STEP-D222: Study of the Safety and Efficacy of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01052077
• Collaborator: (none)
• Enrollment: 773
• Locations: 43
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 18
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This is a Double-blind study wherein patients with Major Depressive Disorder (MDD) will receive either from 1 to 3 mg a day of study medication (OPC-34712)or placebo (an inactive substance) in addition to an FDA approved antidepressant in order to determine if the study medication is effective as an add on treatment of MDD.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: OPC-34712; Drug: Placebo; Drug: ADT	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 773 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of OPDC-34712 (1 to 3 mg/Day) as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder.
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Brexipiprazole + ADT OPC-34712 Tablets, Oral, 1 - 3 mg OPC-34712 + ADT	Drug: OPC-34712; Tablets, Oral, 1 - 3 mg OPC-34712; Drug: Placebo; Placebo; Drug: ADT; Other Names: FDA Approved Antidepressant (ADT)
Placebo Comparator: Placebo + ADT Placebo + ADT	Drug: Placebo; Placebo; Drug: ADT; Other Names: FDA Approved Antidepressant (ADT)

Outcome Measures

Primary Outcome Measures

1. Change From the End of Phase A (Week 8 Visit) to the End of Phase B (Week 14 Visit) in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score. [Baseline (end of week 8) to Week 14]

   The MADRS was utilized as the primary efficacy assessment of a participants level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.

Secondary Outcome Measures

1. Change From End of Phase A (Week 8) to Phase B in Sheehan Disability Scale (SDS) Score. [Baseline (end of week 8) to Week 14]

   The SDS was a self-rated instrument used to measure the effect of the participants symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores ranged from 0 through 10. The number most representative of how much each area was disrupted by symptoms was marked along the line from 0= not at all, to 10= extremely. Scores of 5 and above are associated with significant functional impairment. The SDS total score ranges from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. For the work/school item, no response was to be entered if the participant did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS score were calculated over the three item scores. All three item scores were needed to be available with the exception of the work/school item score when this item was not applicable.

2. Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Trial Week Visit in Phase B. [Baseline (end of week 8) to Week 14]

   The MADRS was utilized as the primary efficacy assessment of a participants level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.

3. Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical Global Impression- Severity Illness Scale (CGI-S) Score. [Baseline (end of week 8) to Week 14]

   The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the investigator had to answer 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.

4. Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Inventory of Depressive Symptomatology (Self-Report) (IDS-SR) Total Score. [Baseline (end of week 8) to Week 14]

   The IDS-SR was a 30-item self-report measure, that was used to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of major depressive disorder (MDD). For individual items, the scores range from 0 to 3. The IDS-SR are scored by summing responses to 28 of the 30 items to obtain a total score ranging from 0 to 84, higher values indicate greater disruption in the depressive symptoms.

5. Change From End of Phase A (Week 8) to End of Phase B (Week 14) in the Hamilton Depression Rating Scale 17-item Version (HAM-D17) Total Score. [Baseline (end of week 8) to Week 14]

   The HAM-D17 was utilized as a secondary assessment of a participants level of depression. The HAM-D (17-Item) consisted of 17 items. Eight items were rated on a 0 to 2 scale (items 4, 5, 6, 12, 13, 14, 16 and 17), while nine items (items 1, 2, 3, 7, 8, 9, 10, 11, and 15) were rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 was the "best" rating and the highest score (2 or 4) was the "worst" rating. The possible total scores were from 0 to 52.

6. Clinical Global Impression- Improvement Scale (CGI-I) Score by Study Week in Phase B Relative to End of Phase A. [Baseline (end of week 8) to Week 14]

   The efficacy of study medication was rated for each participant using the CGI-I. The study physician would rate the participants total improvement whether or not it is due entirely to drug treatment. 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.

7. Number of Participants With MADRS Response During Phase B Relative to the End of Phase A (Week 8) Visit. [Baseline (end of week 8) to Week 14]

   A MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8 visit). The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.

8. Number of Participants With MADRS Remission During Phase B Relative to the End of Phase A (Week 8) Visit. [Baseline (end of week 8) to Week 14]

   A MADRS remission was defined as MADRS Total Score =< 10 and >= 50 percent reduction in MADRS Total Score from end of Phase A (Week 8 visit). The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.

9. Number of Participants With CGI-Improvement Response During Phase B Relative to the End of Phase A (Week 8). [Baseline (end of week 8) to Week 14]

   CGI-I Response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female subjects between 18 and 65 years of age, with diagnosis of major depressive disorder, as defined by DSM-IV-TR criteria

• The current depressive episode must be equal to or greater than 8 weeks in duration

• Subjects must report a history for the current depressive episode of an inadequate response to at least one and no more than three adequate antidepressant treatments.

Exclusion Criteria:

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

• Subjects who report an inadequate response to more than three adequate trials of antidepressant treatments during current depressive episode at a therapeutic dose for an adequate duration.

• Subjects with a current Axis I (DSM-IV-TR) diagnosis of: Delirium, dementia,amnestic or other cognitive disorder Schizophrenia, schizoaffective disorder, or other psychotic disorder Bipolar I or II disorder

• Subjects with a clinically significant current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Pacific Clinical Research Medical Group	Arcadia	California	United States	91007
3	Southwestern Research	Beverly Hills	California	United States	90210
4	Excell Research	Oceanside	California	United States	92056
5	Affiliated Research Institute	San Diego	California	United States	92108
6	Neuropsychiatric Research Center of Orange County	Santa Ana	California	United States	92782
7	California Neuroscience Research Medical Group, Inc.	Sherman Oaks	California	United States	91403
8	CNS Clinical Research Group	Coral Springs	Florida	United States	33067
9	Gulfcoast Clinical Research Center	Fort Myers	Florida	United States	33912
10	Clinical Neuroscience Solutions, Inc.	Jacksonville	Florida	United States	32216
11	Scientific Clinical Research, Inc.	North Miami	Florida	United States	33161
12	Clinical Neuroscience Solutions, Inc.	Orlando	Florida	United States	32806
13	Comprehensive NeuroScience, Inc.	Atlanta	Georgia	United States	30328
14	Carman Research	Smyrna	Georgia	United States	30080
15	Goldpoint Clinical Research, LLC	Indianapolis	Indiana	United States	46260
16	Vince and Associates Clinical Research	Overland Park	Kansas	United States	66212
17	Clinical InSights	Glen Burnie	Maryland	United States	21061
18	Pharmasite Research, Inc.	Pikesville	Maryland	United States	21208
19	MSU/Institute for Health Studies	East Lansing	Michigan	United States	48824
20	Center for Emotional Fitness	Cherry Hill	New Jersey	United States	08002
21	Neurobehavioral Research, Inc.	Cedarhurst	New York	United States	11515
22	Eastside Comprehensive Medical Center	New York	New York	United States	10021
23	Medical & Behavioral Health Research, PC	New York	New York	United States	10023
24	Finger Lakes Clinical Research	Rochester	New York	United States	14618
25	Richmond Behavioral Associates	Staten Island	New York	United States	10312
26	Northcoast Clinical Trials	Beachwood	Ohio	United States	44122
27	Patient Priority Clinical sites, LLC	Cincinnati	Ohio	United States	45242
28	Midwest Clinical Research Center	Dayton	Ohio	United States	45408
29	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
30	Summit Research Network (Oregon), LLC	Portland	Oregon	United States	97210
31	City Line Avenue Family Practice	Bala Cynwyd	Pennsylvania	United States	19004
32	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
33	Lincoln Research	Lincoln	Rhode Island	United States	02865
34	Clinical NeuroScience Solutions, Inc.	Memphis	Tennessee	United States	38119
35	FutureSearch Trials	Austin	Texas	United States	78756
36	FutureSearch Trials of Dallas	Dallas	Texas	United States	75231
37	Clinical Trials of Texas	San Antonio	Texas	United States	78229
38	Radiant Research	Salt Lake City	Utah	United States	84107
39	Psychiatric Alliance of The Blue Ridge	Charlottesville	Virginia	United States	22903
40	NeuroScience, Inc.	Herndon	Virginia	United States	20170
41	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
42	Summit Research Network (Seattle), LLC	Seattle	Washington	United States	98104
43	Northbrooke Research Center	Brown Deer	Wisconsin	United States	53223

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01052077
• Other Study ID Numbers: 331-09-222
• First Posted: Jan 20, 2010
• Last Update Posted: Nov 1, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: OPC-34712; Major Depressive Disorder; Adjunctive Treatment
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Antidepressive Agents

Study Results

Participant Flow

Recruitment Details	This trial was conducted in the United States in 773 participants at 44 centers. A total of 1226 participants were screened, 773 participants were enrolled in Phase A, and 769 were treated in Phase A. Of the 623 participants who completed Phase A, 372 participants were randomized in to Phase B.
Pre-assignment Detail	A 7 to 28-day Screening period, 8-Week single-blind placebo-ADT (antidepressant therapy) prospective Phase, 6-Week double-blind randomization Phase (Phase B), and 30-day follow-up after last dose of medication. Any participant randomized/completed all visits through Week 14 were allowed into an open-label rollover trial (NCT01052077).

Arm/Group Title	Phase A	Brexiprazole	Placebo	Phase A+
Arm/Group Description	Participants entered a single-blind prospective treatment phase during which they received single-blind placebo plus open-label commercially available ADT for 8 weeks at maximally tolerated doses.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.	Participants who met the criteria for a response at the end of the 8 weeks prospective treatment phase received single-blind placebo + ADT for an additional 6 weeks in Phase A+ for a total of 14 weeks.
Period Title: Phase A
STARTED	769	0	0	0
COMPLETED	623	0	0	0
NOT COMPLETED	146	0	0	0
Period Title: Phase A
STARTED	0	185	187	0
COMPLETED	0	167	171	0
NOT COMPLETED	0	18	16	0
Period Title: Phase A
STARTED	0	0	0	251
COMPLETED	0	0	0	230
NOT COMPLETED	0	0	0	21

Baseline Characteristics

Arm/Group Title	Brexpiprazole	Placebo	Total
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.	Total of all reporting groups
Overall Participants	185	187	372
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.7 (11.7)	42.4 (11.7)	43.5 (11.8)
Sex: Female, Male (Count of Participants)
Female	123 66.5%	130 69.5%	253 68%
Male	62 33.5%	57 30.5%	119 32%

Outcome Measures

1. Primary Outcome

Title	Change From the End of Phase A (Week 8 Visit) to the End of Phase B (Week 14 Visit) in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score.
Description	The MADRS was utilized as the primary efficacy assessment of a participants level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the Full Analysis Set (FAS) comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Least Squares Mean (Standard Error) [Units on a scale]	-8.20 (0.62)	-7.02 (0.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1416
	Comments	ANCOVA model, with treatment and study center as main effects and Week 8 value as convariate, is used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.18
	Confidence Interval	(2-Sided) 95%; -2.75 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From End of Phase A (Week 8) to Phase B in Sheehan Disability Scale (SDS) Score.
Description	The SDS was a self-rated instrument used to measure the effect of the participants symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores ranged from 0 through 10. The number most representative of how much each area was disrupted by symptoms was marked along the line from 0= not at all, to 10= extremely. Scores of 5 and above are associated with significant functional impairment. The SDS total score ranges from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. For the work/school item, no response was to be entered if the participant did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS score were calculated over the three item scores. All three item scores were needed to be available with the exception of the work/school item score when this item was not applicable.
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	174	172
Least Squares Mean (Standard Error) [Units on a scale]	-0.91 (0.19)	-0.69 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3778
	Comments	ANCOVA model, with treatment and study center as main effects and Week 8 value as covariate, is used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.69 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Trial Week Visit in Phase B.
Description	The MADRS was utilized as the primary efficacy assessment of a participants level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Week 9 (N= 181, 180)	-3.30 (0.42)	-1.99 (0.42)
Week 10 (N= 184, 181)	-5.92 (0.50)	-4.01 (0.50)
Week 11 (N= 184, 181)	-7.23 (0.57)	-5.22 (0.57)
Week 12 (N= 184, 181)	-8.42 (0.59)	-6.21 (0.59)
Week 13 (N= 184, 181)	-9.00 (0.59)	-7.18 (0.59)
Week 14 (N= 184, 181)	-8.20 (0.62)	-7.02 (0.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0162
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.31
	Confidence Interval	(2-Sided) 95%; -2.38 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.90
	Confidence Interval	(2-Sided) 95%; -3.15 to -0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.01
	Confidence Interval	(2-Sided) 95%; -3.44 to -0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0038
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.21
	Confidence Interval	(2-Sided) 95%; -3.69 to -0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0174
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.82
	Confidence Interval	(2-Sided) 95%; -3.32 to -0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1416
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.18
	Confidence Interval	(2-Sided) 95%; -2.75 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical Global Impression- Severity Illness Scale (CGI-S) Score.
Description	The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the investigator had to answer 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 (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Week 9 (N= 181, 180)	-0.29 (0.05)	-0.20 (0.05)
Week 10 (N= 184, 181)	-0.58 (0.06)	-0.44 (0.06)
Week 11 (N= 184, 181)	-0.76 (0.07)	-0.59 (0.07)
Week 12 (N= 184, 181)	-0.94 (0.07)	-0.68 (0.07)
Week 13 (N= 184, 181)	-1.00 (0.08)	-0.81 (0.08)
Week 14 (N= 184, 181)	-0.95 (0.08)	-0.85 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1481
	Comments	ANCOVA model, with treatment and study center as main effects and Week 8 value as covariate, is used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0691
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0457
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.35 to -0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0061
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.45 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0572
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3318
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Inventory of Depressive Symptomatology (Self-Report) (IDS-SR) Total Score.
Description	The IDS-SR was a 30-item self-report measure, that was used to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of major depressive disorder (MDD). For individual items, the scores range from 0 to 3. The IDS-SR are scored by summing responses to 28 of the 30 items to obtain a total score ranging from 0 to 84, higher values indicate greater disruption in the depressive symptoms.
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Week 9 (N= 181, 179)	-1.65 (0.54)	-1.99 (0.53)
Week 10 (N= 184, 181)	-2.91 (0.60)	-2.93 (0.60)
Week 11 (N= 184, 181)	-3.92 (0.68)	-3.64 (0.68)
Week 12 (N= 184, 181)	-4.82 (0.74)	-4.76 (0.74)
Week 13 (N= 184, 181)	-5.60 (0.75)	-5.59 (0.75)
Week 14 (N= 184, 181)	-5.70 (0.80)	-5.84 (0.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6272
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; -1.02 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9697
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -1.48 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7490
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -2.00 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9459
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -1.94 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9893
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -1.91 to 1.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8918
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -1.89 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From End of Phase A (Week 8) to End of Phase B (Week 14) in the Hamilton Depression Rating Scale 17-item Version (HAM-D17) Total Score.
Description	The HAM-D17 was utilized as a secondary assessment of a participants level of depression. The HAM-D (17-Item) consisted of 17 items. Eight items were rated on a 0 to 2 scale (items 4, 5, 6, 12, 13, 14, 16 and 17), while nine items (items 1, 2, 3, 7, 8, 9, 10, 11, and 15) were rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 was the "best" rating and the highest score (2 or 4) was the "worst" rating. The possible total scores were from 0 to 52.
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	176	172
Least Squares Mean (Standard Error) [Units on a scale]	-5.98 (0.45)	-5.40 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3247
	Comments	ANCOVA model, with treatment and trial center as main effects and Week 8 value as covariate, was used for change from Week 8 comparisons.
	Method	ANCOVA
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 95%; -1.71 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Clinical Global Impression- Improvement Scale (CGI-I) Score by Study Week in Phase B Relative to End of Phase A.
Description	The efficacy of study medication was rated for each participant using the CGI-I. The study physician would rate the participants total improvement whether or not it is due entirely to drug treatment. 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	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Week 9 (N= 181, 179)	3.33 (0.82)	3.37 (0.74)
Week 10 (N= 184, 180)	3.03 (0.97)	3.15 (0.84)
Week 11 (N= 184, 180)	3.00 (1.08)	3.02 (0.99)
Week 12 (N= 184, 180)	2.63 (1.12)	2.91 (1.02)
Week 13 (N= 184, 180)	2.60 (1.14)	2.80 (1.02)
Week 14 (N= 184, 181)	2.68 (1.18)	2.78 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5616
	Comments	Cohran-Mantel-Haenszel (CMH) row mean scores differ test controlling for study center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean: brexpiprazole - placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1900
	Comments	CMH row mean scores differ test controlling for study center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0501
	Comments	CMH row mean scores differ test controlling for study center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0137
	Comments	CMH row mean scores differ test controlling for study center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0711
	Comments	CMH row mean scores differ test controlling for study center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3438
	Comments	CMH row mean scores differ test controlling for study center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.

8. Secondary Outcome

Title	Number of Participants With MADRS Response During Phase B Relative to the End of Phase A (Week 8) Visit.
Description	A MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8 visit). The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Week 9 (N= 181, 180)	11 5.9%	4 2.1%
Week 10 (N= 184, 181)	29 15.7%	16 8.6%
Week 11 (N= 184, 181)	41 22.2%	26 13.9%
Week 12 (N= 184, 181)	56 30.3%	28 15%
Week 13 (N= 184, 181)	55 29.7%	33 17.6%
Week 14 (N= 184, 181)	55 29.7%	36 19.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0679
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Response rate
	Estimated Value	2.79
	Confidence Interval	(2-Sided) 95%; 0.88 to 8.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0360
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.78
	Confidence Interval	(2-Sided) 95%; 1.01 to 3.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0521
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; 0.99 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.93
	Confidence Interval	(2-Sided) 95%; 1.31 to 2.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.64
	Confidence Interval	(2-Sided) 95%; 1.14 to 2.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0339
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 95%; 1.03 to 2.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Participants With MADRS Remission During Phase B Relative to the End of Phase A (Week 8) Visit.
Description	A MADRS remission was defined as MADRS Total Score =< 10 and >= 50 percent reduction in MADRS Total Score from end of Phase A (Week 8 visit). The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS Total Score is the sum of ratings for all 10 items; therefore, possible total scores range from 0 to 60. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place.
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Week 9 (N= 181, 180)	7 3.8%	3 1.6%
Week 10 (N= 184, 181)	15 8.1%	7 3.7%
Week 11 (N= 184, 181)	31 16.8%	18 9.6%
Week 12 (N= 184, 181)	42 22.7%	19 10.2%
Week 13 (N= 184, 181)	46 24.9%	25 13.4%
Week 14 (N= 184, 181)	48 25.9%	27 14.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2404
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Remission Rate
	Estimated Value	2.27
	Confidence Interval	(2-Sided) 95%; 0.55 to 9.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0983
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Remission Rate
	Estimated Value	2.04
	Confidence Interval	(2-Sided) 95%; 0.83 to 4.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0496
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Remission Rate
	Estimated Value	1.67
	Confidence Interval	(2-Sided) 95%; 0.99 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Remission Rate
	Estimated Value	2.12
	Confidence Interval	(2-Sided) 95%; 1.31 to 3.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0068
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH general association test controlling for trial center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 1.17 to 2.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0089
	Comments	The CMH general association test controlling for trial center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Ratio of Remission Rate
	Estimated Value	1.71
	Confidence Interval	(2-Sided) 95%; 1.14 to 2.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Number of Participants With CGI-Improvement Response During Phase B Relative to the End of Phase A (Week 8).
Description	CGI-I Response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).
Time Frame	Baseline (end of week 8) to Week 14

Outcome Measure Data

Analysis Population Description

The efficacy sample was the FAS comprised of participants who received 1 dose of double-blind study medication and had both end of Week 8 visit value and 1 post-randomization efficacy assessment for MADRS total score in double-blind Phase B. The LOCF method was used to impute missing data.

Arm/Group Title	Brexpiprazole	Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
Measure Participants	184	181
Week 9 (N= 181, 179)	23 12.4%	19 10.2%
Week 10 (N= 184, 180)	47 25.4%	39 20.9%
Week 11 (N= 184, 180)	73 39.5%	51 27.3%
Week 12 (N= 184, 181)	88 47.6%	63 33.7%
Week 13 (N= 184, 181)	90 48.6%	70 37.4%
Week 14 (N= 184, 181)	84 45.4%	72 38.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4605
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for study center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.70 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3267
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for study center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0230
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for study center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 1.05 to 1.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0105
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for study center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 1.08 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0417
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for study center.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole, Placebo
	Comments	Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2345
	Comments	CMH general association test controlling for study center.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference = difference in adjusted mean change: brexpiprazole - placebo.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	AEs were recorded from the time the participant entered Phase B, throughout the 6-week treatment period (Week 9 to Week 14) and until follow-up at 30 days after the last dose of medication.
Adverse Event Reporting Description	SAE was any untoward medical occurrence resulting in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. AE was an exacerbation of an existing problem or a new problem experienced by a participant in a trial, whether or not it was drug related. One participant may have experienced multiple events.
Arm/Group Title	Brexpiprazole		Placebo
Arm/Group Description	Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to brexpiprazole arm 1 to 3 mg/day, plus the final dosage of the assigned open-label marketed ADT.		Participants with an incomplete response at the end of treatment phase (Week 8) were randomized to placebo arm plus the final dosage of the assigned open-label marketed ADT.
All Cause Mortality
	Brexpiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Brexpiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/185 (0%)		3/187 (1.6%)
Cardiac disorders
Sinus bradycardia	0/185 (0%)		1/187 (0.5%)
Psychiatric disorders
Depression	0/185 (0%)		1/187 (0.5%)
Vascular disorders
Hypotension	0/185 (0%)		1/187 (0.5%)
Subclavian vein thrombosis	0/185 (0%)		1/187 (0.5%)
Other (Not Including Serious) Adverse Events
	Brexpiprazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/185 (48.6%)		63/187 (33.7%)
Gastrointestinal disorders
Constipation	11/185 (5.9%)		4/187 (2.1%)
Diarrhoea	10/185 (5.4%)		10/187 (5.3%)
General disorders
Fatigue	14/185 (7.6%)		8/187 (4.3%)
Infections and infestations
Nasopharyngitis	12/185 (6.5%)		5/187 (2.7%)
Upper respiratory tract infection	9/185 (4.9%)		10/187 (5.3%)
Investigations
Weight increased	21/185 (11.4%)		5/187 (2.7%)
Metabolism and nutrition disorders
Increased appetite	14/185 (7.6%)		3/187 (1.6%)
Nervous system disorders
Akathisia	22/185 (11.9%)		9/187 (4.8%)
Headache	9/185 (4.9%)		16/187 (8.6%)
Psychiatric disorders
Insomnia	17/185 (9.2%)		6/187 (3.2%)

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.