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Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults with Major Depressive Disorder, the Polaris Trial.

Summary
EudraCT number	2011-001349-33
Trial protocol	DE HU
Global end of trial date	12 Sep 2013

Results information
Results version number	v1(current)
This version publication date	02 Jul 2016
First version publication date	02 Jul 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

331-10-227

ISRCTN number

US NCT number

NCT01360632

WHO universal trial number (UTN)

Other trial identifiers

IND No. : 103,958

Sponsor organisation name

Otsuka Pharmaceutical Development & Commercialization, Inc.

Sponsor organisation address

2440 Research Boulevard, Rockville, United States, Maryland 20850

Public contact

Mary Hobart, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 240-683-3194, Mary.Hobart@otsuka-us.com

Scientific contact

Mary Hobart, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 240-683-3194, Mary.Hobart@otsuka-us.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Jun 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Sep 2013

Global end of trial reached?

Yes

Global end of trial date

12 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of OPC-34712 (1.0 and 3.0 milligrams (mg)/day) to placebo as adjunctive therapy to an assigned open-label antidepressant therapy (ADT) in participants who demonstrated an incomplete response after 8 weeks of prospective treatment with the same assigned open-label ADT.

Protection of trial subjects

This trial was conducted in compliance with Good Clinical Practice (GCP) guidelines for conducting, recording, and reporting trials, as well as for archiving essential documents. Consistent with ethical principles for the protection of human research subjects, no trial procedures were performed on trial candidates until written consent had been obtained from them. The informed consent form (ICF), protocol, and amendments for this trial were submitted to and approved by the institutional review board (IRB) or independent ethics committee (IEC) for each respective trial site or country.

Background therapy

At enrollment the physician carefully considered the participants’s antidepressant treatment (ADT) history and made an ADT assignment for each enrolled participant from the following list of sponsor-provided ADTs: escitalopram, fluoxetine, paroxetine controlled release (CR), sertraline, duloxetine, and venlafaxine extended release (XR). Once assigned to one of these ADTs by the physician in Phase A, participants remained on that ADT for the duration of the trial (ie, baseline through Week 14/end of treatment) or were withdrawn if a change in ADT was needed.

Evidence for comparator

Actual start date of recruitment

25 Jun 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Romania: 12

Country: Number of subjects enrolled

Germany: 77

Country: Number of subjects enrolled

Hungary: 28

Country: Number of subjects enrolled

Canada: 15

Country: Number of subjects enrolled

Russian Federation: 48

Country: Number of subjects enrolled

Ukraine: 55

Country: Number of subjects enrolled

United States: 442

Worldwide total number of subjects

677

EEA total number of subjects

117

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

676

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 1539 participants at 92 trial sites in 7 countries. A total of 677 participants were into Phase B (period 2) and 675 received treatment.

Screening details

The study consisted of a 7 to 28-day Screening period, an 8-Week single-blind placebo + ADT prospective Phase-A, a 6-Week double-blind randomization Phase-B or single-blind Phase A+ for those participants who did not meet criteria for randomization and a Follow-up of 30 (+2) days after the last dose of study medication.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Treatment assignment code list was available to an independent biostatistician and access to randomized treatment codes restricted to personnel charged with generating/ maintaining randomization files, packaging double-blind treatment, operating interactive voice recognition system and reporting serious adverse events (SAEs) to regulatory agencies. All other trial personnel remained blinded to the identity of the treatment until every participant had completed treatment and the database locked.

Are arms mutually exclusive

Yes

Brexpiprazole (1mg) + ADT

Arm description

Participants were administered brexpiprazole (1mg/day) as an adjunctive therapy to an assigned open label ADT (anti-depressant therapy).

Arm type

Experimental

Investigational medicinal product name

Brexpiprazole

Investigational medicinal product code

Other name

OPC-34712

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Brexpiprazole 1mg/day as an adjunctive therapy to an assigned open label ADT.

Brexpiprazole (3mg) + ADT

Arm description

Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.

Arm type

Experimental

Investigational medicinal product name

Brexpiprazole

Investigational medicinal product code

Other name

OPC-34712

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.

Placebo +ADT

Arm description

Participants were administered placebo daily as an adjunctive therapy to an open label ADT.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo daily as adjunctive therapy to an open label ADT.

Number of subjects in period 1	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Started	226	230	221
Completed	216	210	208
Not completed	10	20	13
Consent withdrawn by subject	4	4	7
Physician decision	-	-	1
Met withdrawal criteria	-	2	1
Adverse event	3	9	3
Lost to follow-up	1	1	-
Protocol deviation	1	4	1
Lack of efficacy	1	-	-

Baseline characteristics

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Reporting group title

Brexpiprazole (1mg) + ADT

Reporting group description

Participants were administered brexpiprazole (1mg/day) as an adjunctive therapy to an assigned open label ADT (anti-depressant therapy).

Reporting group title

Brexpiprazole (3mg) + ADT

Reporting group description

Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.

Reporting group title

Placebo +ADT

Reporting group description

Participants were administered placebo daily as an adjunctive therapy to an open label ADT.

Reporting group values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT	Total
Number of subjects	226	230	221	677
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	225	230	221	676
From 65-84 years	1	0	0	1
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	45.7 ( 11.6 )	44.5 ( 11.2 )	46.6 ( 11 )	-
Gender categorical
Units: Subjects
Female	158	156	146	460
Male	68	74	75	217

End points

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Reporting group title

Brexpiprazole (1mg) + ADT

Reporting group description

Participants were administered brexpiprazole (1mg/day) as an adjunctive therapy to an assigned open label ADT (anti-depressant therapy).

Reporting group title

Brexpiprazole (3mg) + ADT

Reporting group description

Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.

Reporting group title

Placebo +ADT

Reporting group description

Participants were administered placebo daily as an adjunctive therapy to an open label ADT.

Subject analysis set title

Efficacy Sample

Subject analysis set type

Intention-to-treat

Subject analysis set description

All participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for Montgomery-Asberg Depression Rating Scale (MADRS) Total Score in Phase B.

Subject analysis set title

Efficacy Sample Per Protocol Amendment 3

Subject analysis set type

Per protocol

Subject analysis set description

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

Primary: Mean change from the end of Phase A (Week 8 visit) to Phase B (Week 14 visit) in the Montgomery-Asberg Depression Rating Scale for the Efficacy Sample Set

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End point title

Mean change from the end of Phase A (Week 8 visit) to Phase B (Week 14 visit) in the Montgomery-Asberg Depression Rating Scale for the Efficacy Sample Set

End point description

The MADRS was utilized as the primary efficacy assessment of a participant's level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the “best” rating and 6 being the “worst” rating. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The MADRS Total Score is the sum of ratings for all 10 items. The possible total scores are from 0 to 60, with higher values indicating worse outcome.

End point type

Primary

End point timeframe

Baseline and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Units on a scale
least squares mean (standard error)	-7.65 ( 0.5 )	-7.98 ( 0.51 )	-6.45 ( 0.51 )

Statistical analysis 1 at Week 14

Statistical analysis description

The primary analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0925

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.19

Confidence interval

level

95%

sides

2-sided

lower limit

-2.58

upper limit

0.2

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0327

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.52

Confidence interval

level

95%

sides

2-sided

lower limit

-2.92

upper limit

-0.13

Primary: Mean Change in MADRS Total Score from Baseline End of Week 8 to Week 14 for the Efficacy Sample per final protocol

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End point title

Mean Change in MADRS Total Score from Baseline End of Week 8 to Week 14 for the Efficacy Sample per final protocol

End point description

The MADRS was utilized as the primary efficacy assessment of a participants level of depression. The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the “best” rating and 6 being the “worst” rating. The possible total scores were from 0 to 6. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. Analysis was based on all participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Primary

End point timeframe

Baseline and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Units on a scale
least squares mean (standard error)	-7.64 ( 0.52 )	-8.29 ( 0.53 )	-6.33 ( 0.53 )

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0737

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-2.73

upper limit

0.13

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0079

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.95

Confidence interval

level

95%

sides

2-sided

lower limit

-3.39

upper limit

-0.51

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Sheehan Disability Scale (SDS) Mean Scores for the Efficacy Sample Set

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End point title

Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Sheehan Disability Scale (SDS) Mean Scores for the Efficacy Sample Set

End point description

This is the key secondary outcome measure. The SDS was a self-rated instrument used to measure the effect of the participants symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores ranged from 0 through 10. The number most representative of how much each area was disrupted by symptoms was marked along the line from 0= not at all to 10= extremely. For the work/school item, no response was to be entered if the participant did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS score were calculated over the three item scores. All three item scores were needed to be available with the exception of the work/school item score when this item was not applicable. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation.

End point type

Secondary

End point timeframe

Week 11 and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Units on a scale
least squares mean (standard error)
Week 11	-1.13 ( 0.13 )	-0.67 ( 0.13 )	-0.58 ( 0.11 )
Week 14	-1.33 ( 0.14 )	-1.21 ( 0.13 )	-0.84 ( 0.13 )

Statistical analysis 1 at Week 14

Statistical analysis description

The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0091

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-0.87

upper limit

-0.12

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0474

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.73

upper limit

Statistical analysis 3 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-0.87

upper limit

-0.23

Statistical analysis 4 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5792

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

0.23

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in SDS Mean Scores for the Efficacy Sample per final protocol

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End point title

Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in SDS Mean Scores for the Efficacy Sample per final protocol

End point description

The SDS was a self-rated instrument used to measure the effect of the participants symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores ranged from 0 through 10. The number most representative of how much each area was disrupted by symptoms was marked along the line from 0= not at all, to 10= extremely. For the work/school item, no response was to be entered if the participant did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS score were calculated over the three item scores. All three item scores were needed to be available with the exception of the work/school item score when this item was not applicable. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Week 11 and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Units on a scale
least squares mean (standard error)
Week 11	-1.11 ( 0.13 )	-0.74 ( 0.13 )	-0.53 ( 0.14 )
Week 14	-1.27 ( 0.15 )	-1.26 ( 0.15 )	-0.78 ( 0.15 )

Statisical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0158

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

-0.09

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0191

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

-0.08

Statistical analysis 3 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0015

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-0.94

upper limit

-0.22

Statistical analysis 4 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2627

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

0.15

Secondary: Mean change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample Set

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End point title

Mean change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample Set

End point description

The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the “best” rating and 6 being the “worst” rating. The possible total scores were from 0 to 6. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week 8 to Week 13

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Units on a scale
least squares mean (standard error)
Week 9 (N= 222, 221, 214)	-3.25 ( 0.3 )	-2.53 ( 0.3 )	-2.19 ( 0.31 )
Week 10 (N= 222, 221, 213)	-5.34 ( 0.38 )	-4.8 ( 0.38 )	-3.91 ( 0.39 )
Week 11 (N= 221, 218, 213)	-6.25 ( 0.41 )	-5.56 ( 0.41 )	-4.85 ( 0.41 )
Week 12 (N= 216, 213, 210)	-7.08 ( 0.43 )	-6.8 ( 0.44 )	-5.52 ( 0.44 )
Week 13 (N= 213, 212, 204)	-7.55 ( 0.46 )	-7.73 ( 0.46 )	-6.02 ( 0.47 )

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0096

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.06

Confidence interval

level

95%

sides

2-sided

lower limit

-1.86

upper limit

-0.26

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4137

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-1.14

upper limit

0.47

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0065

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.44

Confidence interval

level

95%

sides

2-sided

lower limit

-2.47

upper limit

-0.4

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0914 ^[1]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.89

Confidence interval

level

95%

sides

2-sided

lower limit

-1.93

upper limit

0.14

Notes
[1] - MMRM method with an unstructured variance covariance matrix was used, with model terms trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction.

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0139

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.39

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

-0.28

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2097

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-1.82

upper limit

0.4

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0099

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.56

Confidence interval

level

95%

sides

2-sided

lower limit

-2.75

upper limit

-0.38

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.034

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.29

Confidence interval

level

95%

sides

2-sided

lower limit

-2.48

upper limit

-0.1

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0177

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-2.8

upper limit

-0.27

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0085

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.71

Confidence interval

level

95%

sides

2-sided

lower limit

-2.98

upper limit

-0.44

Secondary: Mean Change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample per final protocol

Top of page

End point title

Mean Change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample per final protocol

End point description

The MADRS consisted of 10 items, all rated on a 0 to 6 scale with 0 being the “best” rating and 6 being the “worst” rating. The possible total scores were from 0 to 6. The MADRS total score were to be unevaluable if less than 8 of the 10 items were recorded. If 8 or 9 of the 10 items were recorded, the MADRS total score was the mean of the recorded items multiplied by 10 and then rounded of to the first decimal place. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3

End point type

Secondary

End point timeframe

Week 8 to Week 13

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Units on a scale
least squares mean (standard error)
Week 9 (N=208, 210, 199)	-3.09 ( 0.31 )	-2.6 ( 0.31 )	-2.18 ( 0.32 )
Week 10 (N=208, 208, 199)	-5.12 ( 0.39 )	-4.92 ( 0.39 )	-3.95 ( 0.4 )
Week 11 (N=207, 205, 199)	-6.22 ( 0.42 )	-5.76 ( 0.43 )	-4.86 ( 0.43 )
Week 12 (N=203, 202, 195)	-7.09 ( 0.45 )	-7.11 ( 0.45 )	-5.48 ( 0.46 )
Week 13 (N=200, 199, 191)	-7.56 ( 0.47 )	-8.05 ( 0.48 )	-5.93 ( 0.49 )

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0286

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.92

Confidence interval

level

95%

sides

2-sided

lower limit

-1.74

upper limit

-0.1

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3173

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.42

Confidence interval

level

95%

sides

2-sided

lower limit

-1.24

upper limit

0.4

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0313

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.17

Confidence interval

level

95%

sides

2-sided

lower limit

-2.23

upper limit

-0.11

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0732

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.97

Confidence interval

level

95%

sides

2-sided

lower limit

-2.04

upper limit

0.09

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0206

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.36

Confidence interval

level

95%

sides

2-sided

lower limit

-2.51

upper limit

-0.21

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1233

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.91

Confidence interval

level

95%

sides

2-sided

lower limit

-2.06

upper limit

0.25

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0097

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.61

Confidence interval

level

95%

sides

2-sided

lower limit

-2.84

upper limit

-0.39

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0092

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.63

Confidence interval

level

95%

sides

2-sided

lower limit

-2.86

upper limit

-0.41

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0139

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.63

Confidence interval

level

95%

sides

2-sided

lower limit

-2.94

upper limit

-0.33

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0015

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.12

Confidence interval

level

95%

sides

2-sided

lower limit

-3.42

upper limit

-0.81

Secondary: Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B in Clinical Global Impression Severity of Illness (CGI-S) for the Efficacy Sample Set

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B in Clinical Global Impression Severity of Illness (CGI-S) for the Efficacy Sample Set

End point description

The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician had to answer the following question: “Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?” Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Units on a scale
least squares mean (standard error)
Week 9 (N= 222, 221, 214)	-0.25 ( 0.03 )	-0.22 ( 0.03 )	-0.16 ( 0.03 )
Week 10 (N= 222, 221, 213)	-0.52 ( 0.05 )	-0.46 ( 0.05 )	-0.31 ( 0.05 )
Week 11 (N= 221, 218, 213)	-0.64 ( 0.05 )	-0.51 ( 0.05 )	-0.44 ( 0.05 )
Week 12 (N= 216, 213, 210)	-0.73 ( 0.05 )	-0.72 ( 0.05 )	-0.59 ( 0.05 )
Week 13 (N= 213, 212, 204)	-0.78 ( 0.06 )	-0.77 ( 0.06 )	-0.66 ( 0.06 )
Week 14 (N= 216, 208, 207)	-0.86 ( 0.06 )	-0.9 ( 0.06 )	-0.75 ( 0.06 )

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0436

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1741

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.03

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0012

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.34

upper limit

-0.08

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0266

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

-0.02

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0034

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.33

upper limit

-0.07

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3053

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.06

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0541

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0912

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.02

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1553

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.04

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1855

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

0.05

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2015

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.06

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0852

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

0.02

Secondary: Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B Week in Clinical CGI-S for the Efficacy Sample per final protocol

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B Week in Clinical CGI-S for the Efficacy Sample per final protocol

End point description

The severity of illness for each participant was rated using the CGI-S. To perform this assessment, the study physician had to answer the following question: “Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?” Response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Units on a scale
least squares mean (standard error)
Week 9 (N=208, 210,199)	-0.24 ( 0.03 )	-0.23 ( 0.03 )	-0.16 ( 0.03 )
Week 10 (N=208, 208, 199)	-0.5 ( 0.05 )	-0.47 ( 0.05 )	-0.33 ( 0.05 )
Week 11 (N=207, 205, 199)	-0.64 ( 0.05 )	-0.53 ( 0.05 )	-0.45 ( 0.05 )
Week 12 (N=203, 202, 195)	-0.73 ( 0.06 )	-0.74 ( 0.06 )	-0.58 ( 0.06 )
Week 13 (N=200, 199, 191)	-0.77 ( 0.06 )	-0.8 ( 0.06 )	-0.64 ( 0.06 )
Week 14 (N=204, 196, 193)	-0.87 ( 0.06 )	-0.92 ( 0.06 )	-0.72 ( 0.06 )

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0817

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.01

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1406

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.02

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

-0.04

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0287

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

-0.02

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0071

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

-0.05

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2503

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

0.06

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0539

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0398

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.31

upper limit

-0.01

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1168

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.03

Statistical anaysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0621

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

0.01

Statisical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.089

Method

Mixed models analysis

Parameter type

Median difference (final values)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

0.02

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0213

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

-0.03

Secondary: Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in Inventory of Depressive Symptomatology (Self-Report) IDS-SR Total Score for the Efficacy Sample Set

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in Inventory of Depressive Symptomatology (Self-Report) IDS-SR Total Score for the Efficacy Sample Set

End point description

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

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Units on a scale
least squares mean (standard error)
Week 9 (N= 222, 221, 214)	-3.58 ( 0.41 )	-2.68 ( 0.42 )	-2.31 ( 0.42 )
Week 10 (N= 222, 221, 213)	-4.97 ( 0.49 )	-4 ( 0.5 )	-3.11 ( 0.5 )
Week 11 (N= 220, 218, 213)	-5.83 ( 0.56 )	-4.15 ( 0.56 )	-3.74 ( 0.57 )
Week 12 (N= 216, 213, 210)	-6.33 ( 0.59 )	-5.77 ( 0.59 )	-4.43 ( 0.6 )
Week 13 (N= 213, 212, 204)	-6.96 ( 0.63 )	-6.62 ( 0.63 )	-5.66 ( 0.64 )
Week 14 (N= 216, 208, 207)	-7.02 ( 0.66 )	-6.94 ( 0.66 )	-5.42 ( 0.67 )

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0228

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.28

Confidence interval

level

95%

sides

2-sided

lower limit

-2.37

upper limit

-0.18

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5081

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-1.47

upper limit

0.73

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0064

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.86

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

-0.53

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1898

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.89

Confidence interval

level

95%

sides

2-sided

lower limit

-2.23

upper limit

0.44

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0074

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.09

Confidence interval

level

95%

sides

2-sided

lower limit

-3.62

upper limit

-0.56

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5935

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.42

Confidence interval

level

95%

sides

2-sided

lower limit

-1.95

upper limit

1.11

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0211

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.52

upper limit

-0.29

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1031

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.34

Confidence interval

level

95%

sides

2-sided

lower limit

-2.96

upper limit

0.27

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1366

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-3.02

upper limit

0.41

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2709

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.96

Confidence interval

level

95%

sides

2-sided

lower limit

-2.68

upper limit

0.75

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0812

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

0.2

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.52

Confidence interval

level

95%

sides

2-sided

lower limit

-3.33

upper limit

0.29

Secondary: Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in IDS-SR Total Score for the Efficacy Sample per final protocol

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in IDS-SR Total Score for the Efficacy Sample per final protocol

End point description

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

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Units on a scale
least squares mean (standard error)
Week 9 (N=208, 210, 199)	-3.27 ( 0.42 )	-2.65 ( 0.42 )	-2.15 ( 0.43 )
Week 10 (N=208, 209, 199)	-4.7 ( 0.51 )	-4.13 ( 0.51 )	-2.94 ( 0.52 )
Week 11 (N=206, 205, 199)	-5.77 ( 0.57 )	-4.29 ( 0.58 )	-3.46 ( 0.59 )
Week 12 (N=203, 202, 195)	-6.33 ( 0.61 )	-6.05 ( 0.61 )	-4.18 ( 0.63 )
Week 13 (N=200, 199, 191)	-6.88 ( 0.64 )	-6.97 ( 0.64 )	-5.25 ( 0.66 )
Week 14 (N=204, 196, 193)	-6.97 ( 0.67 )	-7.2 ( 0.68 )	-5.07 ( 0.69 )

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0496

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-2.24

upper limit

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.387

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-1.61

upper limit

0.63

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0125

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.75

Confidence interval

level

95%

sides

2-sided

lower limit

-3.13

upper limit

-0.38

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0898

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.19

Confidence interval

level

95%

sides

2-sided

lower limit

-2.57

upper limit

0.19

Statitical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.31

Confidence interval

level

95%

sides

2-sided

lower limit

-3.88

upper limit

-0.74

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.301 ^[2]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.83

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

0.74

Notes
[2] - MMRM method with an unstructured variance covariance matrix was used, with model terms trial site, treatment group, visit, treatment group-by-visit and Baseline-by-visit interaction.

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0118

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.15

Confidence interval

level

95%

sides

2-sided

lower limit

-3.82

upper limit

-0.48

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0287

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.87

Confidence interval

level

95%

sides

2-sided

lower limit

-3.54

upper limit

-0.19

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0686

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.63

Confidence interval

level

95%

sides

2-sided

lower limit

-3.39

upper limit

0.12

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.056

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.72

Confidence interval

level

95%

sides

2-sided

lower limit

-3.47

upper limit

0.04

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0448

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.75

upper limit

-0.04

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0251

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.13

Confidence interval

level

95%

sides

2-sided

lower limit

-3.98

upper limit

-0.27

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) Hamilton Depression Scale 17 Item Version (HAM)-D17 Total Score for the Efficacy Sample Set

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) Hamilton Depression Scale 17 Item Version (HAM)-D17 Total Score for the Efficacy Sample Set

End point description

The HAM-D17 was utilized as a secondary assessment of a participants level of depression. The HAM-D (17-Item) consisted of 17 items. Eight items were rated on a 0 to 2 scale (items 4, 5, 6, 12, 13, 14, 16 and 17), while nine items (items 1, 2, 3, 7, 8, 9, 10, 11, and 15) were rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 was the “best” rating and the highest score (2 or 4) was the “worst” rating. The possible total scores were from 0 to 52. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Baseline and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	222	220	213
Units: Units on a scale
least squares mean (standard error)	-5.47 ( 0.36 )	-6.14 ( 0.36 )	-4.8 ( 0.37 )

Statistical analysis 1 at Week 14

Statistical analysis description

The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B. The last observation carried forward (LOCF) method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1732 ^[3]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.67

Confidence interval

level

95%

sides

2-sided

lower limit

-1.63

upper limit

0.29

Notes
[3] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariates

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

433

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0066 ^[4]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.34

Confidence interval

level

95%

sides

2-sided

lower limit

-2.31

upper limit

-0.37

Notes
[4] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariates

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-D17 Total Score for the Efficacy Sample Set per final protocol

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-D17 Total Score for the Efficacy Sample Set per final protocol

End point description

The HAM-D17 was utilized as a secondary assessment of a participants level of depression. The HAM-D (17-Item) consisted of 17 items. Eight items were rated on a 0 to 2 scale (items 4, 5, 6, 12, 13, 14, 16 and 17), while nine items (items 1, 2, 3, 7, 8, 9, 10, 11, and 15) were rated on a 0 to 4 scale (twice the weight of the other items). For all of these items, 0 was the “best” rating and the highest score (2 or 4) was the “worst” rating. The possible total scores were from 0 to 52. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Baseline and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	208	207	198
Units: Units on a scale
least squares mean (standard error)	-5.36 ( 0.37 )	-6.26 ( 0.38 )	-4.57 ( 0.39 )

Statistical analysis 1 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

406

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1226 ^[5]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.78

Confidence interval

level

95%

sides

2-sided

lower limit

-1.78

upper limit

0.21

Notes
[5] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariates

Statistical analysis 2 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

405

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[6]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.69

Confidence interval

level

95%

sides

2-sided

lower limit

-2.69

upper limit

-0.68

Notes
[6] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariates

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Hamilton Anxiety Rating Scale (HAM-A) Total Score for the Efficacy Sample Set

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Hamilton Anxiety Rating Scale (HAM-A) Total Score for the Efficacy Sample Set

End point description

The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the “best” rating and 4 is the “worst” rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	220	216	210
Units: Units on a scale
least squares mean (standard error)	-3.43 ( 0.31 )	-3.89 ( 0.31 )	-3.33 ( 0.32 )

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

430

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8164 ^[7]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

0.73

Notes
[7] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariates

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

426

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1939 ^[8]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-1.39

upper limit

0.28

Notes
[8] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariate

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-A Total for the Efficacy Sample per final protocol

Top of page

End point title

Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-A Total for the Efficacy Sample per final protocol

End point description

The HAM-A is utilized for the evaluation of anxiety symptoms. The HAM-A consists of 14 items. Each item is rated on a 0 to 4 scale. For all of these items, 0 is the “best” rating and 4 is the “worst” rating. If no item scores are missing, then the HAM-A total score is the sum of all 14 item scores. The possible total scores are from 0 to 56. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Baseline and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	206	204	195
Units: Units on a scale
least squares mean (standard error)	-3.35 ( 0.32 )	-3.96 ( 0.33 )	-3.07 ( 0.33 )

Statistical analysis 1 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

401

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5192 ^[9]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-1.14

upper limit

0.57

Notes
[9] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariates

Statistical analysis 2 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

399

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0443 ^[10]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.88

Confidence interval

level

95%

sides

2-sided

lower limit

-1.75

upper limit

-0.02

Notes
[10] - ANCOVA model, with treatment as main effects, study centre and Week 8 value as covariates

Secondary: Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample Set

Top of page

End point title

Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample Set

End point description

The efficacy of study medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Units on a scale
arithmetic mean (standard deviation)
Week 9 (N= 222, 221, 214)	3.36 ( 0.68 )	3.4 ( 0.75 )	3.51 ( 0.67 )
Week 10 (N= 225, 226, 218)	3.08 ( 0.85 )	3.09 ( 0.85 )	3.34 ( 0.85 )
Week 11 (N= 225, 226, 218)	2.91 ( 0.82 )	2.99 ( 0.89 )	3.17 ( 0.88 )
Week 12 (N= 225, 226, 218)	2.78 ( 0.87 )	2.81 ( 0.95 )	3.02 ( 0.95 )
Week 13 (N= 225, 226, 218)	2.72 ( 0.87 )	2.73 ( 1.01 )	2.97 ( 1 )
Week 14 (N= 225, 226, 218)	2.69 ( 0.89 )	2.66 ( 1.1 )	2.85 ( 1.01 )

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0248 ^[11]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

-0.02

Notes
[11] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1334 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

0.03

Notes
[12] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center.

Statisitcal analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0009 ^[13]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

-0.11

Notes
[13] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center.

Statisitcal analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0019 ^[14]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

-0.09

Notes
[14] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0009 ^[15]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

-0.11

Notes
[15] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center

Statisitcal analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0254 ^[16]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.34

upper limit

-0.02

Notes
[16] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center.

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0035 ^[17]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

-0.08

Notes
[17] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0152 ^[18]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.39

upper limit

-0.04

Notes
[18] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center.

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[19]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

-0.08

Notes
[19] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center.

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013 ^[20]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

-0.05

Notes
[20] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center.

Statisitical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0755 ^[21]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.33

upper limit

0.02

Notes
[21] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0527 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.39

upper limit

Notes
[22] - P-value and treatment difference (CI) are derived from CMH row mean scores statistics controlling for study center

Secondary: Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample per final protocol

Top of page

End point title

Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample per final protocol

End point description

The efficacy of study medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Units on a scale
arithmetic mean (standard deviation)
Week 9 (N=208, 210, 199)	3.39 ( 0.65 )	3.42 ( 0.74 )	3.54 ( 0.65 )
Week 10 (N=211, 213, 203)	3.1 ( 0.82 )	3.08 ( 0.84 )	3.35 ( 0.84 )
Week 11 (N=211, 213, 203)	2.93 ( 0.8 )	2.99 ( 0.89 )	3.19 ( 0.86 )
Week 12 (N=211, 213, 203)	2.8 ( 0.86 )	2.81 ( 0.94 )	3.06 ( 0.94 )
Week 13 (N=211, 213, 203)	2.75 ( 0.86 )	2.72 ( 1 )	3.01 ( 0.96 )
Week 14 (N=211, 213, 203)	2.71 ( 0.88 )	2.65 ( 1.09 )	2.9 ( 0.99 )

Statistical analysis 1 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0275 ^[23]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

-0.01

Notes
[23] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statisitcal analysis 2 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1583 ^[24]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

0.04

Notes
[24] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 1 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0021 ^[25]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

-0.09

Notes
[25] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 2 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0018 ^[26]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

-0.09

Notes
[26] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 1 at Week 11

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0011 ^[27]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

-0.11

Notes
[27] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 1 at Week 12

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0021 ^[28]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

-0.1

Notes
[28] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 2 at Week 12

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0111 ^[29]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.24

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

-0.05

Notes
[29] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 1 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

-0.09

Statistical analysis 2 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0046 ^[30]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

-0.09

Notes
[30] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 1 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0237 ^[31]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.39

upper limit

-0.03

Notes
[31] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 2 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0171 ^[32]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

-0.04

Notes
[32] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Statistical analysis 2 at Week 11

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0235 ^[33]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.36

upper limit

-0.03

Notes
[33] - P-value and treatment difference (CI) are derived from Cochran-Mantel-Haenszel (CMH) row mean scores statistics controlling for study center.

Secondary: Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set.

Top of page

End point title

Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set.

End point description

MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	222	221	214
Units: Percentage of participants
number (not applicable)
Week 9 (N= 222, 221, 214)	4.5	0.45	2.8
Week 10 (N= 225, 226, 218)	10.2	6.19	5.05
Week 11 (N= 225, 226, 218)	13.3	10.6	8.72
Week 12 (N= 225, 226, 218)	16.9	15.5	10.1
Week 13 (N= 225, 226, 218)	18.2	18.6	15.6
Week 14 (N= 225, 226, 218)	23.1	22.1	15.1

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5279

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

3.68

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0141

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.94

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0484

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

1.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

3.72

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5813

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

2.5

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1236

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.51

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

2.54

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4998

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

2.1

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0365

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.64

Confidence interval

level

95%

sides

2-sided

lower limit

1.03

upper limit

2.61

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0822

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

2.43

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4049

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.78

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2951

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.8

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0248

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.53

Confidence interval

level

95%

sides

2-sided

lower limit

1.06

upper limit

2.2

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0326

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.51

Confidence interval

level

95%

sides

2-sided

lower limit

1.03

upper limit

2.21

Secondary: Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

Top of page

End point title

Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

End point description

MADRS response was defined as >=50 percent reduction in MADRS Total Score from end of Phase A (Week 8). All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Percentage of participants
number (not applicable)
Week 9 (N=208, 210, 199)	3.37	0.48	3.02
Week 10 (N=211, 213, 203)	7.58	6.1	4.93
Week 11 (N=211, 213, 203)	13.3	11.3	8.37
Week 12 (N=211, 213, 203)	16.6	16.4	10.3
Week 13 (N=211, 213, 203)	18	19.2	14.3
Week 14 (N=211, 213, 203)	23.2	23	14.3

Statistical analysis 1 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7993

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

2.55

Statistical analysis 2 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0118

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.93

Statistical analysis 1 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2825

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

3.16

Statistical analysis 2 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6375

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.58

upper limit

2.5

Statistical analysis 1 at Week 11

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0923

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

2.82

Statistical analysis 2 at Week 11

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3812

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

2.3

Statistical analysis 1 at Week 12

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0464

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.63

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

2.65

Statistical analysis 2 at Week 12

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.049

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

1.62

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

2.64

Statistical analysis 1 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2124

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

2.06

Statistical analysis 2 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1078

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

2.14

Statistical analysis 1 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0094

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.69

Confidence interval

level

95%

sides

2-sided

lower limit

1.14

upper limit

2.5

Statistical analysis 2 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0162

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

1.09

upper limit

2.5

Secondary: Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample Set.

Top of page

End point title

Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample Set.

End point description

MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	222	221	214
Units: Percentage of participants
number (not applicable)
Week 9 (N= 222, 221, 214)	3.15	0.45	2.8
Week 10 (N= 225, 226, 218)	4	2.65	4.13
Week 11 (N= 225, 226, 218)	8.44	6.19	5.5
Week 12 (N= 225, 226, 218)	11.1	8.85	5.96
Week 13 (N= 225, 226, 218)	10.7	12.8	9.17
Week 14 (N= 225, 226, 218)	15.1	13.7	11.9

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9498

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.37

upper limit

2.9

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0141

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.94

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8609

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

2.17

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2846

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.22

upper limit

1.54

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.248

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

2.99

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7513

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

2.37

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0554

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.99

upper limit

3.35

Statisitcal analysis 2 ar Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2409

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.48

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

2.87

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5538

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

2.02

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1743

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.44

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

2.41

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

436

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2843

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

2.07

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

435

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.464

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

1.92

Secondary: Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample per final protocol

Top of page

End point title

Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample per final protocol

End point description

MADRS remission was defined as a < or equal to 10 and > or equal to 50% reduction in MADRS Total Score from end of Phase A (Week 8). All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Percentage of participants
number (not applicable)
Week 9 (N=208, 210, 199)	1.92	0.48	3.02
Week 10 (N=211, 213, 203)	2.37	2.82	3.94
Week 11 (N=211, 213, 203)	8.06	6.57	5.42
Week 12 (N=211, 213, 203)	10.4	9.39	6.4
Week 13 (N=211, 213, 203)	9.95	13.1	8.37
Week 14 (N=211, 213, 203)	14.7	14.1	10.8

Statistical analysis 1 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3867

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

1.97

Statistical analysis 2 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0118

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.93

Statistical analysis 1 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.32

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

1.66

Statistical analysis 2 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3266

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

1.62

Statistical analysis 1 at Week 11

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3027

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

3.1

Statistical analysis 2 at Week 11

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.696

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

2.52

Statistical analysis 1 at Week 12

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1368

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.62

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

3.07

Statistical analysis 2 at Week 12

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2387

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.48

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

2.89

Statistical analysis 1 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4498

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

2.28

Statistical analysis 2 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1009

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

2.82

Statistical analysis 1 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1499

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.45

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

2.41

Statistical analysis 2 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3012

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of remission rate

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

2.18

Secondary: Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set

Top of page

End point title

Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set

End point description

A CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved). The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Percentage of participants
number (not applicable)
Week 9 (N= 222, 221, 214)	9.46	10.4	6.54
Week 10 (N= 225, 226, 218)	23.6	23	13.3
Week 11 (N= 225, 226, 218)	28.4	30.1	21.6
Week 12 (N= 225, 226, 218)	35.1	38.1	29.4
Week 13 (N= 225, 226, 218)	40	43.4	28.9
Week 14 (N= 225, 226, 218)	41.8	47.8	36.7

Statistical analysis 1 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2873

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

2.65

Statistical analysis 2 at Week 9

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2677

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

2.36

Statistical analysis 1 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0031

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.21

upper limit

2.68

Statistical analysis 2 at Week 10

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0066

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.15

upper limit

2.5

Statistical analysis 1 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0665

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.83

Statistical analysis 2 at Week 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

1.05

upper limit

1.91

Statistical analysis 1 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2224

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.54

Statistical analysis 2 at Week 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0369

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

1.68

Statistical analysis 1 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0179

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

1.05

upper limit

1.75

Statistical analysis 2 at Week 13

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0011

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.49

Confidence interval

level

95%

sides

2-sided

lower limit

1.17

upper limit

1.89

Statistical analysis 1 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3249

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.41

Statistical analysis 2 at Week 14

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0122

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

1.06

upper limit

1.66

Secondary: Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

Top of page

End point title

Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

End point description

A CGI-I response was defined as a CGI-I score of 1 (very much improved) or 2 (much improved). All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3.

End point type

Secondary

End point timeframe

Week 8 to Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Percentage of participants
number (not applicable)
Week 9 (N=208, 210, 199)	7.69	9.52	5.53
Week 10 (N=211, 213, 203)	21.8	23	12.3
Week 11 (N=211, 213, 203)	27.5	30	19.7
Week 12 (N=211, 213, 203)	34.1	38	27.6
Week 13 (N=211, 213, 203)	38.9	44.1	27.1
Week 14 (N=211, 213, 203)	41.2	48.4	34

Statistical analysis 1 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5836

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

2.49

Statistical analysis 2 at Week 9

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3792

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

2.37

Statistical analysis 1 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0101

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.77

Confidence interval

level

95%

sides

2-sided

lower limit

1.14

upper limit

2.74

Statistical analysis 2 at Week 10

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0065

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.75

Confidence interval

level

95%

sides

2-sided

lower limit

1.17

upper limit

2.63

Statistical analysis 1 at Week 11

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0526

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.41

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.99

Statistical analysis 2 at Week 11

Statistical analysis description

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

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0156

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.51

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

2.11

Statistical analysis 1 at Week 12

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1689

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

1.63

Statistical analysis 2 at Week 12

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0231

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

1.8

Statistical analysis 1 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0175

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.06

upper limit

1.84

Statistical analysis 2 at Week 13

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

1.22

upper limit

2.07

Statistical analysis 1 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1396

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.55

Statistical analysis 2 at Week 14

Statistical analysis description

All participants in the Efficacy Sample who met the revised randomization criteria for incomplete response as defined in Protocol Amendment 3. The LOCF method was used to impute missing data.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016

Method

Cochran-Mantel-Haenszel

Parameter type

Ratio of response rate

Point estimate

1.46

Confidence interval

level

95%

sides

2-sided

lower limit

1.15

upper limit

1.86

Secondary: Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set

Top of page

End point title

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

End point description

The SDS is a self-rated instrument used to measure the effect of the patient’s symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable. The Efficacy Sample Set included all participants who had received at least one dose of study treatment and had both an end of Phase A (Week 8) value and at least 1 post randomization efficacy evaluation for MADRS Total Score in Phase B.

End point type

Secondary

End point timeframe

Week 11 and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	225	226	218
Units: Units on a scale
least squares mean (standard error)
Work/school: Week 11	-1 ( 0.16 )	-0.18 ( 0.18 )	-0.55 ( 0.15 )
Work/school: Week 14	-1.16 ( 0.17 )	-0.91 ( 0.18 )	-0.73 ( 0.17 )
Social life: Week 11	-1.13 ( 0.14 )	-0.76 ( 0.14 )	-0.72 ( 0.14 )
Social life: Week 14	-1.39 ( 0.15 )	-1.31 ( 0.15 )	-0.91 ( 0.15 )
Family life: Week 11	-1.14 ( 0.14 )	-0.74 ( 0.14 )	-0.51 ( 0.12 )
Family life: Week 14	-1.35 ( 0.15 )	-1.28 ( 0.16 )	-0.8 ( 0.15 )

Statistical analysis 1

Statistical analysis description

For Item: Work/School: Week 11. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0377

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

-0.03

Statistical analysis 2

Statistical analysis description

For Item: Work/School: Week 14 . The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0741

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-0.91

upper limit

0.04

Statistical analysis 3

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0966

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.81

Statistical analysis 4

Statistical analysis description

For Item: Work/School: Week 14. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4774

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.66

upper limit

0.31

Statistical analysis 5

Statistical analysis description

Social life: Week 11. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0263

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

-0.05

Statistical analysis 6

Statistical analysis description

Social life: Week 14. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0214

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

-0.07

Statistical analysis 7

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8281

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

0.32

Statistical analysis 8

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.054

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

0.01

Statistical analysis 9

Statistical analysis description

Family life: Week 11. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.63

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

-0.26

Statistical analysis 10

Statistical analysis description

Family life: Week 14. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

443

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0093

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-0.97

upper limit

-0.14

Statistical analysis 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2182

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

-0.14

Statistical analysis 12

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0256

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.06

Secondary: Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set Per Final Protocol

Top of page

End point title

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

End point description

The SDS is a self-rated instrument used to measure the effect of the patient’s symptoms on work/school, social life, and family/home responsibilities. For each of the three items, scores range from 0 through 10. The number most representative of how much each area was disrupted by symptoms is marked along the line from 0 = not at all, to 10 = extremely. For the work/school item, no response was to be entered if the patient did not work or go to school for reasons unrelated to the disorder and a response therefore not being applicable. The Mean SDS Score will be calculated over the three item scores. All three item scores need to be available with the exception of the work/school item score when this item is not applicable. All participants in the efficacy sample who met the revised randomization criteria for incomplete response as defined in protocol amendment 3.

End point type

Secondary

End point timeframe

Week 11 and Week 14

End point values	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Number of subjects analysed	211	213	203
Units: Units on a scale
least squares mean (standard error)
Work/school: Week 11	-1.01 ( 0.18 )	-0.2 ( 0.2 )	-0.48 ( 0.19 )
Work/school: Week 14	-1.11 ( 0.2 )	-0.93 ( 0.21 )	-0.65 ( 0.2 )
Social life: Week 11	-1.11 ( 0.15 )	-0.82 ( 0.15 )	-0.68 ( 0.15 )
Social life: Week 14	-1.34 ( 0.16 )	-1.37 ( 0.16 )	-0.88 ( 0.17 )
Family life: Week 11	-1.17 ( 0.14 )	-0.89 ( 0.15 )	-0.54 ( 0.15 )
Family life: Week 14	-1.32 ( 0.16 )	-1.39 ( 0.16 )	-0.81 ( 0.16 )

Statistical Analysis 1

Statistical analysis description

Work/school: Week 11. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0341

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

-0.04

Statistical Analysis 2

Statistical analysis description

School/work: Week 14. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0816

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

0.06

Statistical Analysis 3

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2561

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.21

upper limit

0.78

Statistical Analysis 4

Statistical analysis description

Work/school: Week 14. The analysis was performed on the Efficacy Sample by fitting a MMRM analysis with an unstructured variance covariance structure, in which the change from the end of Phase A (Week 8) in MADRS Total Score (at Weeks 9 to 14) was the dependent variable. The model included terms for treatment, trial site, visit week, interaction term of treatment by visit week, and interaction term of baseline-by-visit.

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2561

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

0.06

Statistical Analysis 5

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0331

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-0.82

upper limit

-0.03

Statistical Analysis 6

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0352

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.03

Statistical Analysis 7

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.486

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

0.25

Statistical Analysis 8

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0282

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

-0.05

Statistical Analysis 9

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

-0.24

Statistical Analysis 10

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0186

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-0.94

upper limit

-0.09

Statistical Analysis 11

Statistical analysis description

Comparison groups

Brexpiprazole (3mg) + ADT v Placebo +ADT

Number of subjects included in analysis

416

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0824

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-0.73

upper limit

0.04

Statistical Analysis 12

Statistical analysis description

Comparison groups

Brexpiprazole (1mg) + ADT v Placebo +ADT

Number of subjects included in analysis

414

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0077

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-1.02

upper limit

-0.16

Adverse events

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Timeframe for reporting adverse events

AEs were captured from randomization to double-blind treatment at Week 8, throughout the 6 week double blind phase to Follow-up 30 (+ 2) days after last dose of study medication.

Adverse event reporting additional description

Safety sample comprised of randomized participants in Phase B who received at least one dose of double-blind trial medication. Participants were excluded only if there was evidence that the participant did not take trial medication. If a participant was dispensed trial medication and is lost to follow-up that participant was considered exposed.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Brexpiprazole (1mg) + ADT

Reporting group description

Participants were administered brexpiprazole (1mg/day) as an adjunctive therapy to an assigned open label ADT.

Reporting group title

Brexpiprazole (3mg) + ADT

Reporting group description

Participants were administered brexpiprazole 3mg/day as an adjunctive therapy to an assigned open-label ADT.

Reporting group title

Placebo +ADT

Reporting group description

Participants were administered placebo daily as an adjunctive therapy to an open label ADT.

Serious adverse events	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 226 (0.44%)	1 / 229 (0.44%)	0 / 220 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 226 (0.00%)	1 / 229 (0.44%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 226 (0.44%)	0 / 229 (0.00%)	0 / 220 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Brexpiprazole (1mg) + ADT	Brexpiprazole (3mg) + ADT	Placebo +ADT
Total subjects affected by non serious adverse events
subjects affected / exposed	63 / 226 (27.88%)	72 / 229 (31.44%)	29 / 220 (13.18%)
Investigations
Weight increased
subjects affected / exposed	15 / 226 (6.64%)	13 / 229 (5.68%)	2 / 220 (0.91%)
occurrences all number	15	13	2
Nervous system disorders
Akathisia
subjects affected / exposed	10 / 226 (4.42%)	31 / 229 (13.54%)	5 / 220 (2.27%)
occurrences all number	10	35	5
Headache
subjects affected / exposed	21 / 226 (9.29%)	14 / 229 (6.11%)	17 / 220 (7.73%)
occurrences all number	24	18	21
Somnolence
subjects affected / exposed	9 / 226 (3.98%)	13 / 229 (5.68%)	1 / 220 (0.45%)
occurrences all number	9	15	1
Tremor
subjects affected / exposed	9 / 226 (3.98%)	12 / 229 (5.24%)	7 / 220 (3.18%)
occurrences all number	15	16	11
Infections and infestations
Nasopharyngitis
subjects affected / exposed	15 / 226 (6.64%)	7 / 229 (3.06%)	4 / 220 (1.82%)
occurrences all number	15	9	4

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

27 May 2011

Changed history of inadequate response from “3 or fewer adequate antidepressant treatments” to “at least 1 and no more than 3 adequate antidepressant treatments.”; clarified instructions for preparation of whole blood sample for metabolic profiling; made administrative changes and corrected typographical errors.

08 Nov 2011

Clarified dosing of duloxetine to allow participants to titrate from 30 to 40 mg/day rather than forcing titration from 30 to 60 mg/day; specified that participants taking desvenlafaxine at screening should not be assigned to venlafaxine XR in Phase A; clarified requirements for collection of pharmacogenomic sample to indicate that a sample was not required from participants who withdrew during Phase A. In the protocol, clarified rules for ADT dose adjustment at Week 8 (ie, no change for participants entering Phase B, adjustments permitted for participants entering Phase A+); clarified that the serum pregnancy test was the definitive test for determining pregnancy, irrespective of urine pregnancy test result; added language to the prohibited therapies section to indicate that participants who received electroconvulsive for the current major depressive episode were excluded from the trial; Clarified that participants who were sterile (ie, women who had an oophorectomy and/or hysterectomy or had been postmenopausal for at least 12 consecutive months; or men who had orchidectomy) were not required to use two different methods of birth control; per posting from Food and Drug Administration, added linezolid and methylene blue to list of drugs that could result in serotonin syndrome if co-administered with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitor; made administrative changes.

23 Mar 2012

Revised statistical method in response to regulatory feedback; based on the review of completed phase 2 data, revised randomization criteria into Phase B, and trial procedures to increase the precision in the estimation of treatment effects: In the original protocol, the primary efficacy analysis used an analysis of covariance (ANCOVA) model based on the last observation carried forward (LOCF) dataset. The mixed models repeated measures (MMRM) model was included as a sensitivity analysis. Based on feedback from the FDA, the primary analysis method was changed to the MMRM model, with the ANCOVA LOCF used as the sensitivity analysis; Score-based criteria for determination of incomplete response for entry into Phase B were amended to better define incomplete responders as those participants who did not show a response at any visit during the single-blind prospective Phase A. Whereas before Protocol Amendment 3 response was assessed only at Week 8, after Protocol Amendment 3 participants who met response criteria at any time during Phase A were excluded from randomization. This change resulted from review of the data from the completed phase 2 trials (331-08-211 and 331-09-222). In addition, the criteria for response and incomplete response were removed from the main protocol to an addendum so that investigators and raters would be blinded to the randomization criteria in order to minimize potential rater inflation of efficacy scale scores. Eligibility for randomization was confirmed by the medical surveillance team from INC Research and/or through preprogrammed calculations made by the Interactive Voice/Web Recognition System using the prospectively defined score-based criteria. No new visits or assessments were added to the conduct of the trial as a result of this amendment. Therefore, the blinded changes to the randomization criteria did not pose any additional risk to trial participants.

23 Mar 2012

The investigator retained the option not to randomize any participant who met criteria for score-based eligibility, but who, in the investigator’s judgment, should not have been randomized due to safety concerns or other reasons; in order to ensure a more even distribution of ADTs across the participant population, individual sites were not permitted to assign more than 2 out of every 6 participants at a site to any one ADT without permission of the medical monitor; item 32 of the exclusion criteria was clarified to exclude any participant who, in the opinion of the investigator or medical monitor, should not participate in the trial; due to the changes implemented in Amendment 3, the number of participants screened and enrolled into Phase A and randomized into Phase B was increased and the enrollment period and overall trial duration were extended 3 months to allow for enrollment of the additional participants in Phase A. The number of sites was reduced from 90 to 63 to minimize variability introduced by inclusion of multiple sites; made administrative changes.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults with Major Depressive Disorder, the Polaris Trial.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean change from the end of Phase A (Week 8 visit) to Phase B (Week 14 visit) in the Montgomery-Asberg Depression Rating Scale for the Efficacy Sample Set

Primary: Mean change from the end of Phase A (Week 8 visit) to Phase B (Week 14 visit) in the Montgomery-Asberg Depression Rating Scale for the Efficacy Sample Set

Primary: Mean Change in MADRS Total Score from Baseline End of Week 8 to Week 14 for the Efficacy Sample per final protocol

Primary: Mean Change in MADRS Total Score from Baseline End of Week 8 to Week 14 for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Sheehan Disability Scale (SDS) Mean Scores for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Sheehan Disability Scale (SDS) Mean Scores for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in SDS Mean Scores for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in SDS Mean Scores for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample Set

Secondary: Mean Change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample per final protocol

Secondary: Mean Change from end of Phase A (Week 8 visit) in MADRS Total Score for every Study Week visit in Phase B other than Week 14 visit for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B in Clinical Global Impression Severity of Illness (CGI-S) for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B in Clinical Global Impression Severity of Illness (CGI-S) for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B Week in Clinical CGI-S for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to every study week visit in Phase B Week in Clinical CGI-S for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in Inventory of Depressive Symptomatology (Self-Report) IDS-SR Total Score for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in Inventory of Depressive Symptomatology (Self-Report) IDS-SR Total Score for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in IDS-SR Total Score for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) for every study week visit in Phase B in IDS-SR Total Score for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) Hamilton Depression Scale 17 Item Version (HAM)-D17 Total Score for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) Hamilton Depression Scale 17 Item Version (HAM)-D17 Total Score for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-D17 Total Score for the Efficacy Sample Set per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-D17 Total Score for the Efficacy Sample Set per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Hamilton Anxiety Rating Scale (HAM-A) Total Score for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in Hamilton Anxiety Rating Scale (HAM-A) Total Score for the Efficacy Sample Set

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-A Total for the Efficacy Sample per final protocol

Secondary: Mean change from end of Phase A (Week 8 visit) to end of Phase B (Week 14 visit) in HAM-A Total for the Efficacy Sample per final protocol

Secondary: Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample Set

Secondary: Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample Set

Secondary: Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample per final protocol

Secondary: Mean CGI-I Score at each trial week visit in Phase B for the Efficacy Sample per final protocol

Secondary: Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set.

Secondary: Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set.

Secondary: Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

Secondary: Percentage of participants with a MADRS response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

Secondary: Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample Set.

Secondary: Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample Set.

Secondary: Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample per final protocol

Secondary: Percentage of participants with a MADRS Remission during Phase B relative to the end of Phase A (Week 8) for the Efficacy Sample per final protocol

Secondary: Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set

Secondary: Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample Set

Secondary: Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

Secondary: Percentage of participants with a CGI-I response during Phase B relative to the end of Phase A (Week 8 visit) for the Efficacy Sample per final protocol

Secondary: Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set

Secondary: Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set

Secondary: Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set Per Final Protocol

Secondary: Change From Baseline (End of Phase A [Week 8]) in SDS Item Scores for the Efficacy Sample Set Per Final Protocol

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults with Major Depressive Disorder, the Polaris Trial.