Poland	4 3%	1 0.8%	5 1.9%
Age at first manic episode (years) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.2 (10.3)	24.8 (9.9)	25.0 (10.1)
Number of mood episodes past 12 months (Mood episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Mood episodes]	2.2 (1.2)	2.2 (1.1)	2.2 (1.2)
Duration of disease prior to enrollment (years) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.1 (9.2)	13.6 (9.8)	12.9 (9.5)
Number of prior hospitalizations for a mood episode (Prior hospitalization for mood episode) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Prior hospitalization for mood episode]	3.5 (3.9)	3.5 (4.1)	3.5 (4.0)
Young-Mania Rating Scale (YMRS) Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	2.9 (3.5)	2.6 (3.0)	2.8 (3.3)
Montgomery Asberg Depression Rating Scale (MADRS) Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	3.0 (3.4)	2.4 (3.4)	2.7 (3.4)
Clinical Global Impressions - Bipolar Version Severity (CGI-BP-S) - Mania (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	1.5 (0.7)	1.4 (0.6)	1.5 (0.7)

Outcome Measures

1. Primary Outcome

Title	Time From Randomization to Recurrence of Any Mood Episode During Double-bind Placebo-controlled Phase.
Description	This endpoint was defined as meeting any of the following criteria: Hospitalization for any mood episode OR Any of the following: YMRS total score ≥ 15 OR MADRS total score ≥ 15 OR CGI-BP-S score > 4 (overall score) OR SAE of worsening disease (bipolar I disorder) OR Discontinuation due to lack of efficacy or discontinuation due to an AE of worsening disease OR Clinical worsening with the need for treatment of symptoms of an underlying mood disorder by addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, or increase greater than the allowed benzodiazepine doses, or Active suicidality, which is defined as a score of 4 or more on the MADRS item 10 OR an answer of "yes" on question 4 or 5 on the C-SSRS. The time to event is presented in the following table.
Time Frame	Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least one injection of investigational medicinal product (IMP) and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified intent-to-treat (ITT) population.

Arm/Group Title	Aripiprazole IM Depot	Placebo
Arm/Group Description	Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Subjects received placebo intramuscularly up to 52 weeks.
Measure Participants	132	133
Median (95% Confidence Interval) [Days]	NA	308

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole IM Depot, Placebo
	Comments	Significance level 0.05.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.451
	Confidence Interval	(2-Sided) 95%; 0.299 to 0.678
	Parameter Dispersion	Type: Value:
	Estimation Comments	Using the Cox proportional hazards model with term for treatment group. HR is estimated for Aripiprazole IM depot relative to Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole IM Depot, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Using the Cox proportional hazards model with term for treatment group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.22
	Confidence Interval	(2-Sided) 95%; 1.475 to 3.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is estimated for Placebo relative to Aripiprazole IM depot.

2. Secondary Outcome

Title	Number of Subjects Meeting Criteria for Recurrence of Any Mood Episode.
Description	To assess the proportion of subjects who met criteria for recurrence of any mood episode (manic, mixed or depressive). Hierarchical procedure was used to preserve the overall Type I error at 0.05.
Time Frame	Baseline of the Double-blind, Placebo-controlled Phase Up to the end of the study (Week 52).

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.

Arm/Group Title	Aripiprazole IM Depot	Placebo
Arm/Group Description	Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Subjects received placebo intramuscularly up to 52 weeks.
Measure Participants	132	133
Count of Participants [Participants]	35 26.3%	68 51.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole IM Depot, Placebo
	Comments	Statistical analysis for any mood episode
	Type of Statistical Test	Superiority
	Comments	Using a hierarchical procedure to preserve the overall Type I error rate at 0.05, after testing the primary outcome.
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference (Final Values)
	Estimated Value	-24.6
	Confidence Interval	(2-Sided) 95%; -36.7 to -12.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Change From Randomization to Endpoint in the CGI-BP-S (Mania) Score.
Description	CGI-BP-S assessed the subject's severity of Illness (mania) based on a 7-point scale ranging from 1 (normal/ not ill at all) to 7 (very severely ill).
Time Frame	Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.

Arm/Group Title	Aripiprazole IM Depot	Placebo
Arm/Group Description	Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Subjects received placebo intramuscularly up to 52 weeks.
Measure Participants	131	133
Least Squares Mean (Standard Error) [Units on a scale]	-0.16 (0.058)	0.27 (0.126)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole IM Depot, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Using mixed model repeated measures (MMRM) analysis with a restricted maximum likelihood (REML) approach. Analyses included the categorically fixed effects of treatment, region, trial week, and treatment-by-week interaction, as well as the continuously fixed covariates of baseline-score-by-week interaction. An unstructured covariance structure was used to model the within-subject errors and Kenward-Rodger degree of freedom was used to test the fixed effects.
Statistical Test of Hypothesis	p-Value	= 0.0011
	Comments
	Method	Mixed model repeated measure analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time From Randomization to Recurrence Defined by Hospitalization for a Mood Episode.
Description	Analysis of time from randomization to recurrence defined by hospitalization for a mood episode (Double-blind, Placebo-controlled Phase efficacy sample). Time to recurrence is presented in the following table.
Time Frame	Baseline of the Double-blind, Placebo-controlled Phase up to the end of the study (Week 52).

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least one injection of IMP and had at least one post-baseline efficacy assessment in the Double-blind, Placebo-controlled Phase, eg, modified ITT population.

Arm/Group Title	Aripiprazole IM Depot	Placebo
Arm/Group Description	Subjects received aripiprazole 300 mg or 400 mg depot intramuscularly up to 52 weeks.	Subjects received placebo intramuscularly up to 52 weeks.
Measure Participants	132	133
Median (95% Confidence Interval) [Days]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole IM Depot, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0002
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.137
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.465
	Parameter Dispersion	Type: Value:
	Estimation Comments	Using the Cox proportional hazards model with term for treatment group. HR is estimated for Aripiprazole IM depot relative to Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole IM Depot, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	Using the Cox proportional hazards model with term for treatment group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	7.313
	Confidence Interval	(2-Sided) 95%; 2.151 to 24.865
	Parameter Dispersion	Type: Value:
	Estimation Comments	HR is estimated for Placebo relative to Aripiprazole IM depot.

Adverse Events

Time Frame	Any AEs were recorded from the signing of informed consent up to 52 weeks (end of the study).
Adverse Event Reporting Description	Safety analysis set (SAF): The SAF included all subjects who received at least one dose of trial medication in all phases of the study. Safety analysis results were reported for the safety populations.
Arm/Group Title	Conversion Phase.		Oral Aripiprazole Stabilization Phase.		IM Depot Stabilization Phase.		Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase.		Placebo-Double-blind, Placebo-controlled Phase.
Arm/Group Description	During the Oral Conversion Phase, subjects were cross-titrated from other antipsychotics to oral non-generic aripiprazole monotherapy. Received Oral aripiprazole at a target starting dose of 15 mg/day.		Subjects received oral aripiprazole dose ranging from 15 mg to 30 mg daily.		During the depot stabilization phase, subjects were stabilized on aripiprazole depot.		Subjects received IM depot aripiprazole 400 mg or 300 mg, once a month injection.		Subjects received IM Depot Placebo, once a month injection.
All Cause Mortality
	Conversion Phase.		Oral Aripiprazole Stabilization Phase.		IM Depot Stabilization Phase.		Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase.		Placebo-Double-blind, Placebo-controlled Phase.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/459 (0%)		1/614 (0.2%)		0/425 (0%)		1/132 (0.8%)		0/133 (0%)
Serious Adverse Events
	Conversion Phase.		Oral Aripiprazole Stabilization Phase.		IM Depot Stabilization Phase.		Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase.		Placebo-Double-blind, Placebo-controlled Phase.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/459 (7%)		35/614 (5.7%)		36/425 (8.5%)		10/132 (7.6%)		25/133 (18.8%)
Cardiac disorders
Atrial Fibrillation	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	1/132 (0.8%)	1	0/133 (0%)	0
Cardio-respiratory arrest	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Acute myocardial infarction	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Myocardial infarction	0/459 (0%)	0	1/614 (0.2%)	1	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Angina pectoris	1/459 (0.2%)	1	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Gastrointestinal disorders
Colitis ulcerative	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	1/133 (0.8%)	1
Haemorrhoidal haemorrhage	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Abdominal pain	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Food poisoning	0/459 (0%)	0	1/614 (0.2%)	1	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Hepatobiliary disorders
Cholestasis	0/459 (0%)	0	1/614 (0.2%)	1	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Infections and infestations
Pneumonia	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	1/133 (0.8%)	1
Pyelonephritis	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Sepsis	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Vulval abscess	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Injury, poisoning and procedural complications
Radius fracture	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	1/133 (0.8%)	1
Accidental overdose	0/459 (0%)	0	1/614 (0.2%)	1	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Head injury	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Nervous system disorders
Akathisia	3/459 (0.7%)	3	1/614 (0.2%)	1	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Brain injury	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Transient ischaemic attack	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Radiculopathy	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Tremor	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Cerebrovascular accident	1/459 (0.2%)	1	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Extrapyramidal disorder	1/459 (0.2%)	1	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Psychiatric disorders
Affect lability	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Affective disorder	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	1/133 (0.8%)	1
Aggression	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	1/133 (0.8%)	1
Bipolar disorder	6/459 (1.3%)	6	2/614 (0.3%)	2	0/425 (0%)	0	1/132 (0.8%)	1	3/133 (2.3%)	3
Bipolar I disorder	4/459 (0.9%)	4	1/614 (0.2%)	1	4/425 (0.9%)	4	2/132 (1.5%)	2	3/133 (2.3%)	3
Hypomania	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Major depression	1/459 (0.2%)	1	1/614 (0.2%)	1	0/425 (0%)	0	0/132 (0%)	0	2/133 (1.5%)	2
Mania	13/459 (2.8%)	14	17/614 (2.8%)	17	7/425 (1.6%)	7	2/132 (1.5%)	2	10/133 (7.5%)	10
Suicide attempt	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	1/132 (0.8%)	1	1/133 (0.8%)	1
Anxiety	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Depressed mood	2/459 (0.4%)	2	1/614 (0.2%)	1	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Depression	0/459 (0%)	0	4/614 (0.7%)	4	8/425 (1.9%)	8	0/132 (0%)	0	0/133 (0%)	0
Depressive symptom	0/459 (0%)	0	2/614 (0.3%)	2	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Insomnia	0/459 (0%)	0	1/614 (0.2%)	1	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Suicidal ideation	2/459 (0.4%)	2	3/614 (0.5%)	3	3/425 (0.7%)	3	0/132 (0%)	0	0/133 (0%)	0
Agitation	1/459 (0.2%)	1	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	0/133 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Nephrolithiasis	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Renal Tubular Necrosis	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Reproductive system and breast disorders
Pelvic adhesions	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	0/132 (0%)	0	1/133 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	1/459 (0.2%)	2	0/614 (0%)	0	1/425 (0.2%)	1	1/132 (0.8%)	1	0/133 (0%)	0
Respiratory failure	0/459 (0%)	0	0/614 (0%)	0	0/425 (0%)	0	1/132 (0.8%)	1	0/133 (0%)	0
Vascular disorders
Thrombosis	0/459 (0%)	0	0/614 (0%)	0	1/425 (0.2%)	1	0/132 (0%)	0	0/133 (0%)	0
Other (Not Including Serious) Adverse Events
	Conversion Phase.		Oral Aripiprazole Stabilization Phase.		IM Depot Stabilization Phase.		Aripiprazole IM Depot- Double-blind, Placebo-controlled Phase.		Placebo-Double-blind, Placebo-controlled Phase.
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	180/459 (39.2%)		196/614 (31.9%)		194/425 (45.6%)		66/132 (50%)		62/133 (46.6%)
General disorders
Fatigue	14/459 (3.1%)	14	19/614 (3.1%)	19	22/425 (5.2%)	25	4/132 (3%)	4	5/133 (3.8%)	6
Infections and infestations
Nasopharyngitis	18/459 (3.9%)	18	11/614 (1.8%)	11	22/425 (5.2%)	30	10/132 (7.6%)	13	13/133 (9.8%)	29
Investigations
Weight increased	13/459 (2.8%)	13	22/614 (3.6%)	23	47/425 (11.1%)	47	31/132 (23.5%)	31	24/133 (18%)	25
Nervous system disorders
Akathisia	76/459 (16.6%)	84	94/614 (15.3%)	99	74/425 (17.4%)	82	27/132 (20.5%)	32	17/133 (12.8%)	20
Headache	31/459 (6.8%)	64	13/614 (2.1%)	21	12/425 (2.8%)	12	4/132 (3%)	4	9/133 (6.8%)	10
Psychiatric disorders
Anxiety	19/459 (4.1%)	20	24/614 (3.9%)	24	30/425 (7.1%)	36	9/132 (6.8%)	9	6/133 (4.5%)	6
Insomnia	35/459 (7.6%)	37	34/614 (5.5%)	35	41/425 (9.6%)	47	10/132 (7.6%)	11	10/133 (7.5%)	12
Restlessness	36/459 (7.8%)	45	32/614 (5.2%)	34	24/425 (5.6%)	25	6/132 (4.5%)	6	5/133 (3.8%)	5

Limitations/Caveats

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Principal Investigators are NOT employed by the organization sponsoring the study.

Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.