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    Clinical Trial Results:
    Interventional, Randomised, Double-blind, Parallel-group, Placebo-controlled, Flexible-dose Long-term Study to Evaluate the Maintenance of Efficacy and Safety of 1 to 3 mg/Day of Brexpiprazole as Adjunctive Treatment in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment (ADT)

    Summary
    EudraCT number
    		 2012-001380-76
    Trial protocol
    		 EE   SE   FI   LT   GB   BG   IT   LV   PL  
    Global end of trial date
    08 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2017
    First version publication date
    24 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14570A ARGO
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01838681
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    H. Lundbeck A/S
    Sponsor organisation address
    Ottiliavej 9, Valby, Denmark, 2500
    Public contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S , +45 36301311, LundbeckClinicalTrials@lundbeck.com
    Scientific contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S , +45 36301311, LundbeckClinicalTrials@lundbeck.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
    08 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the maintenance of efficacy on depressive symptoms during long-term treatment of 1 to 3 mg once daily brexpiprazole versus placebo as adjunctive treatment to antidepressants in patients with an inadequate response to antidepressant treatment (ADT)
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and ICH Good Clinical Practice (1996)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2013
    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
    Bulgaria: 119
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    Estonia: 161
    Country: Number of subjects enrolled
    Finland: 136
    Country: Number of subjects enrolled
    Germany: 325
    Country: Number of subjects enrolled
    Latvia: 84
    Country: Number of subjects enrolled
    Lithuania: 76
    Country: Number of subjects enrolled
    Mexico: 72
    Country: Number of subjects enrolled
    Poland: 325
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Russian Federation: 121
    Country: Number of subjects enrolled
    Sweden: 85
    Country: Number of subjects enrolled
    Ukraine: 189
    Country: Number of subjects enrolled
    United Kingdom: 168
    Country: Number of subjects enrolled
    United States: 78
    Worldwide total number of subjects
    1986
    EEA total number of subjects
    1494
    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)
    1857
    From 65 to 84 years
    129
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

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

    Period 1
    Period 1 title
    Period A
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Period A, Placebo and ADT (8 weeks)
    Arm description
    		 Placebo adjunct to open label treatment with ATD.
    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
    One daily

    Number of subjects in period 1
    		Period A, Placebo and ADT (8 weeks)
    Started
    1986
    Completed
    1661
    Not completed
    325
         Early response
    148
         Consent withdrawn by subject
    70
         Adverse event, non-fatal
    39
         Administrative or other reason
    17
         Withdrawal before treatment
    4
         Lost to follow-up
    4
         Non-compliance with IMP
    6
         Protocol deviation
    16
         Lack of efficacy
    21
    Period 2
    Period 2 title
    Treatment period (Period B/A+)
    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
    		 Period B, Placebo and ADT (24 weeks randomised treatment)
    Arm description
    		 Placebo adjunct to open-label treatment with a commercially available antidepressant (ADT)
    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
    Once daily

    Arm title
    		 Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Arm description
    		 Brexpiprazole adjunct to ADT. 1, 2, or 3 mg/day, once daily dose. Uptitration in weekly steps from 1 mg/day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One daily. 1, 2, or 3 mg/day, once daily dose, tablets, orally. Uptitration in weekly steps from 1 mg/day

    Arm title
    		 Period A+, Placebo and ADT (Non-randomised Patients)
    Arm description
    		 Placebo adjunct to open label treatment with ATD.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.) Period A+, Placebo and ADT (Non-randomised Patients)
    Started
    442
    444
    770
    Completed
    380
    349
    653
    Not completed
    62
    95
    117
         Consent withdrawn by subject
    28
    35
    47
         Adverse event, non-fatal
    13
    27
    16
         Administrative or other reason
    6
    10
    28
         Withdrawal before treatment
    1
    -
    -
         Lost to follow-up
    2
    5
    11
         Non-compliance with IMP
    2
    3
    3
         Lack of efficacy
    9
    11
    6
         Protocol deviation
    1
    4
    6
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 5 patients completed Period A but never started in Period B/A+

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period A
    Reporting group description
    		 -

    Reporting group values
    		 Period A Total
    Number of subjects
    		 1986 1986
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 1857 1857
        From 65-84 years
    		 129 129
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.3 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    		 1402 1402
        Male
    		 584 584
    Race
    Units: Subjects
        Asian
    		 3 3
        Black or African American
    		 19 19
        White
    		 1918 1918
        Unknown or Not reported
    		 46 46

    End points

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    End points reporting groups
    Reporting group title
    Period A, Placebo and ADT (8 weeks)
    Reporting group description
    		 Placebo adjunct to open label treatment with ATD.
    Reporting group title
    Period B, Placebo and ADT (24 weeks randomised treatment)
    Reporting group description
    		 Placebo adjunct to open-label treatment with a commercially available antidepressant (ADT)

    Reporting group title
    Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Reporting group description
    		 Brexpiprazole adjunct to ADT. 1, 2, or 3 mg/day, once daily dose. Uptitration in weekly steps from 1 mg/day

    Reporting group title
    Period A+, Placebo and ADT (Non-randomised Patients)
    Reporting group description
    		 Placebo adjunct to open label treatment with ATD.

    Primary: Full remission during the randomised treatment period

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    End point title
    		 Full remission during the randomised treatment period
    End point description
    Full remission is defined as a Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment. The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.
    End point type
    Primary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    441
    444
    Units: Number
    110
    95
    Statistical analysis title
    		 Full remission during the rand. treatment period
    Comparison groups
    Period B, Placebo and ADT (24 weeks randomised treatment) v Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects included in analysis
    885
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2641 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.15
    Notes
    [1] - Model included MADRS total score at the randomisation visit, treatment group, country, and the randomisation criteria used

    Secondary: Full functional remission during the randomised treatment period

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    End point title
    		 Full functional remission during the randomised treatment period
    End point description
    Full functional remission is defined as a Sheehan Disability Scale (SDS) total score <=6 and all SDS domain scores <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    441
    444
    Units: Number
    73
    68
    No statistical analyses for this end point

    Secondary: Full global score remission during the randomised treatment period

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    End point title
    		 Full global score remission during the randomised treatment period
    End point description
    Full global score remission is defined as a Clinical Global Impression - Severity of Illness (CGI-S) score <=2 observed for at least 8 consecutive weeks during the randomised treatment period. The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis, on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    441
    444
    Units: Number
    143
    121
    No statistical analyses for this end point

    Secondary: Total time in remission during the randomised treatment period

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    End point title
    		 Total time in remission during the randomised treatment period
    End point description
    The total time the patient spends in remission during randomised treatment. Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score. Time in remission is defined as the sum of days over all periods between Period B visits where remission was obtained. The period between two visits is counted as in remission if the patient was in remission when the period started.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    441
    444
    Units: Number of days
        arithmetic mean (standard deviation)
    33.5 ± 46.1
    30 ± 44.3
    No statistical analyses for this end point

    Secondary: Time to full remission during the randomised treatment period

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    End point title
    		 Time to full remission during the randomised treatment period
    End point description
    The time from randomisation until full remission has been obtained. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment. The time to full remission was calculated using Kaplan-Meier Methods.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    441
    444
    Units: Days
    0
    0
    No statistical analyses for this end point

    Secondary: Full remission sustained during the randomised treatment period

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    End point title
    		 Full remission sustained during the randomised treatment period
    End point description
    Full remission sustained is defined as having obtained full remission and remain in remission until completion of the study. Full remission is defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    441
    444
    Units: Number
    105
    84
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 6 in MADRS total score during the randomised treatment period

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    End point title
    		 Change from randomisation to Week 6 in MADRS total score during the randomised treatment period
    End point description
    The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 Weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    422
    422
    Units: Units on a scale
        least squares mean (standard error)
    -5.9 ± 0.4
    -6.3 ± 0.4
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 24 in MADRS total score during the randomised treatment period

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    End point title
    		 Change from randomisation to Week 24 in MADRS total score during the randomised treatment period
    End point description
    The MADRS is a depression rating scale consisting of 10 items, each rated 0 to 6. The 10 items represent the core symptoms of depressive illness. The overall score ranges from 0 (symptoms absent) to 60 (severe depression). The MADRS total score is the sum of the 10 items.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    361
    333
    Units: Units on a scale
        least squares mean (standard error)
    -12.6 ± 0.6
    -11.5 ± 0.6
    No statistical analyses for this end point

    Secondary: Response at Week 6 During the Randomised Treatment Period

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    End point title
    		 Response at Week 6 During the Randomised Treatment Period
    End point description
    Response is defined as a >=50% decrease from randomisation in MADRS total score.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    440
    442
    Units: Number
    76
    82
    No statistical analyses for this end point

    Secondary: Response at Week 24 during the randomised treatment period

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    End point title
    		 Response at Week 24 during the randomised treatment period
    End point description
    Response is defined as a >=50% decrease from randomisation in MADRS total score.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    440
    442
    Units: Number
    236
    223
    No statistical analyses for this end point

    Secondary: Remission at Week 6 During the Randomised Treatment Period

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    End point title
    		 Remission at Week 6 During the Randomised Treatment Period
    End point description
    Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    440
    442
    Units: Number
    46
    53
    No statistical analyses for this end point

    Secondary: Remission at Week 24 in the randomised treatment period

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    End point title
    		 Remission at Week 24 in the randomised treatment period
    End point description
    Remission is defined as a MADRS total score <=10 and a >=50% decrease from randomisation in MADRS total score.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    440
    442
    Units: Number
    198
    176
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 6 in SDS total score during the randomised treatment period

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    End point title
    		 Change from randomisation to Week 6 in SDS total score during the randomised treatment period
    End point description
    The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    422
    421
    Units: Units on scale
        least squares mean (standard error)
    -3 ± 0.3
    -2.9 ± 0.3
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 24 in SDS total score during the randomised treatment period

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    End point title
    		 Change from randomisation to Week 24 in SDS total score during the randomised treatment period
    End point description
    The SDS assesses functional impairment in 3 domains: work/school, social life or leisure activities, and home life or family responsibilities. The participant rates the extent to which each aspect is impaired on a 10-point visual analog scale, from 0 (not at all) to 10 (extremely). The 3 scores are added together to calculate the total score, which ranges from 0 to 30, with higher scores indicating more impairment.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    361
    333
    Units: Unit on a scale
        least squares mean (standard error)
    -6.7 ± 0.5
    -5.5 ± 0.5
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 6 in CGI-S score during the randomised treatment period

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    End point title
    		 Change from randomisation to Week 6 in CGI-S score during the randomised treatment period
    End point description
    The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    422
    422
    Units: Units on a scale
        least squares mean (standard error)
    -0.8 ± 0.1
    -0.8 ± 0.1
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 24 in CGI-S score during the randomised treatment period

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    End point title
    		 Change from randomisation to Week 24 in CGI-S score during the randomised treatment period
    End point description
    The CGI-S is a 7-point scale where the clinician rates the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis on the following scale: 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    361
    333
    Units: Unit on a scale
        least squares mean (standard error)
    -1.7 ± 0.1
    -1.5 ± 0.1
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 6 in Quality o f Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q (SF)) total score during the randomised treatment period

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    End point title
    		 Change from randomisation to Week 6 in Quality o f Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q (SF)) total score during the randomised treatment period
    End point description
    The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good).
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    422
    421
    Units: Units on scale
        least squares mean (standard error)
    3.5 ± 0.4
    3.2 ± 0.4
    No statistical analyses for this end point

    Secondary: Change from randomisation to Week 24 in Q-LES-Q (SF)

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    End point title
    		 Change from randomisation to Week 24 in Q-LES-Q (SF)
    End point description
    The original Q-LES-Q is a patient self-rated scale designed to measure the degree of enjoyment and satisfaction experienced by patients in various areas of daily life. It consists of 93 items to measure: physical health, feelings, work, household duties, school, leisure time activities, social relations, and general activities. The Q-LES-Q short form (SF) contains 16 items from the general activities section. Each item is rated on a 5-point scale ranging from 1 (very poor) to 5 (very good).
    End point type
    Secondary
    End point timeframe
    From randomisation to end of Period B (24 weeks)
    End point values
    		 Period B, Placebo and ADT (24 weeks randomised treatment) Period B, Brexpiprazole and ADT (24 weeks randomised treatm.)
    Number of subjects analysed
    361
    333
    Units: Units on a scale
        least squares mean (standard error)
    7.7 ± 0.7
    6.2 ± 0.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation to end of study (28 weeks)
    Adverse event reporting additional description
    Treatment-emergent adverse events are reported in this section
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Period B, Brexpiprazole + ADT
    Reporting group description
    		 Brexpiprazole + ADT

    Reporting group title
    Period B, Placebo + ADT
    Reporting group description
    		 Placebo + ADT

    Serious adverse events
    		 Period B, Brexpiprazole + ADT Period B, Placebo + ADT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 444 (2.03%)
    13 / 441 (2.95%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    False positive investigation result
         subjects affected / exposed
    0 / 444 (0.00%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Forearm fracture
         subjects affected / exposed
    0 / 444 (0.00%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 444 (0.00%)
    2 / 441 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 444 (0.00%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 444 (0.00%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Family stress
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed [1]
    0 / 307 (0.00%)
    1 / 302 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 444 (0.23%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Self injurious behaviour
         subjects affected / exposed
    0 / 444 (0.00%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 444 (0.45%)
    3 / 441 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 444 (0.00%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 444 (0.00%)
    1 / 441 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    1 / 444 (0.23%)
    0 / 441 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This AE is only applicable for women
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Period B, Brexpiprazole + ADT Period B, Placebo + ADT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    108 / 444 (24.32%)
    97 / 441 (22.00%)
    Investigations
    Weight increased
         subjects affected / exposed
    42 / 444 (9.46%)
    22 / 441 (4.99%)
         occurrences all number
    42
    22
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    27 / 444 (6.08%)
    25 / 441 (5.67%)
         occurrences all number
    42
    47
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 444 (7.66%)
    31 / 441 (7.03%)
         occurrences all number
    58
    42
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    28 / 444 (6.31%)
    34 / 441 (7.71%)
         occurrences all number
    28
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2013
    The time frame for ECG re-evaluation in case of abnormalities was shortened to ensure patient safety. Exclusion criteria 34 and 35: the definition of unstable cardiovascular disease for exclusion was clarified. Antidepressant treatment: it was clarified that patients could continue on the ADT they had received prior to/at screening if they had been treated with this ADT for <6 weeks and had not responded to this ADT.
    12 Jun 2014
    The randomisation time point at Week 10 was deleted and all eligible patients were randomised at Week 8. Period C was deleted. As a consequence of this, the total study duration was reduced from 40 to 36 weeks. Early responders to ADT treatment were withdrawn at the Week 6 visit because they were not the target population for this study. The randomisation criteria for Period B were modified to improve the randomisation rate without compromising the study outcome: The patient was required to have a MADRS total score ≥18 instead of ≥20 at the randomisation visit. The criterion “CGI-S score ≥4 at every visit in Period A” was deleted. To obtain the required number of randomised patients, the planned number of screened patients was increased from 1950 to 2924 patients and the planned number of enrolled patients was increased from 1462 to 2193 patients.
    07 Apr 2015
    Data monitoring (blinded data) showed that the overall rate of full remission was lower than expected. To maintain the power of the study under the same effect size assumptions, the randomised sample size was increased from 658 to 868 patients. Due to the high number of sites in the study, the site factor was replaced with a country factor in the primary efficacy analysis.

    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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