Brexpiprazole as Adjunctive Treatment in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment

• Sponsor: H. Lundbeck A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01838681
• Collaborator: Otsuka Pharmaceutical Co., Ltd. (Industry)
• Enrollment: 1,986
• Locations: 107
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 18.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

To evaluate the long-term efficacy and safety of brexpiprazole as an adjunctive treatment to an antidepressant treatment (ADT) for adult patients with Major Depressive Disorder (MDD).

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Placebo; Drug: Brexpiprazole; Drug: ADT	Phase 3

Detailed Description

The total duration of the study was 32 weeks and the study consisted of Periods A, B, and A+. Patients entered the study in Period A and were treated open-label with one of six commercially available antidepressant treatments (ADTs) for 8 weeks. Patients who met the blinded response criteria at the Week 6 Visit, were deemed early responders and were withdrawn from the study. At Week 8, patients with inadequate response to placebo + ADT, as per the randomisation criteria, entered Period B and were randomised to received double-blind brexpiprazole + ADT or placebo + ADT for 24 weeks. Non-randomised patients continued in Period A+ and received placebo + ADT until the end of the study. The primary objective was to compare the efficacy and safety of brexpiprazole with placebo. This comparison occurred Period B; therefore, the focus is Period B.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1986 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Interventional, Randomised, Double-blind, Parallel-group, Placebo-controlled, Flexible-dose Long-term Study to Evaluate the Maintenance of Efficacy and Safety of 1 to 3 mg/Day of Brexpiprazole as Adjunctive Treatment in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo adjunct to open-label treatment with a commercially available antidepressant (ADT)	Drug: Placebo; Once daily, tablets, orally; Drug: ADT; Duloxetine, escitalopram, fluoxetine, paroxetine IR, sertraline, venlafaxine XR; dosing according to label
Experimental: Brexpiprazole Brexpiprazole adjunct to open-label treatment with a commercially available ADT	Drug: Brexpiprazole; 1, 2, or 3 mg/day, once daily dose, tablets, orally. Uptitration in weekly steps from 1 mg/day; Drug: ADT; Duloxetine, escitalopram, fluoxetine, paroxetine IR, sertraline, venlafaxine XR; dosing according to label

Outcome Measures

Primary Outcome Measures

1. Full Remission During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   Full remission is defined as a Montomery and Åsberg Depression Rating Scale (MADRS) total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomized treatment. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.

Secondary Outcome Measures

1. Full Functional Remission During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   Full functional remission is defined as a Sheehan Disability Scale (SDS) total score <=6 and all SDS domain scores <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.

2. Full Global Score Remission During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   Full global score remission is defined as a Clinical Global Impression - Severity of Illness (CGI-S) score <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis, on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.

3. Total Time in Remission During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   The total time the patient spends in remission during randomised treatment. Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score. Time in remission is defined as the sum of days over all periods between Period B visits where remission was obtained. The period between two visits is counted as in remission if the patient was in remission when the period started.

4. Time to Full Remission During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   The time from randomisation until full remission has been obtained. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment. The time to full remission was calculated using Kaplan-Meier Methods.

5. Full Remission Sustained During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   Full remission sustained is defined as having obtained full remission and remain in remission until completion of the study. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment.

6. Change From Randomisation to Week 6 in MADRS Total Score During the Randomised Treatment Period [From randomisation to week 6]

   The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.

7. Change From Randomisation to Week 24 in MADRS Total Score During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.

8. Response at Week 6 During the Randomised Treatment Period [From randomisation to week 6]

   Response is defined as a >=50% decrease from randomisation in MADRS total score.

9. Response at Week 24 During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

   Response is defined as a >=50% decrease from randomisation in MADRS total score.

10. Remission at Week 6 During the Randomised Treatment Period [From randomisation to week 6]

    Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score.

11. Remission at Week 24 in the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

    Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score.

12. Change From Randomisation to Week 6 in SDS Total Score During the Randomised Treatment Period [From randomisation to week 6]

    The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.

13. Change From Randomisation to Week 24 in SDS Total Score During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

    The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.

14. Change From Randomisation to Week 6 in CGI-S Score During the Randomised Treatment Period [From randomisation to week 6]

    The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.

15. Change From Randomisation to Week 24 in CGI-S Score During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

    The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.

16. Change From Randomisation to Week 6 in Q-LES-Q (SF) Total Score During the Randomised Treatment Period [From randomisation to week 6]

    The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good). The total score is the sum of the first 14 items. The last two scores are stand-alone items. The total score ranges from 14 to 70.

17. Change From Randomisation to Week 24 in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q (SF)) Total Score During the Randomised Treatment Period [From randomisation to end of Period B (24 weeks)]

    The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good). The total score is the sum of the first 14 items. The last two scores are stand-alone items. The total score ranges from 14 to 70.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The patient is an outpatient consulting a psychiatrist.

• The patient has an MDD diagnosed according to DSM-IV-TR™. The current Major Depressive Episode (MDE) should be confirmed using the Mini International Neuropsychiatric Interview (MINI).

• The patient has a moderate to severe depression and an insufficient response to at least one and no more than three adequate antidepressant treatments.

• The patient agrees to protocol-defined use of effective contraception.

Exclusion Criteria:

• The patient has any current psychiatric disorder or Axis I disorder (DSM-IV-TR™ criteria), established as the primary diagnosis, other than MDD.

• The patient has a current Axis II (DSM-IV-TR™) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypical or histrionic personality disorder.

• The patient has experienced/experiences hallucinations, delusions or any psychotic symptomatology in the current MDE.

• The patient suffers from mental retardation, organic mental disorders, or mental disorders due to a general medical condition (DSM-IV-TR™ criteria).

• The patient, in the opinion of the investigator or according to Columbia-Suicide Severity Rating Scale (C-SSRS), is at significant risk of suicide.

• The patient has had neuroleptic malignant syndrome.

• The patient has any relevant medical history or current presence of systemic disease.

• The patient has, at the Screening Visit an abnormal ECG that is, in the investigator's opinion, clinically significant.

• The patient has a history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of the skin, that has not been in remission for >5 years prior to the first dose of IMP.

• The patient is, in the investigator's opinion, unlikely to comply with the protocol or is unsuitable for any reason.

Other inclusion and exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	US041	Little Rock	Arkansas	United States
2	US043	Cerritos	California	United States
3	US042	Temecula	California	United States
4	US053	Flowood	Mississippi	United States
5	US040	Brooklyn	New York	United States
6	US046	Houston	Texas	United States
7	US052	Houston	Texas	United States
8	US047	Milwaukee	Wisconsin	United States
9	BG007	Kardjali		Bulgaria
10	BG002	Pazardzhik		Bulgaria
11	BG003	Ruse		Bulgaria
12	BG001	Sofia		Bulgaria
13	BG004	Sofia		Bulgaria
14	BG005	Varna		Bulgaria
15	BG006	Varna		Bulgaria
16	CA003	Burlington		Canada
17	CA004	Edmonton, Alberta		Canada
18	CA001	Kingston		Canada
19	CA002	Montral		Canada
20	CA005	Montreal		Canada
21	EE002	Tallinn		Estonia
22	EE003	Tallinn		Estonia
23	EE006	Tallinn		Estonia
24	EE001	Tartu		Estonia
25	EE005	Tartu		Estonia
26	EE004	Voru		Estonia
27	FI002	Helsinki		Finland
28	FI003	Helsinki		Finland
29	FI006	Helsinki		Finland
30	FI001	Kuopio		Finland
31	FI007	Pori		Finland
32	FI009	Tampere		Finland
33	DE007	Berlin		Germany
34	DE014	Berlin		Germany
35	DE015	Berlin		Germany
36	DE006	Bielefeld		Germany
37	DE010	Bochum		Germany
38	DE012	Gelsenkirchen		Germany
39	DE009	Hannover		Germany
40	DE022	Hattingen		Germany
41	DE008	Heidelberg		Germany
42	DE017	Leipzig		Germany
43	DE001	Nuernberg		Germany
44	DE004	Nuernberg		Germany
45	DE002	Schwerin		Germany
46	DE016	Wiesbaden		Germany
47	KR001	Seoul		Korea, Republic of
48	KR004	Seoul		Korea, Republic of
49	LV004	Daugavpils		Latvia
50	LV005	Jelgava		Latvia
51	LV002	Liepaja		Latvia
52	LV003	Riga		Latvia
53	LV001	Strenci		Latvia
54	LT006	Kaunas Region		Lithuania
55	LT003	Kaunas		Lithuania
56	LT001	Palanga		Lithuania
57	LT005	Silute		Lithuania
58	LT002	Vilnius		Lithuania
59	LT004	Vilnius		Lithuania
60	MX009	Guadalajara		Mexico
61	MX008	Leon		Mexico
62	MX003	Monterrey, Nuevo Len		Mexico
63	MX002	Monterrey		Mexico
64	PL010	Bialystok		Poland
65	PL016	Bialystok		Poland
66	PL017	Bydgoszcz		Poland
67	PL007	Chelmno		Poland
68	PL002	Gdansk		Poland
69	PL011	Gorlice		Poland
70	PL018	Kielce		Poland
71	PL013	Leszno		Poland
72	PL001	Lublin		Poland
73	PL006	Lublin		Poland
74	PL014	Szczecin		Poland
75	PL012	Torun		Poland
76	PL019	Torun		Poland
77	RO003	Bucuresti		Romania
78	RO006	Bucuresti		Romania
79	RO001	Iasi		Romania
80	RO004	Timisoara		Romania
81	RU002	Moscow		Russian Federation
82	RU004	Moscow		Russian Federation
83	RU003	Saint-Petersburg		Russian Federation
84	RU006	Saint-Petersburg		Russian Federation
85	RU007	Saint-Petersburg		Russian Federation
86	RU010	Saint-Petersburg		Russian Federation
87	RU014	Saint-Petersburg		Russian Federation
88	RU012	Saratov		Russian Federation
89	RU005	Stavropol		Russian Federation
90	SE008	Halmstad		Sweden
91	SE006	Malmo		Sweden
92	SE009	Skovde		Sweden
93	SE001	Stockholm		Sweden
94	UA006	Kharkiv		Ukraine
95	UA007	Kherson,Vil. Stepanivka		Ukraine
96	UA003	Kiev		Ukraine
97	UA014	Kiev		Ukraine
98	UA002	Kyiv		Ukraine
99	UA005	Lviv		Ukraine
100	UA012	Ternopil		Ukraine
101	UA009	Vinnytsya		Ukraine
102	GB003	Blackpool		United Kingdom
103	GB005	Bognor Regis		United Kingdom
104	GB002	Bradford		United Kingdom
105	GB004	Cannock		United Kingdom
106	GB001	Leeds		United Kingdom
107	GB006	Winwick		United Kingdom

Sponsors and Collaborators

• H. Lundbeck A/S
• Otsuka Pharmaceutical Co., Ltd.

Investigators

• Study Director: Email contact via H. Lundbeck A/S, [e-mail]

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: H. Lundbeck A/S
• ClinicalTrials.gov Identifier: NCT01838681
• Other Study ID Numbers: 14570A; 2012-001380-76
• First Posted: Apr 24, 2013
• Last Update Posted: Aug 9, 2017
• Last Verified: Jul 1, 2017

• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Brexpiprazole

Study Results

Participant Flow

Recruitment Details	1986 patients were enrolled; 1982 received open-label ADT plus double-blind placebo in the 8-week Period A. In the 24-week Period B, 886 patients were randomised and 885 were treated with open-label ADT plus double-blind brexpiprazole or placebo. Non-randomised patients continued in Period A+ and received open-label ADT plus double-blind placebo.

Arm/Group Title	Period A Placebo and ADT (8 Weeks)	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)	Period A+ Placebo and ADT (Non-randomised Patients)
Arm/Group Description	Placebo adjunct to open-label treatment with ADT Placebo: Once daily, tablets, orally	Placebo adjunct to open-label treatment with ADT (same ADT as in Period A) Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with ADT (same ADT as in Period A) Brexpiprazole: flexible dose; 1, 2, or 3 mg/day, once daily, tablets, orally	Placebo adjunct to open-label treatment with ADT (same ADT as in Period A) Placebo: Once daily, tablets, orally
Period Title: Period A
STARTED	1986	0	0	0
COMPLETED	1661	0	0	0
NOT COMPLETED	325	0	0	0
Period Title: Period A
STARTED	0	442	444	770
COMPLETED	0	380	349	653
NOT COMPLETED	0	62	95	117

Baseline Characteristics

Arm/Group Title	All Enrolled Patients
Arm/Group Description	Period A
Overall Participants	1986
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.3 (12.0)
Sex: Female, Male (Count of Participants)
Female	1402 70.6%
Male	584 29.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 0.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	19 1%
White	1918 96.6%
More than one race	0 0%
Unknown or Not Reported	46 2.3%
Region of Enrollment (participants) [Number]
Russian Federation	121 6.1%
Romania	15 0.8%
United States	78 3.9%
Ukraine	189 9.5%
United Kingdom	168 8.5%
Canada	30 1.5%
Latvia	84 4.2%
Sweden	85 4.3%
Finland	136 6.8%
Poland	325 16.4%
Mexico	72 3.6%
Bulgaria	119 6%
Lithuania	76 3.8%
Germany	325 16.4%
Estonia	161 8.1%
Korea, Republic of	2 0.1%

Outcome Measures

1. Primary Outcome

Title	Full Remission During the Randomised Treatment Period
Description	Full remission is defined as a Montomery and Åsberg Depression Rating Scale (MADRS) total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomized treatment. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	441	444
Number [participants]	110 5.5%	95 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Period B Placebo and ADT (24 Weeks Randomised Treatment), Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2641
	Comments
	Method	Regression, Logistic
	Comments	Model included MADRS total score at the randomisation visit, treatment group, country, and the randomisation criteria used
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.60 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Full Functional Remission During the Randomised Treatment Period
Description	Full functional remission is defined as a Sheehan Disability Scale (SDS) total score <=6 and all SDS domain scores <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	441	444
Number [participants]	73 3.7%	68 NaN

3. Secondary Outcome

Title	Full Global Score Remission During the Randomised Treatment Period
Description	Full global score remission is defined as a Clinical Global Impression - Severity of Illness (CGI-S) score <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis, on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	441	444
Number [participants]	143 7.2%	121 NaN

4. Secondary Outcome

Title	Total Time in Remission During the Randomised Treatment Period
Description	The total time the patient spends in remission during randomised treatment. Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score. Time in remission is defined as the sum of days over all periods between Period B visits where remission was obtained. The period between two visits is counted as in remission if the patient was in remission when the period started.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	441	444
Mean (Standard Deviation) [Number of days]	33.5 (46.1)	30.0 (44.3)

5. Secondary Outcome

Title	Time to Full Remission During the Randomised Treatment Period
Description	The time from randomisation until full remission has been obtained. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment. The time to full remission was calculated using Kaplan-Meier Methods.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	441	444
Median (95% Confidence Interval) [Days]	NA	NA

6. Secondary Outcome

Title	Full Remission Sustained During the Randomised Treatment Period
Description	Full remission sustained is defined as having obtained full remission and remain in remission until completion of the study. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	441	444
Number [participants]	105 5.3%	84 NaN

7. Secondary Outcome

Title	Change From Randomisation to Week 6 in MADRS Total Score During the Randomised Treatment Period
Description	The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.
Time Frame	From randomisation to week 6

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	422	422
Least Squares Mean (Standard Error) [units on a scale]	-5.9 (0.4)	-6.3 (0.4)

8. Secondary Outcome

Title	Change From Randomisation to Week 24 in MADRS Total Score During the Randomised Treatment Period
Description	The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	361	333
Least Squares Mean (Standard Error) [Units on a scale]	-12.6 (0.6)	-11.5 (0.6)

9. Secondary Outcome

Title	Response at Week 6 During the Randomised Treatment Period
Description	Response is defined as a >=50% decrease from randomisation in MADRS total score.
Time Frame	From randomisation to week 6

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B. Last Observation Carried Forward (LOCF).

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	440	442
Number [participants]	76 3.8%	82 NaN

10. Secondary Outcome

Title	Response at Week 24 During the Randomised Treatment Period
Description	Response is defined as a >=50% decrease from randomisation in MADRS total score.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B. Last Observation Carried Forward (LOCF).

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	440	442
Number [participants]	236 11.9%	223 NaN

11. Secondary Outcome

Title	Remission at Week 6 During the Randomised Treatment Period
Description	Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score.
Time Frame	From randomisation to week 6

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B. Last Observation Carried Forward (LOCF).

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	440	442
Number [participants]	46 2.3%	53 NaN

12. Secondary Outcome

Title	Remission at Week 24 in the Randomised Treatment Period
Description	Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B. Last Observation Carried Forward (LOCF).

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	440	442
Number [participants]	198 10%	176 NaN

13. Secondary Outcome

Title	Change From Randomisation to Week 6 in SDS Total Score During the Randomised Treatment Period
Description	The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.
Time Frame	From randomisation to week 6

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	422	421
Least Squares Mean (Standard Error) [units on a scale]	-3.0 (0.3)	-2.9 (0.3)

14. Secondary Outcome

Title	Change From Randomisation to Week 24 in SDS Total Score During the Randomised Treatment Period
Description	The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	361	333
Least Squares Mean (Standard Error) [units on a scale]	-6.7 (0.5)	-5.5 (0.5)

15. Secondary Outcome

Title	Change From Randomisation to Week 6 in CGI-S Score During the Randomised Treatment Period
Description	The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
Time Frame	From randomisation to week 6

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	422	422
Least Squares Mean (Standard Error) [units on a scale]	-0.8 (0.1)	-0.8 (0.1)

16. Secondary Outcome

Title	Change From Randomisation to Week 24 in CGI-S Score During the Randomised Treatment Period
Description	The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	361	333
Least Squares Mean (Standard Error) [units on a scale]	-1.7 (0.1)	-1.5 (0.1)

17. Secondary Outcome

Title	Change From Randomisation to Week 6 in Q-LES-Q (SF) Total Score During the Randomised Treatment Period
Description	The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good). The total score is the sum of the first 14 items. The last two scores are stand-alone items. The total score ranges from 14 to 70.
Time Frame	From randomisation to week 6

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	422	421
Least Squares Mean (Standard Error) [units on a scale]	3.5 (0.4)	3.2 (0.4)

18. Secondary Outcome

Title	Change From Randomisation to Week 24 in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q (SF)) Total Score During the Randomised Treatment Period
Description	The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good). The total score is the sum of the first 14 items. The last two scores are stand-alone items. The total score ranges from 14 to 70.
Time Frame	From randomisation to end of Period B (24 weeks)

Outcome Measure Data

Analysis Population Description

All randomised patients who took at least one dose of randomised treatment (brexpiprazole or placebo) in Period B.

Arm/Group Title	Period B Placebo and ADT (24 Weeks Randomised Treatment)	Period B Brexpiprazole and ADT (24 Weeks Randomised Treatment)
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available ADT Placebo: Once daily, tablets, orally	Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, or 3 mg/day, once daily dose, tablets, orally
Measure Participants	361	333
Least Squares Mean (Standard Error) [units on a scale]	7.7 (0.7)	6.2 (0.7)

Adverse Events

Time Frame	Randomisation to end of study (28 weeks)
Adverse Event Reporting Description	Treatment-Emergent Adverse Events are reported in this section
Arm/Group Title	Placebo and ADT		Brexpiprazole and ADT
Arm/Group Description	Placebo adjunct to open-label treatment with a commercially available antidepressant (ADT) Placebo: Once daily, tablets, orally		Brexpiprazole adjunct to open-label treatment with a commercially available ADT Brexpiprazole: 1, 2, 3, mg/day, once daily, tablets, orally
All Cause Mortality
	Placebo and ADT		Brexpiprazole and ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo and ADT		Brexpiprazole and ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/441 (2.9%)		9/444 (2%)
Gastrointestinal disorders
Pancreatitis	0/441 (0%)		1/444 (0.2%)
Infections and infestations
Influenza	1/441 (0.2%)		0/444 (0%)
Injury, poisoning and procedural complications
Forearm fracture	1/441 (0.2%)		0/444 (0%)
Intentional overdose	2/441 (0.5%)		0/444 (0%)
Radius fracture	0/441 (0%)		1/444 (0.2%)
Investigations
False positive investigation result	1/441 (0.2%)		0/444 (0%)
Metabolism and nutrition disorders
Obesity	0/441 (0%)		1/444 (0.2%)
Nervous system disorders
Dizziness	0/441 (0%)		1/444 (0.2%)
Loss of consciousness	0/441 (0%)		1/444 (0.2%)
Ruptured cerebral aneurysm	1/441 (0.2%)		0/444 (0%)
Sciatica	1/441 (0.2%)		0/444 (0%)
Seizure	0/441 (0%)		1/444 (0.2%)
Psychiatric disorders
Major depression	1/441 (0.2%)		1/444 (0.2%)
Self injurious behaviour	1/441 (0.2%)		0/444 (0%)
Suicidal ideation	3/441 (0.7%)		2/444 (0.5%)
Suicide attempt	1/441 (0.2%)		0/444 (0%)
Reproductive system and breast disorders
Ovarian cyst	1/302 (0.3%)		0/307 (0%)
Social circumstances
Family stress	0/441 (0%)		1/444 (0.2%)
Vascular disorders
Circulatory collapse	0/441 (0%)		1/444 (0.2%)
Other (Not Including Serious) Adverse Events
	Placebo and ADT		Brexpiprazole and ADT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	97/441 (22%)		108/444 (24.3%)
Infections and infestations
Nasopharyngitis	34/441 (7.7%)		28/444 (6.3%)
Injury, poisoning and procedural complications
Accidental overdose	25/441 (5.7%)		27/444 (6.1%)
Investigations
Weight increased	22/441 (5%)		42/444 (9.5%)
Nervous system disorders
Headache	31/441 (7%)		34/444 (7.7%)

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.