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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01360645
• Collaborator: (none)
• Enrollment: 826
• Locations: 57
• Arms: 2
• Duration (Months): 23
• Patients Per Site: 14.5
• Patients Per Site Per Month: 0.6

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: 826 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 Fixed Dose OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Pyxis Trial
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase B Drug: OPC-34712 + ADT Drug: Placebo + ADT	Drug: OPC-34712 + ADT; Tablet, Oral, 2 mg OPC-34712 and FDA Approved Antidepressant Therapy (ADT); Drug: Placebo + ADT; Placebo + FDA Approved Antidepressant (ADT)
Placebo Comparator: Phase A Intervention: Drug: Placebo + ADT	Drug: Placebo + ADT; Placebo + FDA Approved Antidepressant (ADT)

Outcome Measures

Primary Outcome Measures

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

   The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.

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

   The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.

Secondary Outcome Measures

1. Mean Change From Baseline (End of Phase A [Week 8]) to Week 14 in Sheehan Disability Scale (SDS) Score for the Efficacy Sample. [Baseline 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.

2. Mean Change From Baseline (End of Phase A [Week 8]) to Week 14 in SDS Score for the Efficacy Sample Per the Final Protocol [Baseline 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.

3. Change From Baseline (End of Phase A [Week 8]) to Week 14 in MADRS Total Score by Trial Week for the Efficacy Sample. [Week 9, 10, 11, 12, and 13]

   The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.

4. Change From Baseline (End of Phase A [Week 8]) to Week 14 in MADRS Total Score by Trial Week for the Efficacy Sample Per the Final Protocol. [Week 9, 10, 11, 12, and 13]

   The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.

5. Mean Clinical Global Impression-Improvement (CGI-I) Scale Score (End of Phase A [Week 8]) to Week 14 by Trial Week for the Efficacy Sample. [Week 9, 10, 11, 12, 13, and 14]

   The items on CGI-I scale are: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. The score of 0 (= not assessed) will be set to missing. The CGI-I is therefore a 7-point scale from 1 through 7. The CGI-I was measured in related to Baseline (Week 8).

6. Mean CGI-I Scale Score (End of Phase A [Week 8]) to Week 14 by Trial Week for the Efficacy Sample Per the Final Protocol. [Week 9, 10, 11, 12, 13, and 14]

   The items on CGI-I scale are: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. The score of 0 (= not assessed) will be set to missing. The CGI-I is therefore a 7-point scale from 1 through 7. The CGI-I was measured in related to Baseline (Week 8).

7. Change From Baseline (End of Phase A [Week 8]) to Week 14 in Clinical Global Impression - Severity of Illness (CGI-S) Scale Score for the Efficacy Sample. [Week 9, 10, 11, 12, 13, and 14]

   Items on CGI-S scale are: 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, 7 = among the most extremely ill patients. The score 0 (= not assessed) will be set to missing. The CGI-S is therefore a 7-point scale from 1 through 7.

8. Change From Baseline (End of Phase A [Week 8]) to Week 14 in CGI-S Scale Score for the Efficacy Sample Per the Final Protocol. [Week 9, 10, 11, 12, 13, and 14]

   Items on CGI-S scale are: 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, 7 = among the most extremely ill patients. The score 0 (= not assessed) will be set to missing. The CGI-S is therefore a 7-point scale from 1 through 7.

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

   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 are not included in the calculation of the total score. Item 11 or item 12 should be completed but not both, and similarly, item 13 or item 14 should be completed but not both. Should items 11 and 12 be rated both, then the maximum of the two scores will be used. The same approach will be used for handling items 13 and 14. The IDS-SR total score is the sum of ratings of 28 item scores. The possible IDS-SR total score ranges from 0 to 84.

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

    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 are not included in the calculation of the total score. Item 11 or item 12 should be completed but not both, and similarly, item 13 or item 14 should be completed but not both. Should items 11 and 12 be rated both, then the maximum of the two scores will be used. The same approach will be used for handling items 13 and 14. The IDS-SR total score is the sum of ratings of 28 item scores. The possible IDS-SR total score ranges from 0 to 84.

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

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

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

    The HAM-D (17-Item) consists of 17 items. Eight items are 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) are rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 is the "best" rating and the highest score (2 or 4) is the "worst" rating. The sum of the scores from the first 17 items; 0-7 =Normal; 8-13 =mild depression; 14-18 =moderate depression; 19-22 =severe depression; ≥23 =very severe depression. The total score ranges from 0 to 52, with higher score indicating worse depressive symptoms.

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

    The HAM-D (17-Item) consists of 17 items. Eight items are 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) are rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 is the "best" rating and the highest score (2 or 4) is the "worst" rating. The sum of the scores from the first 17 items; 0-7 =Normal; 8-13 =mild depression; 14-18 =moderate depression; 19-22 =severe depression; ≥23 =very severe depression. The total score ranges from 0 to 52, with higher score indicating worse depressive symptoms.

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

16. Change From Baseline (End of Phase A [Week 8]) to Week 14 in HAM-A Rating Scale Total Score for the Efficacy Sample Per the 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 scores indicating worse anxiety symptoms.

17. Percentage of Participants With MADRS Response at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample. [Baseline and Week 14]

    The MADRS response was defined as >/=50% reduction in MADRS total score from end of Phase A (Week 8).

18. Percentage of Participants With MADRS Response at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample Per the Final Protocol. [Baseline and Week 14]

    The MADRS response was defined as >/=50% reduction in MADRS total score from end of Phase A (Week 8).

19. Percentage of Participants With MADRS Remission at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample. [Baseline and Week 14]

    MADRS remission was defined as </=10 and >/=50% reduction in MADRS total score from end of Phase A (Week 8).

20. Percentage of Participants With MADRS Remission at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample Per the Final Protocol. [Baseline and Week 14]

    MADRS remission was defined as </=10 and >/=50% reduction in MADRS total score from end of Phase A (Week 8).

21. Percentage of Participants With CGI-I Scale Response Rate at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample. [Baseline and Week 14]

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

22. Percentage of Participants With CGI-I Scale Response Rate at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample Per the Final Protocol. [Baseline and Week 14]

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

Eligibility Criteria

Criteria

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

Inclusion Criteria:

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

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

• Subjects must report a history for the current depressive episode of an inadequate response to 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	Arcadia	California	United States
2	Research Site	Beverly Hills	California	United States
3	Research Site	Fresno	California	United States
4	Research Site	Oceanside	California	United States
5	Research Site	San Diego	California	United States
6	Research Site	San Francisco	California	United States
7	Research Site	Sherman Oaks	California	United States
8	Research Site	Denver	Colorado	United States
9	Research Site	Norwalk	Connecticut	United States
10	Research Site	Coral Springs	Florida	United States
11	Research Site	Fort Myers	Florida	United States
12	Research Site	Hialeah	Florida	United States
13	Research Site	Jacksonville	Florida	United States
14	Research Site	Melbourne	Florida	United States
15	Research Site	Orlando	Florida	United States
16	Research Site	Indianapolis	Indiana	United States
17	Research Site	Prairie Village	Kansas	United States
18	Research Site	Wichita	Kansas	United States
19	Research Site	New Orleans	Louisiana	United States
20	Research Site	Shreveport	Louisiana	United States
21	Research Site	Belmont	Massachusetts	United States
22	Research Site	Boston	Massachusetts	United States
23	Research Site	Lincoln	Nebraska	United States
24	Research Site	New York	New York	United States
25	Research Site	Rochester	New York	United States
26	Research Site	Dayton	Ohio	United States
27	Research Site	Toledo	Ohio	United States
28	Research Site	Salem	Oregon	United States
29	Research Site	Allentown	Pennsylvania	United States
30	Research Site	Bala Cynwyd	Pennsylvania	United States
31	Research Site	Bridgeville	Pennsylvania	United States
32	Research Site	Philadelphia	Pennsylvania	United States
33	Research Site	San Antonio	Texas	United States
34	Research Site	Murray	Utah	United States
35	Research Site	Woodstock	Vermont	United States
36	Research Site	Richmond	Virginia	United States
37	Research Site	Seattle	Washington	United States
38	Research Site	Penticton	British Columbia	Canada
39	Research Site	Toronto	Ontario	Canada
40	Research Site	Gatineau	Quebec	Canada
41	Research Site	Arcachon		France
42	Research Site	Elancourt		France
43	Research Site	Orvault		France
44	Research Site	Palaiseau		France
45	Research Site	Toulouse		France
46	Research Site	Katowice	Upper Silesia	Poland
47	Research Site	Poznan	Woj. Wielkopolskie	Poland
48	Research Site	Belchatow		Poland
49	Research Site	Gdynia		Poland
50	Research Site	Kielce		Poland
51	Research Site	Lublin		Poland
52	Research Site	Tuszyn		Poland
53	Research Site	Warszawa		Poland
54	Research Site	Bratislava		Slovakia
55	Research Site	Kosice-Barca		Slovakia
56	Research Site	Levice		Slovakia
57	Research Site	Michalovce		Slovakia

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: NCT01360645
• Other Study ID Numbers: 331-10-228
• First Posted: May 25, 2011
• Last Update Posted: Nov 26, 2015
• Last Verified: Oct 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	This trial was conducted in 826 subjects at 59 trial sites in the following 5 countries: United States, Canada, Poland, Slovakia, and France.
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 2 mg/Day + 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 received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	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: Placebo+ADT Prospective Phase-A(8 Weeks)
STARTED	824	0	0	0
COMPLETED	710	0	0	0
NOT COMPLETED	114	0	0	0
Period Title: Placebo+ADT Prospective Phase-A(8 Weeks)
STARTED	0	188	191	0
COMPLETED	0	174	178	0
NOT COMPLETED	0	14	13	0
Period Title: Placebo+ADT Prospective Phase-A(8 Weeks)
STARTED	0	0	0	331
COMPLETED	0	0	0	307
NOT COMPLETED	0	0	0	24

Baseline Characteristics

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT	Total
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Total of all reporting groups
Overall Participants	188	191	379
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	44.1 (11.6)	45.2 (11.3)	44.6 (11.5)
Sex: Female, Male (Count of Participants)
Female	130 69.1%	137 71.7%	267 70.4%
Male	58 30.9%	54 28.3%	112 29.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score for the Efficacy Sample.
Description	The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Least Squares Mean (Standard Error) [Units on a scale]	-8.27 (0.61)	-5.15 (0.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind 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	0.0001
	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	-3.12
	Confidence Interval	(2-Sided) 95%; -4.70 to -1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in MADRS Total Score for the Efficacy Sample Per the Final Protocol.
Description	The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.
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 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Least Squares Mean (Standard Error) [Units on a scale]	-8.36 (0.64)	-5.15 (0.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	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	-3.21
	Confidence Interval	(2-Sided) 95%; -4.87 to -1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Change From Baseline (End of Phase A [Week 8]) to Week 14 in Sheehan Disability Scale (SDS) Score for the Efficacy Sample.
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	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	179	181
Least Squares Mean (Standard Error) [Units on a scale]	-1.35 (0.17)	-0.91 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0372
	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%; -0.86 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From Baseline (End of Phase A [Week 8]) to Week 14 in SDS Score for the Efficacy Sample Per the 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	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 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	167	170
Least Squares Mean (Standard Error) [Units on a scale]	-1.35 (0.17)	-0.89 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0349
	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	-0.46
	Confidence Interval	(2-Sided) 95%; -0.88 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in MADRS Total Score by Trial Week for the Efficacy Sample.
Description	The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.
Time Frame	Week 9, 10, 11, 12, and 13

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Week 9	-3.15 (0.40)	-1.86 (0.39)
Week 10	-5.15 (0.47)	-3.43 (0.47)
Week 11	-6.69 (0.52)	-4.06 (0.52)
Week 12	-7.22 (0.55)	-4.63 (0.54)
Week 13	-8.28 (0.58)	-5.10 (0.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0080
	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	-1.29
	Confidence Interval	(2-Sided) 95%; -2.25 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	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	-1.72
	Confidence Interval	(2-Sided) 95%; -2.91 to -0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	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	-2.63
	Confidence Interval	(2-Sided) 95%; -3.96 to -1.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	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	-2.59
	Confidence Interval	(2-Sided) 95%; -4.01 to -1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	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	-3.19
	Confidence Interval	(2-Sided) 95%; -4.68 to -1.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in MADRS Total Score by Trial Week for the Efficacy Sample Per the Final Protocol.
Description	The MADRS consists of 10 items, all rated on a 0 to 6 scale with 0 being the "best" rating and 6 being the "worst" rating. The MADRS total score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60. The MADRS total score will be un-evaluable if less than 8 of the 10 items are recorded. If 8 or 9 of the 10 items are recorded, the MADRS total score will be the mean of the recorded items multiplied by 10 and then rounded to the first decimal place.
Time Frame	Week 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 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Week 9	-3.05 (0.41)	-1.74 (0.41)
Week 10	-5.04 (0.49)	-3.52 (0.48)
Week 11	-6.58 (0.54)	-4.17 (0.53)
Week 12	-7.24 (0.58)	-4.72 (0.57)
Week 13	-8.28 (0.61)	-5.01 (0.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0086
	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	-1.31
	Confidence Interval	(2-Sided) 95%; -2.28 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0149
	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	-1.52
	Confidence Interval	(2-Sided) 95%; -2.74 to -0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	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	-2.42
	Confidence Interval	(2-Sided) 95%; -3.78 to -1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	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	-2.52
	Confidence Interval	(2-Sided) 95%; -4.00 to -1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	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	-3.28
	Confidence Interval	(2-Sided) 95%; -4.84 to -3.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Mean Clinical Global Impression-Improvement (CGI-I) Scale Score (End of Phase A [Week 8]) to Week 14 by Trial Week for the Efficacy Sample.
Description	The items on CGI-I scale are: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. The score of 0 (= not assessed) will be set to missing. The CGI-I is therefore a 7-point scale from 1 through 7. The CGI-I was measured in related to Baseline (Week 8).
Time Frame	Week 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Week 9	3.41 (0.83)	3.62 (0.74)
Week 10	3.17 (0.89)	3.37 (0.82)
Week 11	3.03 (1.02)	3.23 (0.90)
Week 12	2.84 (0.99)	3.19 (1.04)
Week 13	2.74 (1.07)	3.13 (1.06)
Week 14	2.75 (1.13)	3.13 (1.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	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	-0.23
	Confidence Interval	(2-Sided) 95%; -0.38 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0115
	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	-0.22
	Confidence Interval	(2-Sided) 95%; -0.38 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0255
	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	-0.22
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	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	-0.36
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	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	-0.41
	Confidence Interval	(2-Sided) 95%; -0.62 to -0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	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	-0.39
	Confidence Interval	(2-Sided) 95%; -0.60 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Mean CGI-I Scale Score (End of Phase A [Week 8]) to Week 14 by Trial Week for the Efficacy Sample Per the Final Protocol.
Description	The items on CGI-I scale are: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. The score of 0 (= not assessed) will be set to missing. The CGI-I is therefore a 7-point scale from 1 through 7. The CGI-I was measured in related to Baseline (Week 8).
Time Frame	Week 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. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Week 9	3.44 (0.81)	3.67 (0.70)
Week 10	3.21 (0.89)	3.40 (0.82)
Week 11	3.07 (1.01)	3.25 (0.89)
Week 12	2.85 (1.01)	3.23 (1.05)
Week 13	2.78 (1.07)	3.18 (1.06)
Week 14	2.77 (1.14)	3.17 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	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%; -0.40 to -0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0290
	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%; -0.37 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0422
	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	-0.20
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	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	-0.39
	Confidence Interval	(2-Sided) 95%; -0.61 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	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	-0.42
	Confidence Interval	(2-Sided) 95%; -0.64 to -0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	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	-0.42
	Confidence Interval	(2-Sided) 95%; -0.65 to -0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in Clinical Global Impression - Severity of Illness (CGI-S) Scale Score for the Efficacy Sample.
Description	Items on CGI-S scale are: 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, 7 = among the most extremely ill patients. The score 0 (= not assessed) will be set to missing. The CGI-S is therefore a 7-point scale from 1 through 7.
Time Frame	Week 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Week 9	-0.25 (0.05)	-0.12 (0.05)
Week 10	-0.45 (0.05)	-0.31 (0.05)
Week 11	-0.61 (0.06)	-0.40 (0.06)
Week 12	-0.70 (0.07)	-0.45 (0.06)
Week 13	-0.86 (0.07)	-0.50 (0.07)
Week 14	-0.91 (0.07)	-0.58 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0229
	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	-0.13
	Confidence Interval	(2-Sided) 95%; -0.25 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0459
	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	-0.14
	Confidence Interval	(2-Sided) 95%; -0.28 to -0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	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; Baseline-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0038
	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	-0.25
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	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	-0.36
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 14.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	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	-0.34
	Confidence Interval	(2-Sided) 95%; -0.52 to -0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in CGI-S Scale Score for the Efficacy Sample Per the Final Protocol.
Description	Items on CGI-S scale are: 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, 7 = among the most extremely ill patients. The score 0 (= not assessed) will be set to missing. The CGI-S is therefore a 7-point scale from 1 through 7.
Time Frame	Week 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 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Week 9	-0.24 (0.05)	-0.09 (0.05)
Week 10	-0.43 (0.06)	-0.32 (0.06)
Week 11	-0.58 (0.06)	-0.42 (0.06)
Week 12	-0.70 (0.07)	-0.46 (0.07)
Week 13	-0.85 (0.07)	-0.50 (0.07)
Week 14	-0.91 (0.07)	-0.57 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0109
	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	-0.15
	Confidence Interval	(2-Sided) 95%; -0.27 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1286
	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	-0.11
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0521
	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	-0.16
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0084
	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	-0.24
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	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	-0.35
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	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	-0.34
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in the Inventory of Depressive Symptomatology (Self-Report) (IDS-SR) Total Score for the Efficacy Sample.
Description	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 are not included in the calculation of the total score. Item 11 or item 12 should be completed but not both, and similarly, item 13 or item 14 should be completed but not both. Should items 11 and 12 be rated both, then the maximum of the two scores will be used. The same approach will be used for handling items 13 and 14. The IDS-SR total score is the sum of ratings of 28 item scores. The possible IDS-SR total score ranges from 0 to 84.
Time Frame	Week 9, 10, 11, 12, 13, and 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Week 9	-3.02 (0.52)	-1.45 (0.51)
Week 10	-4.17 (0.59)	-2.64 (0.59)
Week 11	-5.41 (0.65)	-4.31 (0.64)
Week 12	-6.16 (0.68)	-4.69 (0.67)
Week 13	-7.00 (0.72)	-5.25 (0.71)
Week 14	-7.49 (0.74)	-5.52 (0.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	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; Baseline-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.57
	Confidence Interval	(2-Sided) 95%; -2.82 to -0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	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; Baseline-visit interaction as an unstructured covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.53
	Confidence Interval	(2-Sided) 95%; -3.01 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1903
	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	-1.10
	Confidence Interval	(2-Sided) 95%; -2.75 to 0.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0951
	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	-1.47
	Confidence Interval	(2-Sided) 95%; -3.21 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0626
	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	-1.75
	Confidence Interval	(2-Sided) 95%; -3.59 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0435
	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	-1.96
	Confidence Interval	(2-Sided) 95%; -3.87 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in the IDS-SR Total Score for the Efficacy Sample Per the Final Protocol.
Description	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 are not included in the calculation of the total score. Item 11 or item 12 should be completed but not both, and similarly, item 13 or item 14 should be completed but not both. Should items 11 and 12 be rated both, then the maximum of the two scores will be used. The same approach will be used for handling items 13 and 14. The IDS-SR total score is the sum of ratings of 28 item scores. The possible IDS-SR total score ranges from 0 to 84.
Time Frame	Week 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 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Week 9	-3.30 (0.53)	-1.59 (0.51)
Week 10	-4.29 (0.61)	-3.13 (0.60)
Week 11	-5.45 (0.67)	-4.73 (0.66)
Week 12	-6.32 (0.71)	-5.06 (0.70)
Week 13	-7.03 (0.74)	-5.60 (0.73)
Week 14	-7.59 (0.77)	-6.05 (0.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 9
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0069
	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	-1.71
	Confidence Interval	(2-Sided) 95%; -2.95 to -0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 10
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1322
	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	-1.16
	Confidence Interval	(2-Sided) 95%; -2.68 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4055
	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	-0.72
	Confidence Interval	(2-Sided) 95%; -2.41 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1715
	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	-1.26
	Confidence Interval	(2-Sided) 95%; -3.08 to 0.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 13
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1424
	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	-1.42
	Confidence Interval	(2-Sided) 95%; -3.33 to 0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1270
	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	-1.54
	Confidence Interval	(2-Sided) 95%; -3.52 to 0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Item: Work/School: Week 11	-0.70 (0.21)	-0.42 (0.22)
Item: Work/School: Week 14	-1.09 (0.22)	-0.90 (0.22)
Item: Social life: Week 11	-1.17 (0.17)	-0.67 (0.17)
Item: Social life: Week 14	-1.54 (0.19)	-1.04 (0.18)
Item: Family life: Week 11	-1.06 (0.18)	-0.43 (0.18)
Item: Family life: Week 14	-1.33 (0.19)	-0.73 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	For Item: Work/School: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3079
	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	-0.28
	Confidence Interval	(2-Sided) 95%; -0.81 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	For Item: Work/School: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4771
	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	-0.19
	Confidence Interval	(2-Sided) 95%; -0.73 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	For Item: Social life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0195
	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	-0.50
	Confidence Interval	(2-Sided) 95%; -0.92 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	For Item: Social life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0323
	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	-0.50
	Confidence Interval	(2-Sided) 95%; -0.96 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	For Item: Family life: Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0058
	Comments
	Method	Cochran-Mantel-Haenszel
	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	-0.63
	Confidence Interval	(2-Sided) 95%; -1.07 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	For Item: Family life: Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0129
	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	-0.60
	Confidence Interval	(2-Sided) 95%; -1.07 to -0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Per the 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 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 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Item: Work/School: Week 11	-0.76 (0.22)	-0.58 (0.22)
Item: Work/School: Week 14	-1.11 (0.23)	-0.96 (0.23)
Item: Social life: Week 11	-1.18 (0.18)	-0.69 (0.18)
Item: Social life: Week 14	-1.57 (0.19)	-1.02 (0.19)
Item: Family life: Week 11	-0.99 (0.19)	-0.43 (0.18)
Item: Family life: Week 14	-0.43 (0.18)	-0.70 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Item: Work/School Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5151
	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	-0.18
	Confidence Interval	(2-Sided) 95%; -0.71 to 0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Item: Work/School Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6080
	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	-0.15
	Confidence Interval	(2-Sided) 95%; -0.70 to 0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Item: Social life-Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0267
	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	-0.49
	Confidence Interval	(2-Sided) 95%; -0.92 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Item: Social life-Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0224
	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	-0.55
	Confidence Interval	(2-Sided) 95%; -1.01 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Item: Family life-Week 11
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0146
	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	-0.56
	Confidence Interval	(2-Sided) 95%; -1.01 to -0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	Statistical analysis for Item: Family life-Week 14
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0113
	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	-0.62
	Confidence Interval	(2-Sided) 95%; -1.09 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in Hamilton Depression (HAM-D) Rating Scale Total Score for the Efficacy Sample.
Description	The HAM-D (17-Item) consists of 17 items. Eight items are 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) are rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 is the "best" rating and the highest score (2 or 4) is the "worst" rating. The sum of the scores from the first 17 items; 0-7 =Normal; 8-13 =mild depression; 14-18 =moderate depression; 19-22 =severe depression; ≥23 =very severe depression. The total score ranges from 0 to 52, with higher score indicating worse depressive symptoms.
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

Efficacy Sample comprised all participants in Safety Sample who had end of Phase A value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B. The Last-observation-carried-forward (LOCF) data set included data recorded at Phase B visit, if no observation was recorded, data was carried forward from previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	183	188
Least Squares Mean (Standard Error) [Units on a scale]	-5.89 (0.48)	-3.55 (0.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	ANCOVA_Last observation carry forward (LOCF) model with treatment and trial site as main effects, and baseline (end of Phase A [Week 8]) value as a covariate was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.34
	Confidence Interval	(2-Sided) 95%; -3.47 to -1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in HAM-D Rating Scale Total Score for the Efficacy Sample Per the Final Protocol.
Description	The HAM-D (17-Item) consists of 17 items. Eight items are 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) are rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 is the "best" rating and the highest score (2 or 4) is the "worst" rating. The sum of the scores from the first 17 items; 0-7 =Normal; 8-13 =mild depression; 14-18 =moderate depression; 19-22 =severe depression; ≥23 =very severe depression. The total score ranges from 0 to 52, with higher score indicating worse depressive 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. The LOCF data set included data recorded at Phase B visit, if no observation was recorded, data was carried forward from previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	172	175
Least Squares Mean (Standard Error) [Units on a scale]	-5.89 (0.51)	-3.59 (0.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.29
	Confidence Interval	(2-Sided) 95%; -3.47 to -1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in Hamilton Anxiety (HAM-A) Rating Scale Total Score for the Efficacy Sample
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 comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	181	188
Least Squares Mean (Standard Error) [Units on a scale]	-3.94 (0.43)	-2.77 (0.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments	ANCOVA_LOCF model with treatment and trial site as main effects, and baseline (end of Phase A [Week 8]) value as a covariate was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0219
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -2.17 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline (End of Phase A [Week 8]) to Week 14 in HAM-A Rating Scale Total Score for the Efficacy Sample Per the 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 scores 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. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	171	175
Least Squares Mean (Standard Error) [Units on a scale]	-3.79 (0.45)	-2.70 (0.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0376
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.09
	Confidence Interval	(2-Sided) 95%; -2.13 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Percentage of Participants With MADRS Response at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample.
Description	The MADRS response was defined as >/=50% reduction in MADRS total score from end of Phase A (Week 8).
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Number [Percentage of participants]	23.5 12.5%	14.7 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0176
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CHM 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%; 1.09 to 2.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Percentage of Participants With MADRS Response at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample Per the Final Protocol.
Description	The MADRS response was defined as >/=50% reduction in MADRS total score from end of Phase A (Week 8).
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. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Number [Percentage of participants]	23.4 12.4%	15.7 8.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0429
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CHM general association test controlling for trial site.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 1.01 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Percentage of Participants With MADRS Remission at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample.
Description	MADRS remission was defined as </=10 and >/=50% reduction in MADRS total score from end of Phase A (Week 8).
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Number [Percentage of participants]	14.4 7.7%	8.38 4.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0586
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CHM general association test controlling for trial site.
Method of Estimation	Estimation Parameter	Ratio of Remission Rate
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 95%; 0.98 to 2.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Percentage of Participants With MADRS Remission at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample Per the Final Protocol.
Description	MADRS remission was defined as </=10 and >/=50% reduction in MADRS total score from end of Phase A (Week 8).
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. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Number [Percentage of participants]	14.9 7.9%	8.99 4.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0671
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CHM general association test controlling for trial site.
Method of Estimation	Estimation Parameter	Ratio of Remission Rate
	Estimated Value	1.67
	Confidence Interval	(2-Sided) 95%; 0.97 to 2.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Percentage of Participants With CGI-I Scale Response Rate at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample.
Description	CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).
Time Frame	Baseline and Week 14

Outcome Measure Data

Analysis Population Description

The Efficacy Sample comprised of all participants in the Safety Sample who had an end of Phase A (i.e, Week 8) value and at least one post-randomization efficacy evaluation for MADRS total score in Phase B. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	187	191
Number [Percentage of participants]	44.4 23.6%	27.7 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CHM general association test controlling for trial site.
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 1.23 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Percentage of Participants With CGI-I Scale Response Rate at Week 14 Relative to Baseline (End of Phase A [Week 8]) for the Efficacy Sample Per the Final Protocol.
Description	CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved).
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. The LOCF data set included data recorded at a Phase B visit, if no observation was recorded, data was carried forward from the previous visit.

Arm/Group Title	Brexpiprazole 2 mg/Day + ADT	Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.	Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
Measure Participants	175	178
Number [Percentage of participants]	43.4 23.1%	26.4 13.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole 2 mg/Day + ADT, Double-blind Placebo + ADT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	CHM 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%; 1.27 to 2.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse Events with an onset date on or after the start of double-blind treatment and occurring up to 30 days after the last day of double-blind treatment were included.
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 2 mg/Day + ADT		Double-blind Placebo + ADT
Arm/Group Description	Participants received Brexpiprazole 2 mg/day as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.		Participants received placebo as an adjunctive therapy over a 2-week period beginning at the Week 8 visit and continued to take the same ADT that was assigned in Phase A at the final dose taken just prior to the Week 8 visit.
All Cause Mortality
	Brexpiprazole 2 mg/Day + ADT		Double-blind Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Brexpiprazole 2 mg/Day + ADT		Double-blind Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/188 (1.1%)		2/191 (1%)
Cardiac disorders
Atrial Fibrillation	0/188 (0%)		1/191 (0.5%)
Gastrointestinal disorders
Abdominal Pain	1/188 (0.5%)		0/191 (0%)
Infections and infestations
Pneumonia	0/188 (0%)		1/191 (0.5%)
Injury, poisoning and procedural complications
Comminuted Fracture	1/188 (0.5%)		0/191 (0%)
Nervous system disorders
Syncope	1/188 (0.5%)		0/191 (0%)
Other (Not Including Serious) Adverse Events
	Brexpiprazole 2 mg/Day + ADT		Double-blind Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/188 (19.7%)		27/191 (14.1%)
Gastrointestinal disorders
Diarrhoea	5/188 (2.7%)		10/191 (5.2%)
Infections and infestations
Upper resporatory tract infection	6/188 (3.2%)		12/191 (6.3%)
Investigations
Weight increased	15/188 (8%)		6/191 (3.1%)
Nervous system disorders
Akathisia	14/188 (7.4%)		2/191 (1%)

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.