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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Brexpiprazole as Adjunctive Therapy in the Maintenance Treatment of Adults With Major Depressive Disorder

    Summary
    EudraCT number
    		 2018-000601-22
    Trial protocol
    		 DE   PL  
    Global end of trial date
    29 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Nov 2023
    First version publication date
    01 Nov 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    331-201-00079
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03538691
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, 20850
    Public contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 609 524-6788, clinicaltransparency@otsuka-us.com
    Scientific contact
    Global Clinical Development , Otsuka Pharmaceutical Development & Commercialization, Inc., +1 609 524-6788, clinicaltransparency@otsuka-us.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to compare the efficacy of brexpiprazole (2 to 3 milligrams per day [mg/day]) to placebo as adjunctive therapy to antidepressant therapy (ADT) for the maintenance treatment in subjects with major depressive disorder (MDD).
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 251
    Country: Number of subjects enrolled
    Germany: 88
    Country: Number of subjects enrolled
    United States: 810
    Worldwide total number of subjects
    1149
    EEA total number of subjects
    339
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1141
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 1149 subjects with MDD participated in the study from 13 July 2018 to 29 July 2022.

    Pre-assignment
    Screening details
    		 Of the 1149 subjects enrolled in Phase A(Acute Treatment) of the trial,766 eligible subjects continued to Phase B (Stabilisation).Eligible subjects completing Phase B were randomised into Phase C(Double-blind Randomised Withdrawal) to receive brexpiprazole or placebo along with open-label antidepressant therapy (ADT) in 1:1 ratio for upto 26 weeks.

    Period 1
    Period 1 title
    Phase A: Acute Treatment (up to 8 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Phase A: Brexpiprazole + ADT
    Arm description
    		 Subjects received brexpiprazole 2 or 3 milligrams per day (mg/day) along with protocol-specified antidepressant therapy (ADT), orally, for 6 to 8 weeks during Phase A. Subjects were initially titrated to a target dose of brexpiprazole 2 mg over a 2 to 4-week period. Thereafter, subjects who had not met response criteria as defined in the blinded addendum, did not have potentially dose-related adverse events (AEs), and had not achieved the maximum dose of medication had their dose increased up to 3 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712, Rexulti
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole tablets 2 or 3 mg/day.

    Investigational medicinal product name
    Antidepressant therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Protocol-specified oral ADTs included: citalopram hydrobromide (Celexa®) tablets, escitalopram (Lexapro®) tablets, fluoxetine (Prozac®) capsules, paroxetine (Paxil CR®) controlled-release tablets, sertraline (Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release capsules, venlafaxine XR (Effexor XR®) extended-release (XR) capsules.

    Number of subjects in period 1
    		Phase A: Brexpiprazole + ADT
    Started
    1149
    Phase A Safety Sample
    1136
    Completed
    766
    Not completed
    383
         Physician decision
    1
         Adverse Event
    82
         Subject Withdrew Consent
    54
         Death
    1
         Not Specified:Not due to COVID-19 Restriction
    15
         Non-Compliance With Study Drug
    9
         Lost to follow-up
    24
         Lack of efficacy
    185
         Protocol deviation
    12
    Period 2
    Period 2 title
    Phase B: Stabilisation (12 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Phase B: Brexpiprazole + ADT
    Arm description
    		 Eligible subjects completing Phase A were enrolled in Phase B to receive brexpiprazole 2 or 3 mg/day along with protocol-specified ADT, orally, for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712, Rexulti
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole tablets 2 or 3 mg/day.

    Investigational medicinal product name
    Antidepressant therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Protocol-specified oral ADTs included: citalopram hydrobromide (Celexa®) tablets, escitalopram (Lexapro®) tablets, fluoxetine (Prozac®) capsules, paroxetine (Paxil CR®) controlled-release tablets, sertraline (Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release capsules, venlafaxine XR (Effexor XR®) extended-release (XR) capsules.

    Number of subjects in period 2
    		Phase B: Brexpiprazole + ADT
    Started
    766
    Phase B Safety Sample
    765
    Completed
    489
    Not completed
    277
         Physician decision
    6
         Adverse Event
    52
         Subject Withdrew Consent
    47
         Due to COVID-19 Restriction
    1
         Not Specified:Not due to COVID-19 Restriction
    11
         Non-Compliance With Study Drug
    9
         Pregnancy
    1
         Lost to follow-up
    5
         Lack of efficacy
    136
         Protocol deviation
    9
    Period 3
    Period 3 title
    Phase C:Randomised Withdrawal (26 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase C: Brexpiprazole + ADT
    Arm description
    		 Eligible subjects completing Phase B received brexpiprazole 2 or 3 mg/day (dose of brexpiprazole that they were receiving at Week 20 of the Stabilisation Phase) along with protocol-specified ADT, orally, for up to 26 weeks during Phase C.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712, Rexulti
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole tablets 2 or 3 mg/day.

    Investigational medicinal product name
    Antidepressant therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Protocol-specified oral ADTs included: citalopram hydrobromide (Celexa®) tablets, escitalopram (Lexapro®) tablets, fluoxetine (Prozac®) capsules, paroxetine (Paxil CR®) controlled-release tablets, sertraline (Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release capsules, venlafaxine XR (Effexor XR®) extended-release (XR) capsules.

    Arm title
    		 Phase C: Placebo + ADT
    Arm description
    		 Eligible subjects completing Phase B received brexpiprazole-matching placebo along with protocol-specified ADT, orally, for up to 26 weeks during Phase C.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole-matching placebo tablets.

    Investigational medicinal product name
    Antidepressant therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Protocol-specified oral ADTs included: citalopram hydrobromide (Celexa®) tablets, escitalopram (Lexapro®) tablets, fluoxetine (Prozac®) capsules, paroxetine (Paxil CR®) controlled-release tablets, sertraline (Zoloft®) tablets, duloxetine (Cymbalta®) delayed-release capsules, venlafaxine XR (Effexor XR®) extended-release (XR) capsules.

    Number of subjects in period 3
    		Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Started
    240
    249
    Phase C Safety Sample
    240
    248
    Completed
    120
    131
    Not completed
    120
    118
         Physician decision
    -
    1
         Adverse Event
    6
    6
         Subject Withdrew Consent
    6
    19
         Lack of Efficacy (Phase C MDD Relapse)
    54
    52
         Not Specified:Not due to COVID-19 Restriction
    4
    6
         Non-Compliance With Study Drug
    1
    2
         Non-compliant Subjects
    32
    28
         Pregnancy
    1
    -
         Lost to follow-up
    16
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase A: Brexpiprazole + ADT
    Reporting group description
    		 Subjects received brexpiprazole 2 or 3 milligrams per day (mg/day) along with protocol-specified antidepressant therapy (ADT), orally, for 6 to 8 weeks during Phase A. Subjects were initially titrated to a target dose of brexpiprazole 2 mg over a 2 to 4-week period. Thereafter, subjects who had not met response criteria as defined in the blinded addendum, did not have potentially dose-related adverse events (AEs), and had not achieved the maximum dose of medication had their dose increased up to 3 mg.

    Reporting group values
    		 Phase A: Brexpiprazole + ADT Total
    Number of subjects
    		 1149 1149
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.3 ( 13.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 734 734
        Male
    		 415 415
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 110 110
        Not Hispanic or Latino
    		 968 968
        Unknown or Not Reported
    		 71 71
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 5 5
        Asian
    		 22 22
        Native Hawaiian or Other Pacific Islander
    		 5 5
        Black or African American
    		 159 159
        White
    		 868 868
        More than one race
    		 0 0
        Unknown or Not Reported
    		 90 90

    End points

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    End points reporting groups
    Reporting group title
    Phase A: Brexpiprazole + ADT
    Reporting group description
    		 Subjects received brexpiprazole 2 or 3 milligrams per day (mg/day) along with protocol-specified antidepressant therapy (ADT), orally, for 6 to 8 weeks during Phase A. Subjects were initially titrated to a target dose of brexpiprazole 2 mg over a 2 to 4-week period. Thereafter, subjects who had not met response criteria as defined in the blinded addendum, did not have potentially dose-related adverse events (AEs), and had not achieved the maximum dose of medication had their dose increased up to 3 mg.
    Reporting group title
    Phase B: Brexpiprazole + ADT
    Reporting group description
    		 Eligible subjects completing Phase A were enrolled in Phase B to receive brexpiprazole 2 or 3 mg/day along with protocol-specified ADT, orally, for 12 weeks.
    Reporting group title
    Phase C: Brexpiprazole + ADT
    Reporting group description
    		 Eligible subjects completing Phase B received brexpiprazole 2 or 3 mg/day (dose of brexpiprazole that they were receiving at Week 20 of the Stabilisation Phase) along with protocol-specified ADT, orally, for up to 26 weeks during Phase C.

    Reporting group title
    Phase C: Placebo + ADT
    Reporting group description
    		 Eligible subjects completing Phase B received brexpiprazole-matching placebo along with protocol-specified ADT, orally, for up to 26 weeks during Phase C.

    Primary: Phase C: Time-to-Relapse by Any Criteria as Defined in Blinded Addendum

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    End point title
    		 Phase C: Time-to-Relapse by Any Criteria as Defined in Blinded Addendum
    End point description
    Relapse criteria:At same visit,increase in MADRS total score(10items,0=no symptoms to 6=severe symptoms)of 50% from randomisation and CGI-S(0=not assessed to 7=most extremely ill)score≥4,hospitalisation for depression,discontinuation for lack of efficacy/worsening of depression,active suicidality(score≥4 on MADRS item10 of suicidality)or ‘yes’ on question 4/5 of C-SSRS(Suicidal Ideation[SI] has 5 questions:wish to be dead,non-specific active suicidal thoughts,active SI with any methods[not plan]without intent to act,active SI with some intent to act without specific plan,active SI with specific plan,intent)or ‘yes’ to any question in suicidal behaviour(preparatory acts/behaviour,aborted attempt,interrupted attempt,actual attempt[non-fatal],completed suicide).PhaseC Efficacy Sample=all subjects randomised to double-blind treatment who had taken atleast 1dose of investigational medicinal product(IMP).Number of subjects analysed for median time to relapse=subjects with impending relapse.
    End point type
    Primary
    End point timeframe
    Up to 14 days post last dose in Phase C (up to 28 weeks)
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    54
    51
    Units: days
        median (full range (min-max))
    63.0 (8 to 185)
    63.0 (8 to 190)
    Statistical analysis title
    		 Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.51
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.138
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.776
         upper limit
    		 1.669
    Notes
    [1] - The hazard ratio and 95% confidence interval (CI) were derived from the Cox proportional hazard model with treatment as fixed effect.

    Secondary: Phase C: Change From Baseline for Randomisation Phase in Sheehan Disability Scale (SDS) Mean Total Score at Week 46

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    End point title
    		 Phase C: Change From Baseline for Randomisation Phase in Sheehan Disability Scale (SDS) Mean Total Score at Week 46
    End point description
    The SDS is a self-rated instrument used to measure the effect of the participant'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. The SDS total score is the mean of the 3 item responses. The SDS total score ranges from 0 to 10, with higher scores indicating greater functional impairment. Baseline was defined as the last available assessment value between Week 14 and Week 20 in Phase B for this outcome measure. Analysis of covariance (ANCOVA) model was used for analysis. Phase C Efficacy Sample included all subjects randomised to the double-blind treatment who had taken at least one dose of IMP in Phase C. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 46
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    239
    242
    Units: score on a scale
        least squares mean (standard error)
    0.72 ( 0.18 )
    0.48 ( 0.18 )
    Statistical analysis title
    		 Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2393 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.62
    Notes
    [2] - P-value was derived from an ANCOVA model with treatment, pooled centre as factor and Baseline value as covariance.

    Secondary: Phase C: Time-to-functional Relapse Based on SDS Criteria

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    End point title
    		 Phase C: Time-to-functional Relapse Based on SDS Criteria
    End point description
    Time-to-functional relapse was based on a 30% increase in the SDS mean total score from Phase C Baseline, at least one SDS sub-score at 4 or greater, and an SDS total score ≥7 when all 3 sub-scores were available. The SDS is a self-rated instrument used to measure the effect of the subject'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. Higher scores of 5 and above are associated with significant functional impairment. Phase C Efficacy Sample included all subjects randomised to the double-blind treatment who had taken at least one dose of IMP in Phase C. Number of subjects analysed for median time to functional relapse is the number of subjects with impending functional relapse.
    End point type
    Secondary
    End point timeframe
    Up to 14 days post last dose in Phase C (up to 28 weeks)
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    81
    73
    Units: days
        median (full range (min-max))
    36.0 (6 to 185)
    35.0 (8 to 176)
    Statistical analysis title
    		 Brexpiprazole + ADT vs Placebo + ADT
    Statistical analysis description
    The hazard ratio and 95% CI were derived from the Cox proportional hazard model with treatment as fixed effect.
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3086
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.857
         upper limit
    		 1.615

    Secondary: Phase C: Percentage of Subjects Meeting Any Relapse Criteria

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    End point title
    		 Phase C: Percentage of Subjects Meeting Any Relapse Criteria
    End point description
    Relapse criteria:50% increase in MADRS total score(10 items,7-point scale,0=no symptoms to 6=severe symptoms,total score=0-60) from randomisation and CGI-S(8-point scale,0=not assessed to 7=most extremely ill)score≥4, hospitalisation for depression,discontinuation for lack of efficacy/worsening of depression,active suicidality(score≥4 on MADRS item 10 of suicidality)or answer 'yes' on question 4/5 of C-SSRS(SI=5 questions:wish to be dead,non-specific active suicidal thoughts,active SI with any methods[not plan]without intent to act,active SI with some intent to act without specific plan,active SI with specific plan,intent)or answer 'yes' to any question in suicidal behaviour section(5 questions:preparatory acts/behaviour,aborted attempt,interrupted attempt,actual attempt[non-fatal],completed suicide).Percentage of subjects were rounded off to single decimal point.Phase C Efficacy Sample=all subjects randomised to double-blind treatment who had taken at least one IMP dose in Phase C.
    End point type
    Secondary
    End point timeframe
    Up to 26 weeks in Phase C
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    240
    248
    Units: percentage of subjects
        number (not applicable)
    22.5
    20.6
    Statistical analysis title
    		 Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.603
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Phase C: Percentage of Subjects Maintaining Remission

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    End point title
    		 Phase C: Percentage of Subjects Maintaining Remission
    End point description
    Subjects maintaining remission was defined as MADRS total score ≤10. The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Subjects were rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. Phase C Efficacy Sample included all subjects randomised to the double-blind treatment who had taken at least one dose of IMP in Phase C. Number of subjects analysed is the number of subjects with data available for analyses. 'n' is the number of subjects with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 21, 23, 25, 29, 33, 37, 41, 45, and 46
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    238
    242
    Units: percentage of subjects
    number (not applicable)
        Week 21 (n=238, 242)
    90.34
    91.3
        Week 23 (n=230, 237)
    85.22
    82.7
        Week 25 (n=217, 224)
    84.79
    82.6
        Week 29 (n=189, 200)
    79.89
    85.5
        Week 33 (n=166, 181)
    88.55
    88.4
        Week 37 (n=149, 164)
    87.92
    89.0
        Week 41 (n=138, 151)
    84.78
    89.4
        Week 45 (n=118, 127)
    88.14
    89.0
        Week 46 (n=121, 132)
    90.91
    91.7
    Statistical analysis title
    		 Week 21: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7081
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 23: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4589
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 25: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5314
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 29: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1433
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 33: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9636
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 37: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7596
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 41: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2402
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 45: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8363
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Week 46: Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8308
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Phase C: Change From Baseline for Randomisation Phase in MADRS Total Score at Week 46

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    End point title
    		 Phase C: Change From Baseline for Randomisation Phase in MADRS Total Score at Week 46
    End point description
    The MADRS is a clinician-rated scale to assess depressive symptomatology during the preceding week. Subjects were rated on 10 items (feelings of sadness, lassitude, pessimism, inner tension, suicidality, reduced sleep or appetite, difficulty concentrating, and a lack of interest) each on a 7-point scale from 0 (no symptoms) to 6 (symptoms of maximum severity). The total score ranges from 0 to 60 with a higher score indicating more depression. A positive change from Baseline indicates worsening of symptoms. Baseline was defined as the last available assessment value in Phase B for this outcome measure. ANCOVA model was used for analysis. Phase C Efficacy Sample included all subjects randomised to the double-blind treatment who had taken at least one dose of IMP in Phase C. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 46
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    240
    247
    Units: score on a scale
        least squares mean (standard error)
    4.09 ( 0.75 )
    4.21 ( 0.73 )
    Statistical analysis title
    		 Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8806 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 1.49
    Notes
    [3] - P-value was derived from an ANCOVA model with treatment, pooled centre as factor and Baseline value as covariance.

    Secondary: Phase C: Change From Baseline for Randomisation Phase in CGI-S Score at Week 46

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    End point title
    		 Phase C: Change From Baseline for Randomisation Phase in CGI-S Score at Week 46
    End point description
    The CGI -S was used to rate the severity of illness for each subject on an 8-point scale ranging from 0 to 7 where 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 subjects. A positive change from Baseline indicates worsening of illness. Baseline was defined as the last available assessment value in Phase B for this outcome measure. ANCOVA model was used for analysis. Phase C Efficacy Sample included all subjects randomised to the double-blind treatment who had taken at least one dose of IMP in Phase C. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 46
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    240
    247
    Units: score on a scale
        least squares mean (standard error)
    0.56 ( 0.10 )
    0.53 ( 0.09 )
    Statistical analysis title
    		 Brexpiprazole + ADT vs Placebo + ADT
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7956 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.24
    Notes
    [4] - P-value was derived from an ANCOVA model with treatment, pooled centre as factor and Baseline value as covariance.

    Secondary: Phase C: Change From Baseline for Randomisation Phase in Each of the SDS Individual Item Scores at Week 46

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    End point title
    		 Phase C: Change From Baseline for Randomisation Phase in Each of the SDS Individual Item Scores at Week 46
    End point description
    The SDS is a self-rated instrument used to measure the effect of the subject'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. Higher scores of 5 and above are associated with significant functional impairment. A positive change from Baseline indicates worsening of symptoms impacting each area. Baseline was defined as the last available assessment value between Week 14 and Week 20 in Phase B for this outcome measure. ANCOVA model was used for analysis. Phase C Efficacy Sample included all subjects randomised to the double-blind treatment who had taken at least one dose of IMP in Phase C. Number of subjects analysed is the number of subjects with data available for analyses. 'n' is the number of subjects with data available for analysis for the specified category.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 46
    End point values
    		 Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Number of subjects analysed
    239
    244
    Units: score on a scale
    least squares mean (standard error)
        Work/School (n=195, 197)
    0.46 ( 0.22 )
    0.31 ( 0.23 )
        Social Life (n=239, 244)
    0.91 ( 0.19 )
    0.56 ( 0.19 )
        Family Life (n=239, 242)
    0.78 ( 0.19 )
    0.52 ( 0.19 )
    Statistical analysis title
    		 SDS Individual Item: Work/School
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5223 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.61
    Notes
    [5] - P-value was derived from an ANCOVA model with treatment, pooled centre as factor and Baseline value as covariance.
    Statistical analysis title
    		 SDS Individual Item: Social Life
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0904 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.77
    Notes
    [6] - P-value was derived from an ANCOVA model with treatment, pooled centre as factor and Baseline value as covariance.
    Statistical analysis title
    		 SDS Individual Item: Family Life
    Comparison groups
    Phase C: Brexpiprazole + ADT v Phase C: Placebo + ADT
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2289 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.67
    Notes
    [7] - P-value was derived from an ANCOVA model with treatment, pooled centre as factor and Baseline value as covariance.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug to 21 days after the last dose (Up to 49 weeks)
    Adverse event reporting additional description
    All-cause Mortality: Enrolled Sample=all subjects who signed ICF; entered PhaseA. Serious; Other AEs: Phase A and B Safety Sample=all subjects who received at least 1 dose of brexpiprazole in Phase A and B respectively. Phase C Safety Sample=all subjects who were randomised to double-blind treatment and received at least one 1 IMP dose in Phase C.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Phase A: Brexpiprazole + ADT
    Reporting group description
    		 Subjects received brexpiprazole 2 or 3 mg/day along with protocol-specified ADT, orally, for 6 to 8 weeks during Phase A. Subjects were initially titrated to a target dose of brexpiprazole 2 mg over a 2 to 4-week period. Thereafter, subjects who had not met response criteria as defined in the blinded addendum, did not have potentially dose-related AEs, and had not achieved the maximum dose of medication had their dose increased up to 3 mg.

    Reporting group title
    Phase B: Brexpiprazole + ADT
    Reporting group description
    		 Eligible subjects completing Phase A were enrolled in Phase B to receive brexpiprazole 2 or 3 mg/day along with protocol-specified ADT, orally, for 12 weeks.

    Reporting group title
    Phase C: Brexpiprazole + ADT
    Reporting group description
    		 Eligible subjects completing Phase B received brexpiprazole 2 or 3 mg/day (dose of brexpiprazole that they were receiving at Week 20 of the Stabilisation Phase) along with protocol-specified ADT, orally, for up to 26 weeks during Phase C.

    Reporting group title
    Phase C: Placebo + ADT
    Reporting group description
    		 Eligible subjects completing Phase B received brexpiprazole-matching placebo along with protocol-specified ADT, orally, for up to 26 weeks during Phase C.

    Serious adverse events
    		 Phase A: Brexpiprazole + ADT Phase B: Brexpiprazole + ADT Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 1136 (0.88%)
    12 / 765 (1.57%)
    1 / 240 (0.42%)
    3 / 248 (1.21%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 1136 (0.00%)
    0 / 765 (0.00%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Dislocation of vertebra
         subjects affected / exposed
    0 / 1136 (0.00%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epicondylitis
         subjects affected / exposed
    0 / 1136 (0.00%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 1136 (0.00%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 1136 (0.00%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 1136 (0.00%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 1136 (0.09%)
    0 / 765 (0.00%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    0 / 1136 (0.00%)
    1 / 765 (0.13%)
    0 / 240 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase A: Brexpiprazole + ADT Phase B: Brexpiprazole + ADT Phase C: Brexpiprazole + ADT Phase C: Placebo + ADT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    423 / 1136 (37.24%)
    232 / 765 (30.33%)
    40 / 240 (16.67%)
    37 / 248 (14.92%)
    Investigations
    Weight increased
         subjects affected / exposed
    48 / 1136 (4.23%)
    122 / 765 (15.95%)
    25 / 240 (10.42%)
    13 / 248 (5.24%)
         occurrences all number
    51
    161
    45
    14
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    109 / 1136 (9.60%)
    33 / 765 (4.31%)
    4 / 240 (1.67%)
    3 / 248 (1.21%)
         occurrences all number
    109
    34
    4
    3
    Headache
         subjects affected / exposed
    113 / 1136 (9.95%)
    41 / 765 (5.36%)
    5 / 240 (2.08%)
    14 / 248 (5.65%)
         occurrences all number
    158
    55
    6
    18
    Somnolence
         subjects affected / exposed
    90 / 1136 (7.92%)
    37 / 765 (4.84%)
    6 / 240 (2.50%)
    3 / 248 (1.21%)
         occurrences all number
    94
    38
    6
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    64 / 1136 (5.63%)
    18 / 765 (2.35%)
    1 / 240 (0.42%)
    0 / 248 (0.00%)
         occurrences all number
    78
    20
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    72 / 1136 (6.34%)
    8 / 765 (1.05%)
    1 / 240 (0.42%)
    2 / 248 (0.81%)
         occurrences all number
    74
    8
    1
    2
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    60 / 1136 (5.28%)
    18 / 765 (2.35%)
    1 / 240 (0.42%)
    4 / 248 (1.61%)
         occurrences all number
    61
    20
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2018
    The following major changes were implemented based on Amendment 1: 1) Corrected EudraCT number.2) Updated trial design schematic noting Phase A Baseline Visit and corrected number of subjects planned to be enrolled in Phase A. 3) Aligned exclusion criteria for clinical laboratory values with other brexpiprazole protocols.4) Collection of pharmacogenomic sample was moved from baseline visit to Week 20/Randomisation visit.
    08 Jul 2020
    The following major changes were implemented based on Amendment 2: 1) Updated the names and contact information of Sponsor representatives. 2) Added trial conduct information after the title page to introduce the coronavirus disease (COVID-19) Addendum. 3) Incorporated the following items from the protocol clarification memo: a. Revised the following text: A QT Interval Corrected Using Fridericia's Formula (QTcF) ≥450 milliseconds (msec) for males and ≥470 msec for females at screening is exclusionary. b. Revised the following text: Based on the QTcF corrections reported by the central service, a subject will be excluded if the correction equals or exceeds 450 msec for males and 470 msec for females for 2 or more of the 3 time points of the electrocardiogram (ECGs) conducted.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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