Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01360632
• Collaborator: (none)
• Enrollment: 1,539
• Locations: 71
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 21.7
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

To compare the effect of OPC-34712 (brexpiprazole) to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with Major Depressive Disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder; Depression; Depressive Disorder, Major; Mood Disorders; Mental Disorders	Drug: OPC-34712 + ADT; Drug: Placebo + ADT; Drug: Placebo + ADT	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1539 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Two Fixed Doses of OPDC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Polaris Trial
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase B Drug: OPC-34712 + ADT Drug: Placebo + ADT	Drug: OPC-34712 + ADT; Tablets, Oral, 1 or 3 mg OPC-34712 and FDA Approved Antidepressant Therapy (ADT); Drug: Placebo + ADT; Placebo + FDA Approved Antidepressant (ADT)
Placebo Comparator: Phase A Drug: Placebo + ADT	Drug: Placebo + ADT; Placebo + FDA Approved Antidepressant (ADT)

Outcome Measures

Primary Outcome Measures

1. Mean Change From the End of Phase A (Week 8 Visit) to Phase B (Week 14 Visit) in the Montgomery-Asberg Depression Rating Scale for the Efficacy Sample Set [Baseline and Week 14]

   The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

2. Mean Change in MADRS Total Score From Baseline End of Week 8 to Week 14 for the Efficacy Sample Per Final Protocol [Baseline and Week 14]

   The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

Secondary Outcome Measures

1. Mean Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Study Week Visit in Phase B Other Than Week 14 Visit for the Efficacy Sample Set [Week 8, 9, 10, 11, 12, and 13]

   The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

2. Mean Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Study Week Visit in Phase B Other Than Week 14 Visit for the Efficacy Sample Per Final Protocol [Week 8, 9, 10, 11, 12, and 13]

   The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

3. Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in Sheehan Disability Scale (SDS) Mean Scores for the Efficacy Sample Set [Week 11 and 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. 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.

4. Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in SDS Mean Scores for the Efficacy Sample Per Final Protocol [Week 11 and 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. 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.

5. Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set [Week 11 and Week 14]

   The SDS is a self-rated instrument used to measure the effect of the patient's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable.

6. Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set Per Final Protocol [Week 11 and Week 14]

   The SDS is a self-rated instrument used to measure the effect of the patient's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable.

7. Mean Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical Global Impression Severity of Illness (CGI-S) for the Efficacy Sample Set [Weeks 8, 9, 10, 11, 12,13 and 14]

   The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician 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.

8. Mean Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical CGI-S for the Efficacy Sample Per Final Protocol [Weeks 8, 9, 10, 11, 12, 13, and 14]

   The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician 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.

9. Mean Change From End of Phase A (Week 8 Visit) for Every Study Week Visit in Phase B in Inventory of Depressive Symptomatology (Self-Report) IDS-SR Total Score for the Efficacy Sample Set [Weeks 8, 9, 10, 11, 12, 13, and 14]

   IDS-SR was a 30-item self-report measured to assess core diagnostic depressive symptoms and atypical and melancholic symptom features of major depressive disorders. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the "best" rating and 3 being the "worst" rating. Besides item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items were not included in the calculation of the total score. The IDS-SR Total Score was the sum of ratings of 28 item scores. The possible IDSSR Total Score ranged from 0 to 84. The IDS-SR Total Score was un-evaluable if less than 23 of the 28 items were recorded. If the number of items recorded was at least 23 and at most 27, the IDS-SR Total Score was the mean of the recorded items multiplied by 28, and was then rounded off to the first decimal place.

10. Mean Change From End of Phase A (Week 8 Visit) for Every Study Week Visit in Phase B in IDS-SR Total Score for the Efficacy Sample Per Final Protocol [Weeks 8, 9, 10, 11, 12, 13, and 14]

    The IDS-SR was a 30-item self-report measured to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of major depressive disorders. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the "best" rating and 3 being the "worst" rating. Besides item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items were not included in the calculation of the total score. The IDSSR Total Score was the sum of ratings of 28 item scores. The possible IDSSR Total Score ranged from 0 to 84. The IDS-SR Total Score was un-evaluable if less than 23 of the 28 items were recorded. If the number of items recorded was at least 23 and at most 27, the IDS-SR Total Score was the mean of the recorded items multiplied by 28, and was then rounded off to the first decimal place.

11. Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) Hamilton Depression Scale 17 Item Version (HAM)-D17 Total Score for the Efficacy Sample Set [Baseline and 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, with higher scores indicating more severe depression.

12. Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in HAM-D17 Total Score for the Efficacy Sample Set Per Final Protocol [Baseline and 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, with higher score indicating more severe depression.

13. Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in Hamilton Anxiety Rating Scale (HAM-A) Total Score for the Efficacy Sample Set [Baseline and Week 14]

    The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the "best" rating and 4 is the "worst" rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56, with higher scores indicating worse anxiety symptoms.

14. Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in HAM-A Total for the Efficacy Sample Per Final Protocol [Baseline and Week 14]

    The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the "best" rating and 4 is the "worst" rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56, with higher score indicating worse anxiety symptoms.

15. Mean CGI-I Score at Each Trial Week Visit in Phase B for the Efficacy Sample Set [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 participant's 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.

16. Mean CGI-I Score at Each Trial Week Visit in Phase B for the Efficacy Sample Per Final Protocol [Weeks 8, 9, 10, 11, 12, 13, and 14]

    The efficacy of study 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. 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.

17. Percentage of Participants With a MADRS Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Set [Weeks 8, 9, 10, 11, 12, 13, and 14]

    MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

18. Percentage of Participants With a MADRS Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Per Final Protocol [Weeks 8, 9, 10, 11, 12, 13, and 14]

    MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

19. Percentage of Participants With a MADRS Remission During Phase B Relative to the End of Phase A (Week 8) for the Efficacy Sample Set [Weeks 8, 9, 10, 11, 12, 13 and 14]

    MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

20. Percentage of Participants With a MADRS Remission During Phase B Relative to the End of Phase A (Week 8) for the Efficacy Sample Per Final Protocol [Weeks 8, 9, 10, 11, 12, 13 and 14]

    MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

21. Percentage of Participants With a CGI-I Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Set [Weeks 8, 9, 10, 11, 12, 13 and 14]

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

22. Percentage of Participants With a CGI-I Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Per Final Protocol [Weeks, 8, 9, 10, 11, 12, 13, and 14]

    A 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 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	Research Site	Birmingham	Alabama	United States
2	Research Site	Costa Mesa	California	United States
3	Research Site	Glendale	California	United States
4	Research Site	Orange	California	United States
5	Research Site	San Diego	California	United States
6	Research Site	Temecula	California	United States
7	Research Site	Jacksonville Beach	Florida	United States
8	Research Site	Jacksonville	Florida	United States
9	Research Site	Miami Springs	Florida	United States
10	Research Site	Tampa	Florida	United States
11	Research Site	Winter Park	Florida	United States
12	Research Site	Atlanta	Georgia	United States
13	Research Site	Smyrna	Georgia	United States
14	Research Site	Chicago	Illinois	United States
15	Research Site	Oak Brook	Illinois	United States
16	Research Site	Lafayette	Indiana	United States
17	Research Site	Owensboro	Kentucky	United States
18	Research Site	Baltimore	Maryland	United States
19	Research Site	Haverhill	Massachusetts	United States
20	Research Site	Weymouth	Massachusetts	United States
21	Research Site	Rochester Hills	Michigan	United States
22	Research Site	Creve Coeur	Missouri	United States
23	Research Site	Las Vegas	Nevada	United States
24	Research Site	Cherry Hill	New Jersey	United States
25	Research Site	Toms River	New Jersey	United States
26	Research Site	Brooklyn	New York	United States
27	Research Site	Fresh Meadows	New York	United States
28	Research Site	New York	New York	United States
29	Research Site	Staten Island	New York	United States
30	Research Site	Raleigh	North Carolina	United States
31	Research Site	Beachwood	Ohio	United States
32	Research Site	Cincinnati	Ohio	United States
33	Research Site	Columbus	Ohio	United States
34	Research Site	Oklahoma City	Oklahoma	United States
35	Research Site	Portland	Oregon	United States
36		Salem	Oregon	United States
37	Research Site	Norristown	Pennsylvania	United States
38	Research Site	Philadelphia	Pennsylvania	United States
39	Research Site	Lincoln	Rhode Island	United States
40	Research Site	Columbia	South Carolina	United States
41	Research Site	Memphis	Tennessee	United States
42	Research Site	Austin	Texas	United States
43	Research Site	Dallas	Texas	United States
44	Research Site	Houston	Texas	United States
45	Research Site	San Antonio	Texas	United States
46	Research Site	Witchita Falls	Texas	United States
47	Research Site	Charlottesville	Virginia	United States
48	Research Site	Herndon	Virginia	United States
49	Research Site	Bellevue	Washington	United States
50	Research Site	Spokane	Washington	United States
51	Research Site	Brown Deer	Wisconsin	United States
52	Research Site	Middleton	Wisconsin	United States
53	Research Site	Toronto	Ontario	Canada
54	Research Site	Pointe-Claire	Quebec	Canada
55	Research Site	Wurzburg	Bavaria	Germany
56	Research Site	Stralsund	Mecklenburg-Vorpommern	Germany
57	Research Site	Bochum	NRW	Germany
58	Research Site	Achim		Germany
59	Research Site	Nyiregyhaza	Szabolcs Szatmar Bereg	Hungary
60	Research Site	Budapest		Hungary
61	Research Site	Gyor		Hungary
62	Research Site	Bucharest		Romania
63	Research Site	Lasi		Romania
64	Research Site	Targu Mures		Romania
65	Research Site	Moscow		Russian Federation
66	Research Site	Rostov on Don		Russian Federation
67	Research Site	Saint Petersburg		Russian Federation
68	Research Site	Chenigiv		Ukraine
69	Research Site	Kharkiv		Ukraine
70	Research Site	Kiev		Ukraine
71	Research Site	Poltava		Ukraine

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: NCT01360632
• Other Study ID Numbers: 331-10-227
• First Posted: May 25, 2011
• Last Update Posted: Jan 1, 2016
• Last Verified: Nov 1, 2015

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

Study Results

Participant Flow

Recruitment Details	The study was conducted in 1539 participants at 92 trial sites in 7 countries. United States, Germany, Ukraine, Russia, Hungary, Canada, and Romania.
Pre-assignment Detail	The study consisted of a 7 to 28-day Screening period, an 8-Week single-blind placebo + ADT prospective Phase-A, a 6-Week double-blind randomization Phase-B or single-blind Phase A+ and a Follow-up of 30 (+2) days after the last dose of study medication.

Arm/Group Title	Single-blind Placebo + ADT	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Double-blind Placebo + ADT	Phase A+ Placebo + ADT
Arm/Group Description	In Phase A, participants were administered placebo as an adjunctive therapy to an open label ADT for 8 weeks.	Participants were administered brexpiprazole of [1mg (milligram)] as an adjunctive therapy to an assigned open-label ADT (anti-depressant therapy).	Participants were administered brexpiprazole of 3mg as an adjunctive therapy to an assigned open-label ADT.	In phase B, participants were administered placebo as an adjunctive therapy to an open label ADT for 6 weeks.	Participants who did not meet criteria for randomization and a follow-up of 30 (+2) days after the last dose of study medication were in Phase A+
Period Title: Phase A (8 Weeks)
STARTED	1532	0	0	0	0
COMPLETED	1277	0	0	0	0
NOT COMPLETED	255	0	0	0	0
Period Title: Phase A (8 Weeks)
STARTED	0	226	230	221	0
COMPLETED	0	216	210	208	0
NOT COMPLETED	0	10	20	13	0
Period Title: Phase A (8 Weeks)
STARTED	0	0	0	0	600
COMPLETED	0	0	0	0	575
NOT COMPLETED	0	0	0	0	25

Baseline Characteristics

Arm/Group Title	Brexpiprazole (1mg + ADT)	Brexpiprazole (3mg + ADT)	Placebo + ADT	Total
Arm/Group Description	Participants were administered brexpiprazole of 1mg as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole of 3mg as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo as an adjunctive therapy to an open label ADT.	Total of all reporting groups
Overall Participants	226	230	221	677
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.7 (11.6)	44.5 (11.2)	46.6 (11.0)	45.6 (11.3)
Sex: Female, Male (Count of Participants)
Female	158 69.9%	156 67.8%	146 66.1%	460 67.9%
Male	68 30.1%	74 32.2%	75 33.9%	217 32.1%

Outcome Measures

1. Primary Outcome

Title	Mean Change From the End of Phase A (Week 8 Visit) to Phase B (Week 14 Visit) in the Montgomery-Asberg Depression Rating Scale for the Efficacy Sample Set
Description	The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Least Squares Mean (Standard Error) [Units on a scale]	-7.65 (0.5)	-7.98 (0.51)	-6.45 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	The primary analysis was performed on the Efficacy Sample by fitting a Mixed Model Repeated Measures (MMRM) analysis with an unstructured variance covariance structure in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included fixed class effect terms for treatment, trial site, visit week, and an interaction term of treatment by visit week.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0925
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.19
	Confidence Interval	(2-Sided) 95%; -2.58 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	The primary analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included fixed class effect terms for treatment, trial site, visit week, and an interaction term of treatment by visit week.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0327
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.52
	Confidence Interval	(2-Sided) 95%; -2.92 to -0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Mean Change in MADRS Total Score From Baseline End of Week 8 to Week 14 for the Efficacy Sample Per Final Protocol
Description	The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Analysis was based on all participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Least Squares Mean (Standard Error) [Units on a scale]	-7.64 (0.52)	-8.29 (0.53)	6.33 (0.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0737
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.30
	Confidence Interval	(2-Sided) 95%; -2.73 to 0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0079
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.95
	Confidence Interval	(2-Sided) 95%; -3.39 to -0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Study Week Visit in Phase B Other Than Week 14 Visit for the Efficacy Sample Set
Description	The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Week 8, 9, 10, 11, 12, and 13

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Week 9	-3.25 (0.3)	-2.53 (0.3)	-2.19 (0.31)
Week 10	-5.34 (0.38)	-4.8 (0.38)	-3.91 (0.39)
Week 11	-6.25 (0.41)	-5.56 (0.41)	-4.85 (0.41)
Week 12	-7.08 (0.43)	-6.8 (0.44)	-5.52 (0.44)
Week 13	-7.55 (0.46)	-7.73 (0.46)	-6.04 (0.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0096
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.06
	Confidence Interval	(2-Sided) 95%; -1.86 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4137
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -1.14 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0065
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.44
	Confidence Interval	(2-Sided) 95%; -2.47 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0914
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.89
	Confidence Interval	(2-Sided) 95%; -1.93 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0139
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -2.5 to -0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2097
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) 95%; -1.82 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0099
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.56
	Confidence Interval	(2-Sided) 95%; -2.75 to -0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.29
	Confidence Interval	(2-Sided) 95%; -2.48 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0177
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.53
	Confidence Interval	(2-Sided) 95%; -2.8 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.71
	Confidence Interval	(2-Sided) 95%; -2.98 to -0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) in MADRS Total Score for Every Study Week Visit in Phase B Other Than Week 14 Visit for the Efficacy Sample Per Final Protocol
Description	The MADRS was utilized as the primary efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Week 8, 9, 10, 11, 12, and 13

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 9	-3.09 (0.31)	-2.6 (0.31)	-2.18 (0.32)
Week 10	-5.12 (0.39)	-4.92 (0.39)	-3.95 (0.4)
Week 11	-6.22 (0.42)	-5.76 (0.43)	-4.86 (0.43)
Week 12	-7.09 (0.45)	-7.11 (0.45)	-5.48 (0.46)
Week 13	-7.56 (0.47)	-8.05 (0.48)	-5.93 (0.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0286
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.92
	Confidence Interval	(2-Sided) 95%; -1.74 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3173
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -1.24 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0313
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -2.23 to -0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0732
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.97
	Confidence Interval	(2-Sided) 95%; -2.04 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0206
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.36
	Confidence Interval	(2-Sided) 95%; -2.51 to -0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1233
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.91
	Confidence Interval	(2-Sided) 95%; -2.06 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0097
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.61
	Confidence Interval	(2-Sided) 95%; -2.84 to -0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0092
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 95%; -2.86 to -0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0139
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 95%; -2.94 to -0.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.12
	Confidence Interval	(2-Sided) 95%; -3.42 to -0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in Sheehan Disability Scale (SDS) Mean Scores for the Efficacy Sample Set
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. 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	Week 11 and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Week 11	-1.13 (0.13)	-0.67 (0.13)	-0.58 (0.11)
Week 14	-1.33 (0.14)	-1.21 (0.13)	-0.84 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -0.87 to -0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5792
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0091
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.87 to -0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0474
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.73 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in SDS Mean Scores for the Efficacy Sample Per Final Protocol
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. 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	Week 11 and Week 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 11	-1.11 (0.13)	-0.74 (0.13)	-0.53 (0.14)
Week 14	-1.27 (0.15)	-1.26 (0.15)	-0.78 (0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -0.94 to -0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2627
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0158
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.89 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0191
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.88 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set
Description	The SDS is a self-rated instrument used to measure the effect of the patient's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable.
Time Frame	Week 11 and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Work/school: Week 11	-1.00 (0.16)	-0.18 (0.18)	-0.55 (0.15)
Work/school: Week 14	-1.16 (0.17)	-0.91 (0.18)	-0.73 (0.17)
Social life: Week 11	-1.13 (0.14)	-0.76 (0.14)	-0.72 (0.14)
Social life: Week 14	-1.39 (0.15)	-1.31 (0.15)	-0.91 (0.15)
Family life: Week 11	-1.14 (0.14)	-0.74 (0.14)	-0.51 (0.12)
Family life: Week 14	-1.35 (0.15)	-1.28 (0.16)	-0.80 (0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	For Item: Work/School: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0377
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 95%; -0.88 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	For Item: Work/School: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0741
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.91 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	-0.43

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	For Item: Work/School: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0966
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	For Item: Work/School: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4774
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.66 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Social life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0263
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -0.76 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Social life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0214
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.89 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Social life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8281
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Social life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0540
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -0.80 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Family life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95%; -0.99 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Family life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0093
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -0.97 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Family life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2182
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.59 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Family life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0256
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.90 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set Per Final Protocol
Description	The SDS is a self-rated instrument used to measure the effect of the patient's symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable.
Time Frame	Week 11 and Week 14

Outcome Measure Data

Analysis Population Description

All participants in the efficacy sample who met the revised randomization criteria for incomplete response as defined in protocol amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Work/school: Week 11	-1.01 (0.18)	-0.20 (0.20)	-0.48 (0.19)
Work/school: Week 14	-1.11 (0.20)	-0.93 (0.21)	-0.65 (0.20)
Social life: Week 11	-1.11 (0.15)	-0.82 (0.15)	-0.68 (0.15)
Social life: Week 14	-1.34 (0.16)	-1.37 (0.16)	-0.88 (0.17)
Family life: Week 11	-1.17 (0.14)	-0.89 (0.15)	-0.54 (0.15)
Family life: Week 14	-1.32 (0.16)	-1.39 (0.16)	-0.81 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT
	Comments	Work/school: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0341
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -1.01 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	School/work: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0816
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -0.99 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Work/school: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2561
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Work/school: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2952
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.82 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Social life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0331
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.82 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Social life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0352
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.90 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Social life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4860
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.54 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Social life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0282
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.93 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Family life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -1.01 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Family life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0186
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.51
	Confidence Interval	(2-Sided) 95%; -0.94 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Family life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0824
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.73 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Family life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0077
	Comments	MMRM method was used with trial site; treatment group-visit; Baseline-visit interaction as an unstructured covariate.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.59
	Confidence Interval	(2-Sided) 95%; -1.02 to -0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical Global Impression Severity of Illness (CGI-S) for the Efficacy Sample Set
Description	The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician 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	Weeks 8, 9, 10, 11, 12,13 and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Week 9	-0.25 (0.03)	-0.22 (0.03)	-0.16 (0.03)
Week 10	-0.52 (0.05)	-0.46 (0.05)	-0.31 (0.05)
Week 11	-0.64 (0.05)	-0.51 (0.05)	-0.44 (0.05)
Week 12	-0.73 (0.05)	-0.72 (0.05)	-0.59 (0.05)
Week 13	-0.78 (0.06)	-0.77 (0.06)	-0.66 (0.06)
Week 14	-0.86 (0.06)	-0.9 (0.06)	-0.75 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0436
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.18 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	-0.06
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.34 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0266
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.27 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.33 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3053
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0541
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.29 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0912
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1553
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1855
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2015
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0852
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to Phase B by Study Week in Clinical CGI-S for the Efficacy Sample Per Final Protocol
Description	The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician 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	Weeks 8, 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 9	-0.24 (0.03)	-0.23 (0.03)	-0.16 (0.03)
Week 10	-0.5 (0.05)	-0.47 (0.05)	-0.33 (0.05)
Week 11	-0.64 (0.05)	-0.53 (0.05)	-0.45 (0.05)
Week 12	-0.73 (0.06)	-0.74 (0.06)	-0.58 (0.06)
Week 13	-0.77 (0.06)	-0.8 (0.06)	-0.64 (0.06)
Week 14	-0.87 (0.06)	-0.92 (0.06)	-0.72 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0817
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1406
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.29 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0287
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.27 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0071
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.32 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2503
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.22 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0539
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.3 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0398
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.31 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1168
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0621
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0213
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.38 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) for Every Study Week Visit in Phase B in Inventory of Depressive Symptomatology (Self-Report) IDS-SR Total Score for the Efficacy Sample Set
Description	IDS-SR was a 30-item self-report measured to assess core diagnostic depressive symptoms and atypical and melancholic symptom features of major depressive disorders. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the "best" rating and 3 being the "worst" rating. Besides item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items were not included in the calculation of the total score. The IDS-SR Total Score was the sum of ratings of 28 item scores. The possible IDSSR Total Score ranged from 0 to 84. The IDS-SR Total Score was un-evaluable if less than 23 of the 28 items were recorded. If the number of items recorded was at least 23 and at most 27, the IDS-SR Total Score was the mean of the recorded items multiplied by 28, and was then rounded off to the first decimal place.
Time Frame	Weeks 8, 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Week 9	-3.58 (0.41)	-2.68 (0.42)	-2.31 (0.42)
Week 10	-4.97 (0.49)	-4.00 (0.5)	-3.11 (0.5)
Week 11	-5.83 (0.56)	-4.15 (0.56)	-3.74 (0.57)
Week 12	-6.33 (0.59)	-5.77 (0.59)	-4.43 (0.6)
Week 13	-6.96 (0.63)	-6.62 (0.63)	-5.66 (0.64)
Week 14	-7.02 (0.66)	-6.94 (0.66)	-5.42 (0.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0228
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.28
	Confidence Interval	(2-Sided) 95%; -2.37 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5081
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -1.47 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0064
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.86
	Confidence Interval	(2-Sided) 95%; -3.2 to -0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1898
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.89
	Confidence Interval	(2-Sided) 95%; -2.23 to 0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.09
	Confidence Interval	(2-Sided) 95%; -3.62 to -0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5935
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -1.95 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0211
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -3.52 to -0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1031
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.34
	Confidence Interval	(2-Sided) 95%; -2.96 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1366
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1366
	Confidence Interval	(2-Sided) 95%; -3.02 to 0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2709
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.96
	Confidence Interval	(2-Sided) 95%; -2.68 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0812
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -3.4 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1001
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.52
	Confidence Interval	(2-Sided) 95%; -3.33 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) for Every Study Week Visit in Phase B in IDS-SR Total Score for the Efficacy Sample Per Final Protocol
Description	The IDS-SR was a 30-item self-report measured to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of major depressive disorders. The IDS-SR consists of 30 items, all rated on a 0 to 3 scale with 0 being the "best" rating and 3 being the "worst" rating. Besides item 9, two sub-items 9A and 9B exist, with possible scores of 1, 2 or 3 for item 9A, and 0 or 1 for item 9B. The scores for these two sub-items were not included in the calculation of the total score. The IDSSR Total Score was the sum of ratings of 28 item scores. The possible IDSSR Total Score ranged from 0 to 84. The IDS-SR Total Score was un-evaluable if less than 23 of the 28 items were recorded. If the number of items recorded was at least 23 and at most 27, the IDS-SR Total Score was the mean of the recorded items multiplied by 28, and was then rounded off to the first decimal place.
Time Frame	Weeks 8, 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 9	-3.27 (0.42)	-2.65 (0.42)	-2.15 (0.43)
Week 10	-4.7 (0.51)	-4.13 (0.51)	-2.94 (0.52)
Week 11	-5.77 (0.57)	-4.29 (0.58)	-3.46 (0.59)
Week 12	-6.33 (0.61)	-6.05 (0.61)	-4.18 (0.63)
Week 13	-6.88 (0.64)	-6.97 (0.64)	-5.25 (0.66)
Week 14	-6.97 (0.67)	-7.2 (0.68)	-5.07 (0.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0496
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.12
	Confidence Interval	(2-Sided) 95%; -2.24 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.387
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -1.61 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0125
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.75
	Confidence Interval	(2-Sided) 95%; -3.13 to -0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0898
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.19
	Confidence Interval	(2-Sided) 95%; -2.57 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.31
	Confidence Interval	(2-Sided) 95%; -3.88 to -0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.301
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.83
	Confidence Interval	(2-Sided) 95%; -2.4 to 0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0118
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.15
	Confidence Interval	(2-Sided) 95%; -3.82 to -0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0287
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.87
	Confidence Interval	(2-Sided) 95%; -3.54 to -0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0686
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 95%; -3.39 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.72
	Confidence Interval	(2-Sided) 95%; -3.47 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0448
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -3.75 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0251
	Comments
	Method	Mixed Models Analysis
	Comments	MMRM method was used with trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.13
	Confidence Interval	(2-Sided) 95%; -3.98 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) Hamilton Depression Scale 17 Item Version (HAM)-D17 Total Score for the Efficacy Sample Set
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, with higher scores indicating more severe depression.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	222	220	213
Least Squares Mean (Standard Error) [Units on a scale]	-5.47 (0.36)	-6.14 (0.36)	-4.8 (0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The last observation carried forward (LOCF) method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1732
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.67
	Confidence Interval	(2-Sided) 95%; -1.63 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The last observation carried forward (LOCF) method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.34
	Confidence Interval	(2-Sided) 95%; -2.31 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in HAM-D17 Total Score for the Efficacy Sample Set Per Final Protocol
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, with higher score indicating more severe depression.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	208	207	198
Least Squares Mean (Standard Error) [Units on a scale]	-5.36 (0.37)	-6.26 (0.38)	-4.57 (0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1226
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.78
	Confidence Interval	(2-Sided) 95%; -1.78 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.69
	Confidence Interval	(2-Sided) 95%; -2.69 to -0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in Hamilton Anxiety Rating Scale (HAM-A) Total Score for the Efficacy Sample Set
Description	The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the "best" rating and 4 is the "worst" rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56, with higher scores indicating worse anxiety symptoms.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	220	216	210
Least Squares Mean (Standard Error) [Units on a scale]	-3.43 (0.31)	-3.89 (0.31)	-3.33 (0.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8164
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.93 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1939
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -1.39 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Mean Change From End of Phase A (Week 8 Visit) to End of Phase B (Week 14 Visit) in HAM-A Total for the Efficacy Sample Per Final Protocol
Description	The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the "best" rating and 4 is the "worst" rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56, with higher score indicating worse anxiety symptoms.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	206	204	195
Least Squares Mean (Standard Error) [Units on a scale]	-3.35 (0.32)	-3.96 (0.33)	-3.07 (0.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5192
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -1.14 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0443
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.88
	Confidence Interval	(2-Sided) 95%; -1.75 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Mean CGI-I Score at Each Trial Week Visit in Phase B for the Efficacy Sample Set
Description	The efficacy of study 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. 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 8 to Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Week 9	3.36 (0.68)	3.4 (0.75)	3.51 (0.67)
Week 10	3.08 (0.85)	3.09 (0.85)	3.34 (0.85)
Week 11	2.91 (0.82)	2.99 (0.89)	3.17 (0.88)
Week 12	2.78 (0.87)	2.81 (0.95)	3.02 (0.95)
Week 13	2.72 (0.87)	2.73 (1.01)	2.97 (1.00)
Week 14	2.69 (0.89)	2.66 (1.1)	2.85 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0248
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.26 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1334
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.38 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0254
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.34 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0035
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0152
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.39 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0755
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0527
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.39 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Mean CGI-I Score at Each Trial Week Visit in Phase B for the Efficacy Sample Per Final Protocol
Description	The efficacy of study 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. 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	Weeks 8, 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 9	3.39 (0.65)	3.42 (0.74)	3.54 (0.65)
Week 10	3.1 (0.82)	3.08 (0.84)	3.35 (0.84)
Week 11	2.93 (0.8)	2.99 (0.89)	3.19 (0.86)
Week 12	2.8 (0.86)	2.81 (0.94)	3.06 (0.94)
Week 13	2.75 (0.86)	2.72 (1)	3.01 (0.96)
Week 14	2.71 (0.88)	2.65 (1.09)	2.9 (0.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0275
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.26 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1583
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.4 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.43 to -0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0235
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.36 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0111
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0030
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0046
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.47 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0237
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.39 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0171
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	P-value and treatment difference (CI) are derived from CMH row mean score differ test controlling for study center.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.45 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Percentage of Participants With a MADRS Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Set
Description	MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Weeks 8, 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Week 9	4.5 2%	0.45 0.2%	2.8 1.3%
Week 10	10.2 4.5%	6.19 2.7%	5.05 2.3%
Week 11	13.3 5.9%	10.6 4.6%	8.72 3.9%
Week 12	16.9 7.5%	15.5 6.7%	10.1 4.6%
Week 13	18.2 8.1%	18.6 8.1%	15.6 7.1%
Week 14	23.1 10.2%	22.1 9.6%	15.1 6.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5279
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.51 to 3.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0141
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0484
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.92
	Confidence Interval	(2-Sided) 95%; 0.99 to 3.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5813
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.60 to 2.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1236
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 0.90 to 2.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4998
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; 0.70 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0365
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.64
	Confidence Interval	(2-Sided) 95%; 1.03 to 2.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0822
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.95 to 2.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4049
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2951
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0248
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; 1.06 to 2.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0326
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 1.03 to 2.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Percentage of Participants With a MADRS Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Per Final Protocol
Description	MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Weeks 8, 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 9	3.37 1.5%	0.48 0.2%	3.02 1.4%
Week 10	7.58 3.4%	6.1 2.7%	4.93 2.2%
Week 11	13.3 5.9%	11.3 4.9%	8.37 3.8%
Week 12	16.6 7.3%	16.4 7.1%	10.3 4.7%
Week 13	18 8%	19.2 8.3%	14.3 6.5%
Week 14	23.2 10.3%	23 10%	14.3 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7993
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.30 to 2.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0118
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2825
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.71 to 3.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6375
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.58 to 2.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0923
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.62
	Confidence Interval	(2-Sided) 95%; 0.92 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3812
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.73 to 2.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0464
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.63
	Confidence Interval	(2-Sided) 95%; 1.00 to 2.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0490
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.62
	Confidence Interval	(2-Sided) 95%; 1.00 to 2.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2124
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 0.85 to 2.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1078
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 0.93 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0094
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.69
	Confidence Interval	(2-Sided) 95%; 1.14 to 2.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0162
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.65
	Confidence Interval	(2-Sided) 95%; 1.09 to 2.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Percentage of Participants With a MADRS Remission During Phase B Relative to the End of Phase A (Week 8) for the Efficacy Sample Set
Description	MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Weeks 8, 9, 10, 11, 12, 13 and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	222	221	214
Week 9	3.15 1.4%	0.45 0.2%	2.8 1.3%
Week 10	4 1.8%	2.65 1.2%	4.13 1.9%
Week 11	8.44 3.7%	6.19 2.7%	5.5 2.5%
Week 12	11.1 4.9%	8.85 3.8%	5.96 2.7%
Week 13	10.7 4.7%	12.8 5.6%	9.17 4.1%
Week 14	15.1 6.7%	13.7 6%	11.9 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9498
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of remission rate
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.37 to 2.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0141
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8609
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.40 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2846
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.22 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2480
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.75 to 2.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7513
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.54 to 2.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0554
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.82
	Confidence Interval	(2-Sided) 95%; 0.99 to 3.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2409
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.48
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5538
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.69 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1743
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 95%; 0.85 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2843
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95%; 0.81 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4640
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Percentage of Participants With a MADRS Remission During Phase B Relative to the End of Phase A (Week 8) for the Efficacy Sample Per Final Protocol
Description	MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). The MADRS was utilized as an efficacy assessment of a participant's 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 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. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.
Time Frame	Weeks 8, 9, 10, 11, 12, 13 and 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 9	1.92 0.8%	0.48 0.2%	3.02 1.4%
Week 10	2.37 1%	2.82 1.2%	3.94 1.8%
Week 11	8.06 3.6%	6.57 2.9%	5.42 2.5%
Week 12	10.4 4.6%	9.39 4.1%	6.4 2.9%
Week 13	9.95 4.4%	13.1 5.7%	8.37 3.8%
Week 14	14.7 6.5%	14.1 6.1%	10.8 4.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3867
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.18 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0118
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3200
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.21 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3266
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.23 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11 All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3027
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 95%; 0.70 to 3.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11 All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6960
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 0.54 to 2.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12 All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1368
	Comments	CMH general association test controlling for trial site
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.62
	Confidence Interval	(2-Sided) 95%; 0.86 to 3.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2387
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.48
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4498
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.69 to 2.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1009
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95%; 0.91 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1499
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95%; 0.87 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3012
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 0.78 to 2.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Percentage of Participants With a CGI-I Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Set
Description	A CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).
Time Frame	Weeks 8, 9, 10, 11, 12, 13 and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	225	226	218
Week 9	9.46 4.2%	10.4 4.5%	6.54 3%
Week 10	23.6 10.4%	23 10%	13.3 6%
Week 11	28.4 12.6%	30.1 13.1%	21.6 9.8%
Week 12	35.1 15.5%	38.1 16.6%	29.4 13.3%
Week 13	40 17.7%	43.4 18.9%	28.9 13.1%
Week 14	41.8 18.5%	47.8 20.8%	36.7 16.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2873
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 0.75 to 2.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2677
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 0.79 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.80
	Confidence Interval	(2-Sided) 95%; 1.21 to 2.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.70
	Confidence Interval	(2-Sided) 95%; 1.15 to 2.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0665
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0250
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 1.05 to 1.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2224
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0369
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0179
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 1.05 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 1.17 to 1.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3249
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0122
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 1.06 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Percentage of Participants With a CGI-I Response During Phase B Relative to the End of Phase A (Week 8 Visit) for the Efficacy Sample Per Final Protocol
Description	A CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).
Time Frame	Weeks, 8, 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

Arm/Group Title	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole 1mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.	Participants were administered placebo daily as an adjunctive therapy to an open label ADT.
Measure Participants	211	213	203
Week 9	7.69 3.4%	9.52 4.1%	5.53 2.5%
Week 10	21.8 9.6%	23 10%	12.3 5.6%
Week 11	27.5 12.2%	30 13%	19.7 8.9%
Week 12	34.1 15.1%	38 16.5%	27.6 12.5%
Week 13	38.9 17.2%	44.1 19.2%	27.1 12.3%
Week 14	41.2 18.2%	48.4 21%	34 15.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5836
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.60 to 2.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 9. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3792
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 0.73 to 2.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0101
	Comments
	Method	Ratio of response rate
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.77
	Confidence Interval	(2-Sided) 95%; 1.14 to 2.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 10. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0065
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.75
	Confidence Interval	(2-Sided) 95%; 1.17 to 2.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0526
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 1.00 to 1.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 11. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0156
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 1.08 to 2.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1689
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 12. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0231
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95%; 1.04 to 1.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0175
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.40
	Confidence Interval	(2-Sided) 95%; 1.06 to 1.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 13. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.59
	Confidence Interval	(2-Sided) 95%; 1.22 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (1mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 1 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1396
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (3mg) + ADT, Placebo + ADT
	Comments	Statistical analysis 2 at Week 14. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CMH general association test controlling for trial site
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; 1.15 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	AEs were captured from randomization to double-blind treatment at Week 8 to Follow-up 30 (+ 2) days after last dose of study medication.
Adverse Event Reporting Description	Safety sample comprised of randomized participants in Phase B who received at least one dose of double-blind trial medication. Participants were excluded only if there was evidence that the participant did not take trial medication. If a participant was dispensed trial medication and is lost to follow-up that participant was considered exposed.
Arm/Group Title	Brexpiprazole (1mg + ADT)		Brexpiprazole (3mg + ADT)		Placebo + ADT
Arm/Group Description	Participants were administered brexpiprazole of 1mg as an adjunctive therapy to an assigned open-label ADT.		Participants were administered brexpiprazole of 3mg as an adjunctive therapy to an assigned open-label ADT.		Participants were administered placebo as an adjunctive therapy to an open label ADT.
All Cause Mortality
	Brexpiprazole (1mg + ADT)		Brexpiprazole (3mg + ADT)		Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Brexpiprazole (1mg + ADT)		Brexpiprazole (3mg + ADT)		Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/226 (0.4%)		1/229 (0.4%)		0/220 (0%)
Infections and infestations
Pneumonia	1/226 (0.4%)		0/229 (0%)		0/220 (0%)
Nervous system disorders
Epilepsy	0/226 (0%)		1/229 (0.4%)		0/220 (0%)
Other (Not Including Serious) Adverse Events
	Brexpiprazole (1mg + ADT)		Brexpiprazole (3mg + ADT)		Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/226 (27.9%)		72/229 (31.4%)		29/220 (13.2%)
Infections and infestations
Nasopharyngitis	15/226 (6.6%)		7/229 (3.1%)		4/220 (1.8%)
Investigations
Weight increased	15/226 (6.6%)		13/229 (5.7%)		2/220 (0.9%)
Nervous system disorders
Akathisia	10/226 (4.4%)		31/229 (13.5%)		5/220 (2.3%)
Headache	21/226 (9.3%)		14/229 (6.1%)		17/220 (7.7%)
Somnolence	9/226 (4%)		13/229 (5.7%)		1/220 (0.5%)
Tremor	9/226 (4%)		12/229 (5.2%)		7/220 (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.