BEACON: Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01393613
• Collaborator: (none)
• Enrollment: 674
• Locations: 60
• Arms: 4
• Duration (Months): 31.1
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy, safety, and tolerability of fixed doses of OPC-34712 versus placebo for the treatment of adult subjects with an acute relapse of schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Acute Schizophrenia	Drug: OPC-34712; Drug: OPC-34712; Drug: OPC-34712; Drug: Placebo	Phase 3

Detailed Description

Schizophrenia is a severely debilitating mental illness that affects approximately 1% of the world population. Hallucinations and delusions are the most striking characteristic positive symptoms of schizophrenia; however, more subtle negative symptoms (eg, social withdrawal and lack of emotion, energy, and motivation) may also be present. The first antipsychotics developed for the treatment of schizophrenia were effective against positive symptoms, but showed little efficacy for negative symptoms and were also associated with a high incidence of side effects. Second generation antipsychotics, represent a significant advancement in the treatment of psychotic disorders because they are effective and at the same time exhibit fewer side effects than first generation antipsychotics. Although generally safer than first generation antipsychotics, the second-generation antipsychotics are not devoid of undesirable side effects such as Hyperprolactinemia and weight gain. In addition, the safety of these drugs vary considerably.

Study Design

• Study Type: Interventional
• Actual Enrollment: 674 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Fixed-dose OPC-34712 in the Treatment of Adults With Acute Schizophrenia
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose 3 OPC 34712 Higher dose, tablet, once daily, for six weeks	Drug: OPC-34712; Higher dose tablet, once daily, for six weeks,
Experimental: Dose 2 OPC 34712 Middle dose, tablet, once daily, for six weeks	Drug: OPC-34712; Middle dose tablet, once daily, for six weeks
Experimental: Dose 1 OPC 34712 Lower dose, tablet, once daily, for six weeks	Drug: OPC-34712; Lower dose tablet, once daily, for six weeks
Placebo Comparator: Placebo Placebo, once daily, for six weeks	Drug: Placebo; Placebo, once daily, for six weeks

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).

Secondary Outcome Measures

1. Mean Change From Baseline to Week 6 in Clinical Global Impression-Severity (CGI-S) Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   Severity of illness for each participant was rated using the CGI-S, which was the key secondary efficacy endpoint. To perform this assessment, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.

2. Mean Change From Baseline to Week 6 in Personal and Social Performance (PSP) Score. [Baseline, Week 3 and Week 6]

   PSP is a validated clinician-rated scale that measures personal and social functioning in 4 domains: socially useful activities (e.g. work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment to determine the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented manifest disabilities of various degrees and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision.

3. Mean Change From Baseline to Week 6 in PANSS Positive Subscale Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome). The analysis of secondary endpoints was conducted if both comparisons of brexpiprazole 4 mg/day vs placebo and brexpiprazole 2 mg/day vs placebo of the primary endpoint were significant. Although only the comparison of brexpiprazole 4 mg/day vs placebo met the gatekeeping threshold in the primary analysis, statistical testing for the other doses was reported for information.

4. Mean Change From Baseline to Week 6 in PANSS Negative Subscale Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).

5. Mean Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 6. [Week 6]

   The efficacy of trial medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at Baseline prior to the first dose of double-blind study medication. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

6. Percentage of Participants With Response at Week 6. [Week 6]

   The response rate was defined as reduction of ≥30% from Baseline in PANSS Total Score or CGI-I score of 1 or 2.

7. Percentage of Participants With Discontinuation Rate for Lack of Efficacy at Week 6. [Week 6]

   Participants discontinued for lack of efficacy during the trial were reported here.

8. Mean Change From Baseline to Week 6 in PANSS Excited Component (PEC) Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe).

9. Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Positive Symptoms Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

   Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome).

10. Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Negative Symptoms Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome).

11. Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Disorganized Thought Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome).

12. Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Uncontrolled Hostility and Excitement Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome).

13. Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Anxiety and Depression Score. [Baseline, Weeks 1, 2, 3, 4, 5, and 6]

    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female subjects between 18 and 65 years of age, with a diagnosis of schizophrenia, as defined by DSM-IV-TR criteria

2. Subjects who have been recently hospitalized or who would benefit from hospitalization for an acute relapse of schizophrenia

3. Subjects experiencing an acute exacerbation of psychotic symptoms

4. Other protocol specific inclusion criteria may apply

Exclusion Criteria:

1. Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving study drug

2. Subjects with a current DSM-IV-TR Axis I diagnosis of:

• Schizoaffective disorder

• MDD

• Bipolar disorder

• Delirium, dementia, amnestic or other cognitive disorder

• Borderline, paranoid, histrionic, schizotypal, schizoid or antisocial personality disorder

1. Subjects presenting with a first episode of schizophrenia

2. Other protocol specific exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States	72201
2		Springdale	Arkansas	United States	72764
3		Escondido	California	United States	92025
4		Long Beach	California	United States	90813
5		Orange	California	United States	92868
6		Pico Rivera	California	United States	90660
7		San Diego	California	United States	92102
8		North Miami	Florida	United States	33161
9		North Miami	Florida	United States	33162
10		Overland Park	Kansas	United States	66212
11		Lake Charles	Louisiana	United States	70629
12		Shreveport	Louisiana	United States	71104
13		Flowood	Mississippi	United States	39232
14		St. Louis	Missouri	United States	63118
15		Buffalo	New York	United States	14215
16		Memphis	Tennessee	United States	38119
17		Austin	Texas	United States	78756
18		Dallas	Texas	United States	75243
19		Houston	Texas	United States	77007
20		Bogota		Colombia	00000
21		Medellin		Colombia	00000
22		Pereira		Colombia	00000
23		Rijeka		Croatia	51000
24		Zagreb		Croatia	10000
25		Zagreb		Croatia	10090
26		Col. Florida	Distrito Federal	Mexico	01030
27		Mexico	Distrito Federal	Mexico	05300
28		Monterrey	Nuevo Leon	Mexico	64060
29		San Luis Potosi	San Luis Potos	Mexico	78218
30		Monterrey		Mexico	64060
31		Cebu City		Philippines	6000
32		Davano City		Philippines	8000
33		Makati City		Philippines	1229
34		Mandaluyong City		Philippines	1553
35		Manila		Philippines	1000
36		Arkhangelsk		Russian Federation	163530
37		Moscow Region		Russian Federation	142601
38		Moscow		Russian Federation	117152
39		Moscow		Russian Federation	119991
40		Nizhniy Novgorod		Russian Federation	603155
41		Petrozavodsk		Russian Federation	185000
42		Samara		Russian Federation	443016
43		Saratov		Russian Federation	410060
44		St. Petersburg		Russian Federation	190005
45		St. Petersburg		Russian Federation	190121
46		St. Petersburg		Russian Federation	192019
47		St. Petersburg		Russian Federation	194214
48		St. Petersburg		Russian Federation	197341
49		Tomsk		Russian Federation	634014
50		Village Nikolskoe		Russian Federation	188357
51		Bojnice		Slovakia	97201
52		Bratislava		Slovakia	82606
53		Michalovace		Slovakia	07101
54		Rimavska Sobota		Slovakia	97912
55		Roznava		Slovakia	04801
56		Kaohsiung		Taiwan	802
57		New Taipei City		Taiwan	249
58		Taichung		Taiwan	40447
59		Taipei		Taiwan	110
60		Taoyuan		Taiwan	333

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Study Director: Aleksandar Skuban, M.D., Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01393613
• Other Study ID Numbers: 331-10-230
• First Posted: Jul 13, 2011
• Last Update Posted: Nov 26, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Recruitment Details	This trial was conducted in 674 participants from 68 trial sites in 8 countries.
Pre-assignment Detail	Adults with schizophrenia as defined by Diagnostic and Statistical Manual of Mental Health Disorders 4th Edition Text Revision criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI) for schizophrenia and psychotic disorders studies were included.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Period Title: Overall Study
STARTED	120	186	184	184
COMPLETED	81	129	130	118
NOT COMPLETED	39	57	54	66

Baseline Characteristics

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo	Total
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.	Total of all reporting groups
Overall Participants	120	186	184	184	674
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.1 (11.9)	36.9 (10.9)	38.6 (11.0)	39.3 (10.8)	38.4 (11.1)
Sex: Female, Male (Count of Participants)
Female	43 35.8%	64 34.4%	71 38.6%	73 39.7%	251 37.2%
Male	77 64.2%	122 65.6%	113 61.4%	111 60.3%	423 62.8%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score.
Description	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-3.32 (0.83)	-4.35 (0.68)	-5.58 (0.68)	-3.48 (0.68)
Week 2	-7.61 (1.09)	-8.70 (0.88)	-8.42 (0.88)	-6.61 (0.89)
Week 3	-11.56 (1.30)	-10.69 (1.06)	-12.63 (1.05)	-8.95 (1.06)
Week 4	-13.97 (1.49)	-13.12 (1.21)	-15.55 (1.19)	-11.10 (1.22)
Week 5	-14.47 (1.71)	-14.11 (1.38)	-17.26 (1.37)	-11.89 (1.40)
Week 6	-16.90 (1.86)	-16.61 (1.49)	-20.00 (1.48)	-13.53 (1.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare the average effect analysis for brexpiprazole 2 mg/day and 4 mg/day and placebo combined treatment groups at Week 6. The primary analysis was performed by fitting a Mixed Model Repeated Measures (MMRM) with an unstructured variance covariance structure. The model included fixed class effect terms for treatment, trial site, visit week, baseline, baseline and visit interaction and an interaction term of treatment by visit week.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0093
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.47
	Confidence Interval	(2-Sided) 95%; -10.6 to -2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1448
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.08
	Confidence Interval	(2-Sided) 95%; -7.23 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, trial site, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1588
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.37
	Confidence Interval	(2-Sided) 95%; -8.06 to 1.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in Clinical Global Impression-Severity (CGI-S) Score.
Description	Severity of illness for each participant was rated using the CGI-S, which was the key secondary efficacy endpoint. To perform this assessment, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	120	180	183	181
Week 1	-0.11 (0.05)	-0.16 (0.04)	-0.22 (0.04)	-0.12 (0.04)
Week 2	-0.31 (0.06)	-0.40 (0.05)	-0.40 (0.05)	-0.36 (0.05)
Week 3	-0.63 (0.07)	-0.60 (0.06)	-0.69 (0.06)	-0.44 (0.06)
Week 4	-0.67 (0.09)	-0.72 (0.07)	-0.85 (0.07)	-0.58 (0.07)
Week 5	-0.81 (0.10)	-0.79 (0.08)	-1.02 (0.08)	-0.68 (0.08)
Week 6	-0.91 (0.11)	-0.99 (0.09)	-1.19 (0.08)	-0.81 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare the average effect analysis for brexpiprazole 2 mg/day and 4 mg/day and placebo combined treatment groups at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0069
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. The analysis of this key secondary endpoint was conducted if both comparisons of brexpiprazole 4 mg/day vs placebo and brexpiprazole 2 mg/day vs placebo of the primary endpoint were significant. Because only the comparison of brexpiprazole 4 mg/day vs placebo met the threshold in the primary analysis, the following analysis is not part of the formal statistical testing and is descriptive only.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.62 to -0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1269
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4449
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in Personal and Social Performance (PSP) Score.
Description	PSP is a validated clinician-rated scale that measures personal and social functioning in 4 domains: socially useful activities (e.g. work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment to determine the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 were considered to have mild functional difficulty. Scores of 31 to 70 represented manifest disabilities of various degrees and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision.
Time Frame	Baseline, Week 3 and Week 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	105	170	174	163
Week 3	6.97 (0.90)	6.85 (0.73)	7.12 (0.71)	5.80 (0.73)
Week 6	11.73 (1.19)	10.52 (0.95)	13.11 (0.94)	8.52 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.59
	Confidence Interval	(2-Sided) 95%; 2.02 to 7.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1286
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95%; -0.58 to 4.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0332
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.21
	Confidence Interval	(2-Sided) 95%; 0.26 to 6.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Positive Subscale Score.
Description	PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome). The analysis of secondary endpoints was conducted if both comparisons of brexpiprazole 4 mg/day vs placebo and brexpiprazole 2 mg/day vs placebo of the primary endpoint were significant. Although only the comparison of brexpiprazole 4 mg/day vs placebo met the gatekeeping threshold in the primary analysis, statistical testing for the other doses was reported for information.
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-0.93 (0.28)	-1.43 (0.23)	-1.80 (0.23)	-1.25 (0.23)
Week 2	-2.54 (0.39)	-2.76 (0.32)	-2.93 (0.32)	-2.56 (0.32)
Week 3	-3.94 (0.46)	-3.56 (0.37)	-4.43 (0.37)	-3.34 (0.37)
Week 4	-4.83 (0.52)	-4.35 (0.42)	-5.16 (0.41)	-3.93 (0.42)
Week 5	-4.80 (0.58)	-4.68 (0.47)	-6.04 (0.46)	-4.33 (0.47)
Week 6	-5.63 (0.62)	-5.42 (0.50)	-6.65 (0.50)	-4.95 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0166
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.70
	Confidence Interval	(2-Sided) 95%; -3.08 to -0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5101
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -1.86 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3938
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95%; -2.26 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Negative Subscale Score.
Description	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-0.31 (0.25)	-0.52 (0.20)	-0.88 (0.20)	-0.40 (0.20)
Week 2	-1.27 (0.29)	-1.31 (0.23)	-1.42 (0.23)	-0.79 (0.24)
Week 3	-2.06 (0.35)	-1.80 (0.28)	-2.15 (0.28)	-1.18 (0.28)
Week 4	-2.56 (0.40)	-2.09 (0.32)	-2.69 (0.32)	-1.67 (0.33)
Week 5	-2.71 (0.44)	-2.50 (0.35)	-2.82 (0.35)	-1.74 (0.36)
Week 6	-2.92 (0.48)	-2.91 (0.38)	-3.36 (0.38)	-2.14 (0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0231
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.22
	Confidence Interval	(2-Sided) 95%; -2.28 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1547
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.77
	Confidence Interval	(2-Sided) 95%; -1.83 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2004
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.78
	Confidence Interval	(2-Sided) 95%; -1.98 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 6.
Description	The efficacy of trial medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at Baseline prior to the first dose of double-blind study medication. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	120	180	183	181
Mean (Standard Deviation) [Units on a scale]	3.20 (1.45)	3.17 (1.34)	2.95 (1.33)	3.48 (1.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenzel (CMH) row mean scores differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.78 to -0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0422
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH row mean scores differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.60 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1358
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH row mean scores differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants With Response at Week 6.
Description	The response rate was defined as reduction of ≥30% from Baseline in PANSS Total Score or CGI-I score of 1 or 2.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Number [percentage of participants]	43.6 36.3%	38.5 20.7%	49.7 27%	31.7 17.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 1.20 to 2.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1680
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0433
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 1.02 to 1.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With Discontinuation Rate for Lack of Efficacy at Week 6.
Description	Participants discontinued for lack of efficacy during the trial were reported here.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Number [percentage of participants]	7.69 6.4%	11.2 6%	8.84 4.8%	11.7 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5202
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.44 to 1.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9894
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4586
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Excited Component (PEC) Score.
Description	The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-0.35 (0.25)	-0.46 (0.21)	-1.01 (0.21)	-0.48 (0.21)
Week 2	-0.76 (0.32)	-1.31 (0.26)	-1.21 (0.26)	-0.62 (0.26)
Week 3	-1.21 (0.35)	-1.31 (0.28)	-1.81 (0.28)	-0.82 (0.29)
Week 4	-1.58 (0.37)	-1.52 (0.29)	-2.12 (0.29)	-1.12 (0.30)
Week 5	-1.16 (0.42)	-1.48 (0.34)	-2.27 (0.34)	-0.97 (0.35)
Week 6	-1.94 (0.41)	-1.90 (0.33)	-2.86 (0.33)	-1.47 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -2.30 to -0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3559
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -1.34 to 0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3646
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -1.51 to 0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Positive Symptoms Score.
Description	Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-1.44 (0.29)	-1.77 (0.23)	-1.75 (0.24)	-1.30 (0.24)
Week 2	-2.97 (0.39)	-3.10 (0.32)	-3.03 (0.32)	-3.03 (0.32)
Week 3	-4.48 (0.47)	-4.09 (0.38)	-4.39 (0.37)	-3.78 (0.38)
Week 4	-5.42 (0.53)	-4.93 (0.43)	-5.48 (0.43)	-4.67 (0.44)
Week 5	-5.86 (0.58)	-5.35 (0.47)	-6.41 (0.46)	-5.47 (0.47)
Week 6	-6.56 (0.66)	-6.26 (0.53)	-7.05 (0.53)	-5.91 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1273
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.14
	Confidence Interval	(2-Sided) 95%; -2.61 to 0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6400
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -1.83 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4423
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 95%; -2.32 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Negative Symptoms Score.
Description	Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-0.70 (0.28)	-0.85 (0.22)	-1.12 (0.23)	-0.66 (0.22)
Week 2	-1.71 (0.32)	-1.86 (0.26)	-1.72 (0.26)	-1.38 (0.26)
Week 3	-2.55 (0.37)	-2.30 (0.30)	-2.64 (0.30)	-1.83 (0.30)
Week 4	-3.21 (0.43)	-2.63 (0.34)	-3.17 (0.34)	-2.16 (0.35)
Week 5	-3.35 (0.47)	-3.13 (0.38)	-3.21 (0.37)	-2.24 (0.38)
Week 6	-3.55 (0.48)	-3.53 (0.39)	-3.84 (0.39)	-2.55 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0194
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.28
	Confidence Interval	(2-Sided) 95%; -2.36 to -0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0754
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.98
	Confidence Interval	(2-Sided) 95%; -2.06 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1080
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -2.22 to 0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Disorganized Thought Score.
Description	Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-0.40 (0.23)	-0.46 (0.19)	-0.78 (0.19)	-0.42 (0.19)
Week 2	-1.42 (0.27)	-1.15 (0.22)	-1.37 (0.22)	-0.71 (0.23)
Week 3	-2.35 (0.31)	-1.71 (0.25)	-2.32 (0.25)	-1.35 (0.26)
Week 4	-2.56 (0.36)	-2.27 (0.29)	-2.83 (0.29)	-1.77 (0.30)
Week 5	-2.95 (0.41)	-2.55 (0.33)	-3.42 (0.32)	-2.01 (0.33)
Week 6	-3.46 (0.43)	-2.94 (0.35)	-3.98 (0.34)	-2.59 (0.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. Because only the comparison of brexpiprazole 4 mg/day versus placebo met the threshold in the primary analysis, the following analysis is not part for the formal statistical testing and is descriptive only.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -2.34 to -0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4753
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -1.31 to 0.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1150
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -1.96 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Uncontrolled Hostility and Excitement Score.
Description	Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 1-week period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose the day after the Week 1 visit (ie, the beginning of Week 2).	Placebo tablet once daily for 6 weeks. Participants were titrated to the target dose of placebo over a 1-week period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose the day after the Week 1 visit (ie, the beginning of Week 2).
Measure Participants	117	179	181	180
Week 1	0.03 (0.22)	-0.10 (0.18)	-0.63 (0.18)	-0.21 (0.18)
Week 2	-0.15 (0.28)	-0.65 (0.23)	-0.68 (0.23)	-0.13 (0.23)
Week 3	-0.46 (0.30)	-0.61 (0.24)	-1.16 (0.24)	-0.19 (0.24)
Week 4	-0.74 (0.32)	-0.74 (0.26)	-1.31 (0.25)	-0.39 (0.26)
Week 5	-0.34 (0.36)	-0.60 (0.29)	-1.50 (0.29)	-0.22 (0.30)
Week 6	-0.90 (0.36)	-0.81 (0.29)	-1.89 (0.29)	-0.64 (0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.26
	Confidence Interval	(2-Sided) 95%; -2.05 to -0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6792
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.97 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5752
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -1.16 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Mean Change From Baseline to Week 6 in PANSS Marder Factor Scores: Anxiety and Depression Score.
Description	Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
Time Frame	Baseline, Weeks 1, 2, 3, 4, 5, and 6

Outcome Measure Data

Analysis Population Description

Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.

Arm/Group Title	Brexpiprazole 1 mg	Brexpiprazole 2 mg	Brexpiprazole 4 mg	Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.	Brexpiprazole 2 mg tablet once daily for 6 weeks.	Brexpiprazole 4 mg tablet once daily for 6 weeks.	Placebo tablet once daily for 6 weeks.
Measure Participants	117	179	181	180
Week 1	-1.18 (0.22)	-1.10 (0.18)	-1.26 (0.18)	-0.96 (0.18)
Week 2	-1.86 (0.27)	-1.91 (0.22)	-1.60 (0.22)	-1.47 (0.22)
Week 3	-2.43 (0.28)	-2.10 (0.23)	-2.24 (0.23)	-1.97 (0.23)
Week 4	-2.85 (0.29)	-2.70 (0.23)	-2.93 (0.23)	-2.60 (0.23)
Week 5	-2.93 (0.31)	-2.87 (0.25)	-3.09 (0.25)	-2.69 (0.26)
Week 6	-3.57 (0.30)	-3.62 (0.24)	-3.78 (0.24)	-2.93 (0.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 4 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0104
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.86
	Confidence Interval	(2-Sided) 95%; -1.51 to -0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0373
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.70
	Confidence Interval	(2-Sided) 95%; -1.35 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 1 mg, Placebo
	Comments	Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0890
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM analysis fixed effect of treatment, trial site, visit, treatment visit interaction, Baseline value, Baseline visit interaction as covariates.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95%; -1.39 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were monitored from signing of the informed consent form until follow-up for up to 30 (+2) days after the last dose of study medication.
Adverse Event Reporting Description	A serious adverse event (SAE) was an untoward medical occurrence that resulted in death or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or a new problem experienced by a participant when enrolled in a trial whether or not it was considered drug related by study physician.
Arm/Group Title	Brexpiprazole 1 mg		Brexpiprazole 2 mg		Brexpiprazole 4 mg		Placebo
Arm/Group Description	Brexpiprazole 1 mg tablet once daily for 6 weeks.		Brexpiprazole 2 mg tablet once daily for 6 weeks.		Brexpiprazole 4 mg tablet once daily for 6 weeks.		Placebo tablet once daily for 6 weeks.
All Cause Mortality
	Brexpiprazole 1 mg		Brexpiprazole 2 mg		Brexpiprazole 4 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Brexpiprazole 1 mg		Brexpiprazole 2 mg		Brexpiprazole 4 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/120 (2.5%)		4/186 (2.2%)		4/184 (2.2%)		10/184 (5.4%)
General disorders
Irritability	0/120 (0%)		0/186 (0%)		0/184 (0%)		1/184 (0.5%)
Psychiatric disorders
Acute psychosis	0/120 (0%)		0/186 (0%)		0/184 (0%)		1/184 (0.5%)
Aggression	1/120 (0.8%)		0/186 (0%)		0/184 (0%)		0/184 (0%)
Psychotic disorder	1/120 (0.8%)		2/186 (1.1%)		1/184 (0.5%)		1/184 (0.5%)
Schizophrenia	1/120 (0.8%)		2/186 (1.1%)		3/184 (1.6%)		8/184 (4.3%)
Suicidal ideation	0/120 (0%)		0/186 (0%)		1/184 (0.5%)		0/184 (0%)
Other (Not Including Serious) Adverse Events
	Brexpiprazole 1 mg		Brexpiprazole 2 mg		Brexpiprazole 4 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/120 (30.8%)		65/186 (34.9%)		66/184 (35.9%)		71/184 (38.6%)
Gastrointestinal disorders
Dyspepsia	7/120 (5.8%)		7/186 (3.8%)		6/184 (3.3%)		6/184 (3.3%)
Nervous system disorders
Akathisia	5/120 (4.2%)		9/186 (4.8%)		12/184 (6.5%)		13/184 (7.1%)
Headache	9/120 (7.5%)		20/186 (10.8%)		19/184 (10.3%)		27/184 (14.7%)
Psychiatric disorders
Agitation	10/120 (8.3%)		16/186 (8.6%)		13/184 (7.1%)		13/184 (7.1%)
Insomnia	15/120 (12.5%)		25/186 (13.4%)		28/184 (15.2%)		27/184 (14.7%)
Schizophrenia	4/120 (3.3%)		6/186 (3.2%)		7/184 (3.8%)		10/184 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.