Safety and Tolerability of Oral OPC-34712 as Adjunctive Therapy in Adults With Major Depressive Disorder (the Orion Trial)

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01360866
• Collaborator: (none)
• Enrollment: 2,944
• Locations: 144
• Arms: 6
• Actual Duration (Months): 67.5
• Patients Per Site: 20.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To assess the long-term safety and tolerability of oral OPC-34712 (brexpiprazole), given in addition to an FDA approved antidepressant (ADT) for the treatment of adults with Major Depressive Disorder (MDD)

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder; Depression; Depressive Disorder, Major; Mood Disorders; Mental Disorders	Drug: OPC-34712; Drug: Escitalopram; Drug: Fluoxetine; Drug: Paroxetine CR; Drug: Sertraline; Drug: Duloxetine; Drug: Venlafaxine XR	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2944 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Long-term, Phase 3, Multicenter, Open-label Trial to Evaluate the Safety and Tolerability of Oral OPC-34712 as Adjunctive Therapy in Adults With Major Depressive Disorder, the Orion Trial
• Actual Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Apr 18, 2017
• Actual Study Completion Date: May 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OPC-34712 (Brexpiprazole) and Escitalopram OPC-34712: Oral tablet; 0.5 to 3 mg/day Escitalopram: Oral tablet; 10 or 20 mg/day	Drug: OPC-34712; Tablet; Drug: Escitalopram; Tablet; Other Names: Lexapro
Experimental: OPC-34712 and Fluoxetine OPC-34712: Oral tablet; 0.5 to 3 mg/day Fluoxetine: Oral capsules; 20 or 40 mg/day	Drug: OPC-34712; Tablet; Drug: Fluoxetine; Capsule; Other Names: Prozac
Experimental: OPC-34712 and Paroxetine CR OPC-34712: Oral tablet; 0.5 to 3 mg/day Paroxetine CR: Oral controlled-release tablets; 37.5 or 50 mg/day	Drug: OPC-34712; Tablet; Drug: Paroxetine CR; Controlled-release tablets; Other Names: Paxil CR
Experimental: OPC-34712 and Sertraline OPC-34712: Oral tablet; 0.5 to 3 mg/day Sertraline: Oral tablets; 100, 150, or 200 mg/day	Drug: OPC-34712; Tablet; Drug: Sertraline; Tablets; Other Names: Zoloft
Experimental: OPC-34712 and Duloxetine OPC-34712: Oral tablet; 0.5 to 3 mg/day Duloxetine: Oral delayed-release capsules; 40 or 60 mg/day	Drug: OPC-34712; Tablet; Drug: Duloxetine; Delayed-release capsules; Other Names: Cymbalta
Experimental: OPC-34712 and Venlafaxine XR OPC-34712: Oral tablet; 0.5 to 3 mg/day Venlafaxine XR: Oral extended-release capsules; 75, 150, or 225 mg/day	Drug: OPC-34712; Tablet; Drug: Venlafaxine XR; Extended-release capsules; Other Names: Effexor XR

Outcome Measures

Primary Outcome Measures

1. Adverse Events (AEs) - All Participants [From screening to week 52/early termination]

   To assess the frequency and severity of AEs as the variables of safety and tolerability of brexpiprazole.

Secondary Outcome Measures

1. Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score [From screening to week 52/early termination]

   The severity of illness for each participant was rated using the CGI-S . On the basis of the investigator answer to the question: "Considering your total clinical experience with this particular population, how mentally ill was the participant at that time?" Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.

2. Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score [From screening to week 52/early termination]

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

3. Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score [From screening to week 52/early termination]

   The SDS was a self-rated instrument used to measure the effect of the participant's symptoms on regular life responsibilities. The SDS was a visual analogue scale that used spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the 3 domains with scores from 0 = not at all, to 10 = extremely. Scores of 5 and above were associated with significant functional impairment.

4. Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score [From screening to week 52/early termination]

   The IDS-SR was a 30-item self-report measure used to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of MDD. 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. The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR Total Score ranges from 0 (best) to 84 (worst). Under 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. If the number of items recorded is at least 23 and at most 27, the IDS-SR Total Score will be the mean of the recorded items multiplied by 28 and then rounded to the first decimal place.

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 18-65 years of age

Eligible subjects from Trials 331-10-227, 331-10-228 or 331-12-282:

• Subjects who completed participation in the Double-blind Randomization Phase (i.e. Week 14 visit) in Trial 331-10-227, Trial 331-10-228, or Trial 331-12-282 or

• Subjects who met criteria for a response, but did not meet criteria for remission at Week 14 of either trial

Eligible subjects from other Phase 3, Double-blind, Brexpiprazole MDD trials:

• Subjects who completed the last scheduled visit of the prior Double-blind Randomized Phase 3 trial.

Exclusion Criteria:

• Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving OPC-34712.

• Subjects with a major protocol violation during the course of their participation in the Double-blind Randomization Phase

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States
2	Research Site	Phoenix	Arizona	United States
3	Research Site	Little Rock	Arkansas	United States
4	Research Site	Beverly Hills	California	United States
5	Research Site	Costa Mesa	California	United States
6	Research Site	Glendale	California	United States
7	Research Site	Irvine	California	United States
8	Research Site	Oceanside	California	United States
9	Research Site	Redlands	California	United States
10	Research Site	San Diego	California	United States
11	Research Site	San Francisco	California	United States
12	Research Site	Santa Ana	California	United States
13	Research Site	Sherman Oaks	California	United States
14	Research Site	Temecula	California	United States
15	Research Site	Upland	California	United States
16	Research Site	Norwalk	Connecticut	United States
17	Research Site	Coral Gables	Florida	United States
18	Research Site	Coral Springs	Florida	United States
19	Research Site	Fort Myers	Florida	United States
20	Research Site	Gainesville	Florida	United States
21	Research Site	Hialeah	Florida	United States
22	Research Site	Jacksonville Beach	Florida	United States
23	Research Site	Jacksonville	Florida	United States
24	Research Site	Melbourne	Florida	United States
25	Research Site	Miami Springs	Florida	United States
26	Research Site	Miami	Florida	United States
27	Research Site	Oakland Park	Florida	United States
28	Research Site	Orlando	Florida	United States
29	Research Site	The Villages	Florida	United States
30	Research Site	Winter Park	Florida	United States
31	Research Site	Alpharetta	Georgia	United States
32	Research Site	Atlanta	Georgia	United States
33	Research Site	Decatur	Georgia	United States
34	Research Site	Smyrna	Georgia	United States
35	Research Site	Oak Brook	Illinois	United States
36	Research Site	Indianapolis	Indiana	United States
37	Research Site	Lafayette	Indiana	United States
38	Research Site	Prairie Village	Kansas	United States
39	Research Site	Wichita	Kansas	United States
40	Research Site	Lake Charles	Louisiana	United States
41	Research Site	New Orleans	Louisiana	United States
42	Research Site	Shreveport	Louisiana	United States
43	Research Site	Baltimore	Maryland	United States
44	Research Site	Belmont	Massachusetts	United States
45	Research Site	Boston	Massachusetts	United States
46	Research Site	Methuen	Massachusetts	United States
47	Research Site	Watertown	Massachusetts	United States
48	Research Site	Weymouth	Massachusetts	United States
49	Research Site	Rochester Hills	Michigan	United States
50	Research Site	Creve Coeur	Missouri	United States
51	Research Site	Las Vegas	Nevada	United States
52	Research Site	Cherry Hill	New Jersey	United States
53	Research Site	Tom River	New Jersey	United States
54	Research Site	Brooklyn	New York	United States
55	Research Site	Jamaica	New York	United States
56	Research Site	New York	New York	United States
57	Research Site	Rochester	New York	United States
58	Research Site	Staten Island	New York	United States
59	Research Site	Raleigh	North Carolina	United States
60	Research Site	Wilmington	North Carolina	United States
61	Research Site	Beachwood	Ohio	United States
62	Research Site	Cincinnati	Ohio	United States
63	Research Site	Columbus	Ohio	United States
64	Research Site	Dayton	Ohio	United States
65	Research Site	Toledo	Ohio	United States
66	Research Site	Oklahoma City	Oklahoma	United States
67	Research Site	Portland	Oregon	United States
68	Research Site	Salem	Oregon	United States
69	Research Site	Allentown	Pennsylvania	United States
70	Research Site	Bala-Cynwyd	Pennsylvania	United States
71	Research Site	Bridgeville	Pennsylvania	United States
72	Research Site	Norristown	Pennsylvania	United States
73	Research Site	Philadelphia	Pennsylvania	United States
74	Research Site	Lincoln	Rhode Island	United States
75	Research Site	Columbia	South Carolina	United States
76	Research Site	Memphis	Tennessee	United States
77	Research Site	Arlington	Texas	United States
78	Research Site	Austin	Texas	United States
79	Research Site	Dallas	Texas	United States
80	Research Site	Houston	Texas	United States
81	Research Site	San Antonio	Texas	United States
82	Research Site	Wichita Falls	Texas	United States
83	Research Site	Murray	Utah	United States
84	Research Site	Woodstock	Vermont	United States
85	Research Site	Charlottesville	Virginia	United States
86	Research Site	Herndon	Virginia	United States
87	Research Site	Richmond	Virginia	United States
88	Research Site	Bellevue	Washington	United States
89	Research Site	Kirkland	Washington	United States
90	Research Site	Seattle	Washington	United States
91	Research Site	Spokane	Washington	United States
92	Research Site	Brown Deer	Wisconsin	United States
93	Research Site	Middleton	Wisconsin	United States
94	Research Site	Gatineau		Canada
95	Research Site	Penticton		Canada
96	Research Site	Pointe-Claire		Canada
97	Research Site	Sherbrooke		Canada
98	Research Site	Toronto		Canada
99	Research Site	Arcachon		France
100	Research Site	Douai		France
101	Research Site	Elancourt		France
102	Research Site	Jarnac		France
103	Research Site	Orvault		France
104	Research Site	Palaiseau		France
105	Research Site	Toulouse		France
106	Research Site	Achim		Germany
107	Research Site	Bochum		Germany
108	Research Site	Mittweida		Germany
109	Research Site	Stralsund		Germany
110	Research Site	Wurzburg		Germany
111	Research Site	Budapest		Hungary
112	Research Site	Belchatow		Poland
113	Research Site	Bydgoszcz		Poland
114	Research Site	Katowice		Poland
115	Research Site	Kielce		Poland
116	Research Site	Lublin		Poland
117	Research Site	Poznań		Poland
118	Research Site	Pruszcz Gdanski		Poland
119	Research Site	Tuszyn		Poland
120	Research Site	Wroclaw		Poland
121	Research Site	Wrocław		Poland
122	Research Site	Bucharest		Romania
123	Research Site	Iași		Romania
124	Research Site	Târgu-Mureş		Romania
125	Research Site	Arkhangelsk Region		Russian Federation
126	Research Site	Moscow		Russian Federation
127	Research Site	Roshchino		Russian Federation
128	Research Site	Rostov-na-Donu		Russian Federation
129	Research Site	Saint Petersberg		Russian Federation
130	Research Site	Saint Petersburg		Russian Federation
131	Research Site	Smolensk		Russian Federation
132	Research Site	St. Petersburg		Russian Federation
133	Research Site	Tonnel'nyy		Russian Federation
134	Research Site	Belgrade		Serbia
135	Research Site	Kragujevac		Serbia
136	Research Site	Nis		Serbia
137	Research Site	Novi Knezevac		Serbia
138	Research Site	Bratislava		Slovakia
139	Research Site	Košice		Slovakia
140	Research Site	Michalovce		Slovakia
141	Research Site	Chernihiv		Ukraine
142	Research Site	Kharkiv		Ukraine
143	Research Site	Kiev		Ukraine
144	Research Site	Poltava		Ukraine

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 13, 2014
• Statistical Analysis Plan - May 25, 2017

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01360866
• Other Study ID Numbers: 331-10-238
• First Posted: May 26, 2011
• Last Update Posted: Sep 17, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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; Duloxetine Hydrochloride; Citalopram; Fluoxetine; Paroxetine; Venlafaxine Hydrochloride; Sertraline

Study Results

Participant Flow

Recruitment Details	This trial was conducted in 2944 participants at 188 sites in 11 countries: Canada, France, Germany, Hungary, Poland, Romania, Russian Federation, Serbia, Slovakia, Ukraine, and United States (US).
Pre-assignment Detail	The study population consisted of eligible participants who completed one of the double-blind, phase 3 brexpiprazole major depressive disorder (MDD) trials and who, could potentially benefit from adjunctive treatment with oral brexpiprazole for MDD.

Arm/Group Title	Prior Placebo	Prior Brexpiprazole	Prior ADT	Prior Seroquel
Arm/Group Description	Participants who received placebo with antidepressant therapy [ADT] in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received only ADT in previous double blind phase 3 studies and were not randomized, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.
Period Title: Overall Study
STARTED	516	707	1645	76
COMPLETED	295	420	1126	54
NOT COMPLETED	221	287	519	22

Baseline Characteristics

Arm/Group Title	Prior Placebo	Prior Brexpiprazole	Prior ADT	Prior Seroquel	Total
Arm/Group Description	Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Total of all reporting groups
Overall Participants	516	707	1645	76	2944
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.0 (11.0)	45.0 (11.0)	44.0 (12.0)	44.0 (11.0)	45.0 (12.0)
Sex: Female, Male (Count of Participants)
Female	367 71.1%	479 67.8%	1108 67.4%	51 67.1%	2005 68.1%
Male	149 28.9%	228 32.2%	537 32.6%	25 32.9%	939 31.9%
Race/Ethnicity, Customized (Count of Participants)
White	452 87.6%	609 86.1%	1459 88.7%	68 89.5%	2588 87.9%
Black or African American	55 10.7%	76 10.7%	149 9.1%	8 10.5%	288 9.8%
American Indian or Alaska Native	0 0%	6 0.8%	8 0.5%	0 0%	14 0.5%
Asian	5 1%	8 1.1%	8 0.5%	0 0%	21 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	6 0.4%	0 0%	6 0.2%
Other	4 0.8%	8 1.1%	15 0.9%	0 0%	27 0.9%

Outcome Measures

1. Primary Outcome

Title	Adverse Events (AEs) - All Participants
Description	To assess the frequency and severity of AEs as the variables of safety and tolerability of brexpiprazole.
Time Frame	From screening to week 52/early termination

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs.

Arm/Group Title	Prior Placebo	Prior Brexpiprazole	Prior ADT	Prior Seroquel
Arm/Group Description	Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.
Measure Participants	516	706	1640	76
Participants with adverse events	400 77.5%	511 72.3%	1165 70.8%	51 67.1%
Participants with treatment emergent AE (TEAE)	399 77.3%	510 72.1%	1163 70.7%	51 67.1%
Participants with serious TEAE	14 2.7%	23 3.3%	33 2%	1 1.3%
Participants with severe TEAE	48 9.3%	64 9.1%	99 6%	4 5.3%
Partcipants discontinued due to AEs	55 10.7%	58 8.2%	134 8.1%	6 7.9%

2. Secondary Outcome

Title	Mean Change From Baseline in Clinical Global Impression - Severity (CGI-S) of Illness Score
Description	The severity of illness for each participant was rated using the CGI-S . On the basis of the investigator answer to the question: "Considering your total clinical experience with this particular population, how mentally ill was the participant at that time?" Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Time Frame	From screening to week 52/early termination

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.

Arm/Group Title	Prior Placebo	Prior Brexpiprazole	Prior ADT	Prior Seroquel
Arm/Group Description	Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.
Measure Participants	512	698	1630	76
Mean (Standard Deviation) [units on a scale]	-0.77 (1.11)	-0.63 (1.16)	-0.48 (1.04)	-0.93 (0.85)

3. Secondary Outcome

Title	Change From Baseline in Mean Clinical Global Impression - Improvement (CGI-I) Score
Description	The efficacy of trial treatment was rated for each participant using the CGI-I. The investigator rated the participant's total improvement whether or not it was due entirely to drug treatment. All responses were compared to the participant's condition at screening. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse and 7 = very much worse.
Time Frame	From screening to week 52/early termination

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.

Arm/Group Title	Prior Placebo	Prior Brexpiprazole	Prior ADT	Prior Seroquel
Arm/Group Description	Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.
Measure Participants	505	693	1606	75
Mean (Standard Deviation) [units on a scale]	2.60 (1.30)	2.63 (1.34)	2.63 (1.39)	2.40 (1.17)

4. Secondary Outcome

Title	Summary of Mean Change From Baseline in Sheehan Disability Scale (SDS) Mean Score
Description	The SDS was a self-rated instrument used to measure the effect of the participant's symptoms on regular life responsibilities. The SDS was a visual analogue scale that used spatio-visual, numeric, and verbal descriptive anchors simultaneously to assess disability across the 3 domains with scores from 0 = not at all, to 10 = extremely. Scores of 5 and above were associated with significant functional impairment.
Time Frame	From screening to week 52/early termination

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.

Arm/Group Title	Prior Placebo	Prior Brexpiprazole	Prior ADT	Prior Seroquel
Arm/Group Description	Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.
Measure Participants	346	457	1165	53
Mean (Standard Deviation) [units on a scale]	-0.80 (2.80)	-0.70 (2.60)	-0.40 (2.30)	-1.00 (1.70)

5. Secondary Outcome

Title	Change From Baseline in the Inventory of Depressive Symptomatology - Self Report (IDS-SR) Total Score
Description	The IDS-SR was a 30-item self-report measure used to assess core diagnostic depressive symptoms as well as atypical and melancholic symptom features of MDD. 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. The IDS-SR Total Score is the sum of ratings of 28 item scores. The possible IDS-SR Total Score ranges from 0 (best) to 84 (worst). Under 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. If the number of items recorded is at least 23 and at most 27, the IDS-SR Total Score will be the mean of the recorded items multiplied by 28 and then rounded to the first decimal place.
Time Frame	From screening to week 52/early termination

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of open-label brexpiprazole as adjunctive therapy to one of the allowed ADTs and had at least one post-baseline efficacy evaluation of CGI-S.

Arm/Group Title	Prior Placebo	Prior Brexpiprazole	Prior ADT	Prior Seroquel
Arm/Group Description	Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.	Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.
Measure Participants	491	664	1556	75
Mean (Standard Deviation) [units on a scale]	-5.25 (12.21)	-4.76 (11.79)	-3.94 (10.57)	-7.44 (8.89)

Adverse Events

Time Frame	From screening to 30 (+ 2) days following the 52 weeks treatment period or early termination.
Adverse Event Reporting Description	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug-related. An AE was considered serious if it resulted in any of the following outcomes: fatal; life threatening; persistently or significantly disabling or incapacitating; required inpatient hospitalization or prolonged existing hospitalization; a congenital anomaly/birth defect; or other medically significant event
Arm/Group Title	Prior Placebo		Prior Brexpiprazole		Prior ADT		Prior Seroquel
Arm/Group Description	Participants who received placebo with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.		Participants who received Brexpiprazole with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.		Participants who received only ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.		Participants who received Seroquel with ADT in previous double blind phase 3 studies, received 0.5 to 3 mg/day Brexpiprazole + ADT for weeks 1, 2, 4, 8,14, 20, 26, 32, 38, 44 and 52 with dose adjustment.
All Cause Mortality
	Prior Placebo		Prior Brexpiprazole		Prior ADT		Prior Seroquel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/516 (0.4%)		2/706 (0.3%)		0/1640 (0%)		0/76 (0%)
Serious Adverse Events
	Prior Placebo		Prior Brexpiprazole		Prior ADT		Prior Seroquel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/516 (2.7%)		23/706 (3.3%)		33/1640 (2%)		1/76 (1.3%)
Blood and lymphatic system disorders
Iron Deficiency Anaemia	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Cardiac disorders
Aortic Valve Incompetence	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Cardiac Failure Congestive	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Ventricular Dysfunction	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Eye disorders
Blepharospasm	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Retinal Vein Thrombosis	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Gastrointestinal disorders
Abdominal Pain	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Crohn's Disease	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Gastric Ulcer Perforation	1/516 (0.2%)		0/706 (0%)		0/1640 (0%)		0/76 (0%)
General disorders
Chest Pain	0/516 (0%)		0/706 (0%)		2/1640 (0.1%)		0/76 (0%)
Drug Withdrawal Syndrome	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Hepatobiliary disorders
Cholelithiasis	0/516 (0%)		0/706 (0%)		2/1640 (0.1%)		0/76 (0%)
Hepatitis Acute	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Infections and infestations
Bronchitis	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Cellulitis	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Diverticulitis	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Gastroenteritis	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Herpes Zoster	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Kidney Infection	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Peritonitis	1/516 (0.2%)		0/706 (0%)		0/1640 (0%)		0/76 (0%)
Pneumonia	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Upper Respiratory Tract Infection	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Injury, poisoning and procedural complications
Contusion	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Fall	1/516 (0.2%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Intentional Overdose	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Patella Fracture	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Investigations
Electrocardiogram Qt Prolonged	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Metabolism and nutrition disorders
Type 2 Diabetes Mellitus	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion	1/516 (0.2%)		0/706 (0%)		0/1640 (0%)		0/76 (0%)
Lumbar Spinal Stenosis	0/516 (0%)		0/706 (0%)		0/1640 (0%)		1/76 (1.3%)
Spinal Osteoarthritis	1/516 (0.2%)		0/706 (0%)		0/1640 (0%)		0/76 (0%)
Spondylolisthesis	0/516 (0%)		0/706 (0%)		0/1640 (0%)		1/76 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer	0/516 (0%)		1/706 (0.1%)		1/1640 (0.1%)		0/76 (0%)
Intraductal Proliferative Breast Lesion	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Ovarian Cancer	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Pancreatic Neuroendocrine Tumour	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Rectal Adenocarcinoma	1/516 (0.2%)		0/706 (0%)		0/1640 (0%)		0/76 (0%)
Renal Cell Carcinoma	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Nervous system disorders
Cerebrovascular Accident	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Dizziness	0/516 (0%)		0/706 (0%)		2/1640 (0.1%)		0/76 (0%)
Dyskinesia	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Extrapyramidal Disorder	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Lumbar Radiculopathy	1/516 (0.2%)		0/706 (0%)		0/1640 (0%)		0/76 (0%)
Ruptured Cerebral Aneurysm	1/516 (0.2%)		0/706 (0%)		0/1640 (0%)		0/76 (0%)
Sciatica	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Syncope	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Psychiatric disorders
Completed Suicide	0/516 (0%)		2/706 (0.3%)		0/1640 (0%)		0/76 (0%)
Depression	2/516 (0.4%)		3/706 (0.4%)		3/1640 (0.2%)		0/76 (0%)
Depressive Symptom	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Intentional Self-Injury	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Major Depression	1/516 (0.2%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Mania	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Suicidal Ideation	0/516 (0%)		1/706 (0.1%)		1/1640 (0.1%)		0/76 (0%)
Suicide Attempt	2/516 (0.4%)		1/706 (0.1%)		1/1640 (0.1%)		0/76 (0%)
Renal and urinary disorders
Renal Disorder	0/516 (0%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Reproductive system and breast disorders
Pelvic Adhesions	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/516 (0.2%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Chronic Obstructive Pulmonary	0/516 (0%)		0/706 (0%)		1/1640 (0.1%)		0/76 (0%)
Pulmonary Embolism	2/516 (0.4%)		1/706 (0.1%)		0/1640 (0%)		0/76 (0%)
Other (Not Including Serious) Adverse Events
	Prior Placebo		Prior Brexpiprazole		Prior ADT		Prior Seroquel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	296/516 (57.4%)		323/706 (45.8%)		787/1640 (48%)		33/76 (43.4%)
Gastrointestinal disorders
Constipation	14/516 (2.7%)		15/706 (2.1%)		33/1640 (2%)		4/76 (5.3%)
Nausea	26/516 (5%)		32/706 (4.5%)		61/1640 (3.7%)		4/76 (5.3%)
General disorders
Fatigue	37/516 (7.2%)		50/706 (7.1%)		88/1640 (5.4%)		3/76 (3.9%)
Infections and infestations
Viral Upper Respiratory Tract Infection	25/516 (4.8%)		35/706 (5%)		98/1640 (6%)		2/76 (2.6%)
Investigations
Weight Increased	118/516 (22.9%)		100/706 (14.2%)		296/1640 (18%)		5/76 (6.6%)
Metabolism and nutrition disorders
Increased Appetite	37/516 (7.2%)		28/706 (4%)		117/1640 (7.1%)		3/76 (3.9%)
Nervous system disorders
Akathisia	54/516 (10.5%)		37/706 (5.2%)		99/1640 (6%)		7/76 (9.2%)
Headache	42/516 (8.1%)		55/706 (7.8%)		105/1640 (6.4%)		9/76 (11.8%)
Somnolence	40/516 (7.8%)		60/706 (8.5%)		130/1640 (7.9%)		5/76 (6.6%)
Psychiatric disorders
Anxiety	39/516 (7.6%)		37/706 (5.2%)		76/1640 (4.6%)		0/76 (0%)
Insomnia	30/516 (5.8%)		40/706 (5.7%)		108/1640 (6.6%)		6/76 (7.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.