A Study of Flexible-dose Brexpiprazole as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Delphinus Trial

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01727726
• Collaborator: (none)
• Enrollment: 2,182
• Locations: 76
• Arms: 3
• Duration (Months): 47.3
• Patients Per Site: 28.7
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

To compare the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy to an assigned open label antidepressant therapy (ADT) in the proposed subject population with MDD.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder; Depression; Depressive Disorder, Major; Mood Disorders; Mental Disorders	Drug: Brexpiprazole; Drug: Seroquel XR; Drug: Placebo	Phase 3

Detailed Description

This is a trial designed to assess the safety and efficacy of brexpiprazole (flexible dose) as adjunctive therapy to an assigned known anti-depressant in depressed subjects. The trial consists of a continuous 18-week double-blind treatment period with a 30-day follow-up. Subjects who complete all trial visits through the Week 18 visit may be offered entry into an optional open-label rollover trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo and Active Comparator Controlled Trial of Flexible-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Delphinus Trial
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Oct 17, 2016
• Actual Study Completion Date: Nov 10, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo + ADT Matching Placebo and assigned ADT	Drug: Placebo; tablet/capsule
Experimental: Brexpiprazole + ADT Brexpiprazole, flexible dose and assigned ADT	Drug: Brexpiprazole; tablet/capsule; Other Names: OPC-34712
Active Comparator: Seroquel XR + ADT Seroquel XR, flexible dose and assigned ADT	Drug: Seroquel XR; tablet/capsule

Outcome Measures

Primary Outcome Measures

1. Montgomery Asberg Depression Rating Scale (MADRS) [Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).]

   To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.

Secondary Outcome Measures

1. Sheehan Disability Scale (SDS) [Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).]

   To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale is a measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains ( work/social life/family life/home responsibilities). 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. Scores of 5 and above are associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.

2. Change From End of Phase A in MADRS Total Score for Trial Week 2 and Week 4. [Change from baseline to week 2 and week 4 in Phase B (week 10/12 and week 12/14)]

   Change from end of Phase A in MADRS Total Score. The MADRS was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.

3. Clinical Global Impression Score [From randomization to Phase B week 6 (14/16 weeks after randomization).]

   Mean change from end of Phase A in Clinical Global Impression - Severity of Illness scale (CGI-S) score and Improvement scale (CGI-I) during double-blind randomized Phase B treatment. CGI-S score assessed how mentally ill the patient was at that time. CGI-S score is calculated from 0 to 7 (0 indicates not assessed 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and7 indicated among the most extremely ill patient). CGI-I score is compared to his/her condition at baseline, how much has the patient changed. CGI-I score is calculated from 0 to 7 (0 indicates not assessed and 7 indicates very much worse).

4. MADRS Response at Week 6 [Phase B week 6 (14/16 weeks after randomization).]

   MADRS Response Rate, where response was defined as 50% reduction in MADRS Total Score, during double-blind randomized Phase B treatment.

5. Number of Participants With MADRS [Phase B week 6 (14/16 weeks after randomization).]

   MADRS Remission Rate, where remission was defined as MADRS Total Score ≤ 10 and 50% reduction in MADRS Total Score, for every trial week visit during double-blind randomized Phase B treatment.

6. CGI-I Response Rate [Phase B week 6 (14/16 weeks after randomization).]

   CGI-I Response rate, where response was defined as a CGI-I score of 1 or 2 (very much improved or much improved), during double-blind randomized Phase B treatment.

7. Number of Participants With Adverse Events [From screening (Day -28 to Day-1) upto post treatment follow-up.]

   To evaluate the safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with MDD as AE variables.

8. Sheehan Disability Scale (SDS) Individual Item Scores. [Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).]

   To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale (a self rated questionnaire) was used for measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains (work/school work, social life/leisure activities and family life/home responsibilities). All domains were rated on a score scale ranged from 0 (no impairment) to 10 (most severe). Score of 5 and above indicated significant functional impairment. A total score was addition of the 3 individual scores and the total score ranged from 0 (no impairment) to 30 (most severe).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male and female outpatients 18 to 65 years of age, inclusive, at the time of informed consent.

• Subjects with both a diagnosis of MDD, and in a current major depressive episode, as defined by DSM-IV-TR criteria

• Subjects willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts prior to and during the trial period.

Exclusion Criteria:

• Females who are breast-feeding and/or who have a positive pregnancy test result during screening prior to receiving trial medication

• Subject has a current Axis I (DSM-IV-TR) diagnosis of: dementia, Schizophrenia, Bipolar, Eating disorder , Obsessive-compulsive disorder, Panic disorder, Posttraumatic stress disorder

• Subjects experiencing hallucinations, delusions or any psychotic symptomatology in the current major depressive episode.

• Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 days

• Subjects currently treated with insulin for diabetes.

• Subjects with uncontrolled hypertension

• Subjects with known ischemic heart disease or history of myocardial infarction, congestive heart failure, angioplasty, stenting, or coronary artery bypass Surgery

• Subjects with a positive drug screen for cocaine, marijuana, or other illicit drugs

• Inability to swallow tablets or tolerate oral medication

• Abnormal laboratory test results, vital signs and ECG results

• Subjects who previously participated in any prior brexpiprazole clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Phoenix	Arizona	United States
3		Little Rock	Arkansas	United States
4		Bellflower	California	United States
5		Beverly Hills	California	United States
6		Costa Mesa	California	United States	92626
7		Glendale	California	United States
8		Irvine	California	United States
9		Redlands	California	United States
10		San Diego	California	United States
11		Upland	California	United States
12		Gainesville	Florida	United States
13		Jacksonville Beach	Florida	United States
14		Jacksonville	Florida	United States
15		Leesburg	Florida	United States
16		Melbourne	Florida	United States
17		Miami	Florida	United States	33015
18		Miami	Florida	United States	33145
19		Oakland Park	Florida	United States
20		Orange City	Florida	United States
21		Orlando	Florida	United States
22		Decatur	Georgia	United States
23		Lake Charles	Louisiana	United States
24		Baltimore	Maryland	United States
25		Belmont	Massachusetts	United States
26		Roslindale	Massachusetts	United States
27		Watertown	Massachusetts	United States	02472
28		Creve Coeur	Missouri	United States
29		Lebanon	New Hampshire	United States
30		New York	New York	United States	10003
31		New York	New York	United States	10168
32		Columbus	Ohio	United States
33		Dayton	Ohio	United States
34		Edmond	Oklahoma	United States	73013
35		Portland	Oregon	United States
36		Salem	Oregon	United States
37		Dallas	Texas	United States
38		Murray	Utah	United States
39		Herndon	Virginia	United States
40		Richmond	Virginia	United States
41		Bellevue	Washington	United States
42		Kirkland	Washington	United States
43		Seattle	Washington	United States
44		Brown Deer	Wisconsin	United States
45		Penticton	British Columbia	Canada
46		Dijon		France
47		Douai		France
48		Elancourt		France
49		Jarnac		France
50		Montepellier		France
51		Orvault		France
52		Achim		Germany
53		Mittweida		Germany
54		Stralsund		Germany
55		Wuerzburg		Germany
56		Belchatow		Poland
57		Bydgoszcz		Poland
58		Gdynia		Poland
59		Kielce		Poland
60		Lublin		Poland
61		Tuszyn		Poland
62		Wroclaw		Poland
63		Arkhangelsk		Russian Federation	163530
64		Moscow		Russian Federation	107076
65		Moscow		Russian Federation	127083
66		Saint-Petersburg		Russian Federation	190020
67		Saint-Petersburg		Russian Federation	191040
68		Saint-Petersburg		Russian Federation	192019
69		Saint-Petersburg		Russian Federation	199034
70		Smolensk		Russian Federation
71		Tonnelniy		Russian Federation
72		Belgrade		Serbia	11000
73		Belgrade		Serbia
74		Kragujevac		Serbia
75		Nis		Serbia
76		Novi Knezevac		Serbia

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Study Director: Mary Hobart, Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01727726
• Other Study ID Numbers: 331-12-282
• First Posted: Nov 16, 2012
• Last Update Posted: Jun 8, 2018
• Last Verified: May 1, 2018

• 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; Quetiapine Fumarate; Brexpiprazole

Study Results

Participant Flow

Recruitment Details	Trial was conducted at 75 trial sites in 7 countries (United States, Russia, Poland, France, Serbia,Germany & Canada). Phase A non-responders entered Phase B (503 subjects randomized in 2:2:1 (197+100+206) ratio - brexpiprazole/Seroquel extended release tablets/placebo +ADT).
Pre-assignment Detail	Screening period ranged from a minimum of 7 days to a maximum of 28 days and began when informed consent was signed. The purpose of the screening period was to assess eligibility criteria at 1 or more visits (as necessary to complete screening assessments) and to washout (minimum of 24 hours) prohibited concomitant pharmacotherapy, if applicable.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule at 1 mg, 2 mg, 3 mg.	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule at 50 mg, 150 mg, 300 mg.	Matching Placebo and assigned ADT Placebo: tablet/capsule
Period Title: Overall Study
STARTED	197	100	206
COMPLETED	171	86	186
NOT COMPLETED	26	14	20

Baseline Characteristics

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT	Total
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule	Total of all reporting groups
Overall Participants	197	100	206	503
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	197 100%	100 100%	206 100%	503 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.6 (11.5)	44.6 (11.6)	41.8 (11.7)	43 (11.7)
Sex: Female, Male (Count of Participants)
Female	128 65%	66 66%	149 72.3%	343 68.2%
Male	69 35%	34 34%	57 27.7%	160 31.8%

Outcome Measures

1. Primary Outcome

Title	Montgomery Asberg Depression Rating Scale (MADRS)
Description	To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.
Time Frame	Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).

Outcome Measure Data

Analysis Population Description

All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
Least Squares Mean (Standard Error) [Units on a scale]	-6.04 (0.43)	-4.86 (0.57)	-4.57 (0.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0078
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.48
	Confidence Interval	(2-Sided) 95%; -2.56 to -0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6642
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -1.63 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Sheehan Disability Scale (SDS)
Description	To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale is a measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains ( work/social life/family life/home responsibilities). 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. Scores of 5 and above are associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.
Time Frame	Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).

Outcome Measure Data

Analysis Population Description

All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for SDS Score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
Least Squares Mean (Standard Error) [units on a scale]	-0.97 (0.12)	-0.32 (0.16)	-0.74 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1334
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0237
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.06 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From End of Phase A in MADRS Total Score for Trial Week 2 and Week 4.
Description	Change from end of Phase A in MADRS Total Score. The MADRS was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS depression rating scale was used to assess the subject's level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts), each rated 0 to 6. The overall score ranged from 0 (symptoms absent) to 60 (severe depression). Lower score indicated decreased severity of depression.
Time Frame	Change from baseline to week 2 and week 4 in Phase B (week 10/12 and week 12/14)

Outcome Measure Data

Analysis Population Description

All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
Phase B Week 2	-2.57 (0.32)	-2.26 (0.41)	-1.04 (0.31)
Phase B Week 4	-4.39 (0.39)	-3.30 (0.51)	-3.22 (0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Phase B week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.53
	Confidence Interval	(2-Sided) 95%; -2.29 to -0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Phase B Week 2
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0103
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.22
	Confidence Interval	(2-Sided) 95%; -2.15 to -0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Phase B week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0185
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -2.15 to -0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Phase B Week 4
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8949
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -1.27 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Clinical Global Impression Score
Description	Mean change from end of Phase A in Clinical Global Impression - Severity of Illness scale (CGI-S) score and Improvement scale (CGI-I) during double-blind randomized Phase B treatment. CGI-S score assessed how mentally ill the patient was at that time. CGI-S score is calculated from 0 to 7 (0 indicates not assessed 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and7 indicated among the most extremely ill patient). CGI-I score is compared to his/her condition at baseline, how much has the patient changed. CGI-I score is calculated from 0 to 7 (0 indicates not assessed and 7 indicates very much worse).
Time Frame	From randomization to Phase B week 6 (14/16 weeks after randomization).

Outcome Measure Data

Analysis Population Description

All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for CGI-S score and CGI-I score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
CGI-Severity of Illness Scale	3.98 (0.56)	4.07 (0.58)	4.02 (0.58)
CGI-Improvement Scale Score	2.55 (0.84)	2.71 (0.87)	2.74 (0.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	CGI-Severity of Illness Scale Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0350
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.29 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	CGI-Severity of Illness Scale Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5601
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.22 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	CGI-Improvement Scale Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0146
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.35 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	CGI-Improvement Scale Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7127
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	MADRS Response at Week 6
Description	MADRS Response Rate, where response was defined as 50% reduction in MADRS Total Score, during double-blind randomized Phase B treatment.
Time Frame	Phase B week 6 (14/16 weeks after randomization).

Outcome Measure Data

Analysis Population Description

All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
Count of Participants [Participants]	20 10.2%	8 8%	14 6.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Phase B Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2242
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Ratio of response rate
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 0.78 to 2.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Phase B Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5998
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.53 to 2.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Participants With MADRS
Description	MADRS Remission Rate, where remission was defined as MADRS Total Score ≤ 10 and 50% reduction in MADRS Total Score, for every trial week visit during double-blind randomized Phase B treatment.
Time Frame	Phase B week 6 (14/16 weeks after randomization).

Outcome Measure Data

Analysis Population Description

Number of subjects in the Safety Sample who had an end of Phase A (ie, Week 8 or 10) value and at least one post randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
Count of Participants [Participants]	13 6.6%	2 2%	9 4.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Phase B Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3321
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.66 to 3.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Phase B Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3917
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.11 to 2.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	CGI-I Response Rate
Description	CGI-I Response rate, where response was defined as a CGI-I score of 1 or 2 (very much improved or much improved), during double-blind randomized Phase B treatment.
Time Frame	Phase B week 6 (14/16 weeks after randomization).

Outcome Measure Data

Analysis Population Description

All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
Count of Participants [Participants]	100 50.8%	48 48%	79 38.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Phase B Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0032
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.35
	Confidence Interval	(2-Sided) 95%; 1.10 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Phase B Week 6
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0898
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Ratio of Response Rate
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	To evaluate the safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with MDD as AE variables.
Time Frame	From screening (Day -28 to Day-1) upto post treatment follow-up.

Outcome Measure Data

Analysis Population Description

Randomized subjects in Phase B who received at least one dose of double-blind trial medication as indicated on the dosing record.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	197	100	206
Death	0 0%	0 0%	0 0%
Serious TEAE	0 0%	1 1%	1 0.5%
Discontinuation due to TEAE	2 1%	4 4%	1 0.5%
Any TEAE	100 50.8%	58 58%	107 51.9%

9. Secondary Outcome

Title	Sheehan Disability Scale (SDS) Individual Item Scores.
Description	To evaluate mean change in SDS score from randomization (End of Phase A) to end of Phase B. The Sheehan Disability Scale (a self rated questionnaire) was used for measurement of functional disability and impairment due to psychiatric symptoms. The SDS is a visual analogue scale that uses spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the three domains (work/school work, social life/leisure activities and family life/home responsibilities). All domains were rated on a score scale ranged from 0 (no impairment) to 10 (most severe). Score of 5 and above indicated significant functional impairment. A total score was addition of the 3 individual scores and the total score ranged from 0 (no impairment) to 30 (most severe).
Time Frame	Randomization Visit (week 8 or week 10) to End of Double-Blind Treatment (week 14 or week 16).

Outcome Measure Data

Analysis Population Description

All subjects in the Safety Sample who have an end of Phase A (ie, Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.

Arm/Group Title	Brexpiprazole + ADT	Seroquel XR + ADT	Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule	Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule	Matching Placebo and assigned ADT Placebo: tablet/capsule
Measure Participants	191	99	205
Work/School Score	-0.59 (0.16)	-0.22 (0.21)	-0.74 (0.16)
Social Life Score	-1.03 (0.13)	-0.26 (0.17)	-0.70 (0.12)
Family Life Score	-1.02 (0.13)	-0.34 (0.18)	-0.67 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Work/School Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4480
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Work/School Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0380
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.03 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Social Life Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0436
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Social Life Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0350
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole + ADT, Seroquel XR + ADT
	Comments	Family Life Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0424
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Seroquel XR + ADT, Placebo + ADT
	Comments	Family Life Score
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1230
	Comments
	Method	MMRM
	Comments	Mixed-model repeated measures (MMRM)
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were recorded from screening (Day -28 to Day-1) upto post treatment follow-up.
Adverse Event Reporting Description	All adverse events which started after start of double blind study drug treatment; or if the event was continuous from end of phase A and was worsening, serious, study drug related, or resulted in death, discontinuation, interruption or reduction of study therapy. Subjects in Phase B who received at least one dose of double-blind IMP as indicated on the dosing record. If a subject was dispensed IMP and was lost to follow up, he/she was considered exposed.
Arm/Group Title	Brexpiprazole + ADT		Seroquel XR + ADT		Placebo + ADT
Arm/Group Description	Brexpiprazole, flexible dose and assigned ADT Brexpiprazole: tablet/capsule		Seroquel XR, flexible dose and assigned ADT Seroquel XR: tablet/capsule		Matching Placebo and assigned ADT Placebo: tablet/capsule
All Cause Mortality
	Brexpiprazole + ADT		Seroquel XR + ADT		Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/197 (0%)		0/100 (0%)		0/206 (0%)
Serious Adverse Events
	Brexpiprazole + ADT		Seroquel XR + ADT		Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/197 (0%)		1/100 (1%)		1/206 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignanat melanoma	0/197 (0%)	0	1/100 (1%)	1	0/206 (0%)	0
Psychiatric disorders
panic attack	0/197 (0%)	0	0/100 (0%)	0	1/206 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Brexpiprazole + ADT		Seroquel XR + ADT		Placebo + ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/197 (31.5%)		33/100 (33%)		39/206 (18.9%)
General disorders
Asthenia	4/197 (2%)		2/100 (2%)		0/206 (0%)
fatigue	3/197 (1.5%)		4/100 (4%)		3/206 (1.5%)
Infections and infestations
Nasopharyngitis	9/197 (4.6%)		2/100 (2%)		9/206 (4.4%)
Investigations
Weight Increased	7/197 (3.6%)		4/100 (4%)		4/206 (1.9%)
Metabolism and nutrition disorders
Increased Appetite	5/197 (2.5%)		5/100 (5%)		2/206 (1%)
Nervous system disorders
Akathisia	12/197 (6.1%)		3/100 (3%)		4/206 (1.9%)
Dizziness	7/197 (3.6%)		3/100 (3%)		5/206 (2.4%)
Headache	11/197 (5.6%)		1/100 (1%)		10/206 (4.9%)
Somnolence	11/197 (5.6%)		18/100 (18%)		2/206 (1%)
Psychiatric disorders
Insomnia	5/197 (2.5%)		3/100 (3%)		4/206 (1.9%)
Irritability	4/197 (2%)		1/100 (1%)		3/206 (1.5%)
Restlessness	5/197 (2.5%)		1/100 (1%)		2/206 (1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.