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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo- and Active Comparator-controlled Trial of Flexible-dose Brexpiprazole (OPC-34712) as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder, the Delphinus Trial.

    Summary
    EudraCT number
    2012-003948-67
    Trial protocol
    DE   SK   FR   ES  
    Global end of trial date
    10 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jan 2018
    First version publication date
    26 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    331-12-282
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND No.: 103, 958
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization,
    Sponsor organisation address
    2440 Research Boulevard, Rockville, Maryland , United States, 20850
    Public contact
    Regulatory Project Manager, INC Research, +34 916307400, ricardo.sanz-gadea@incresearch.com
    Scientific contact
    Regulatory Project Manager, INC Research, +34 916307400, ricardo.sanz-gadea@incresearch.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
    10 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy to an assigned openlabel antidepressant therapy (ADT) in the proposed subject population with major depressive disorder (MDD).
    Protection of trial subjects
    The study was conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline, and the applicable local laws and regulatory requirements of the countries in which the trial was conducted, copies of the protocol, any amendments, and the informed consent form (ICF) were reviewed and approved by the governing institutional review board (IRB) or independent ethics committee (IEC) for each investigational site or country, as appropriate, prior to trial start or prior to implementation of the protocol or protocol amendment, if any, at that site and/or country.. Written informed consent (translated in Canadian French, German, French, Russian, Polish, and Serbian) was obtained from all subjects (or their guardian or legal representative, as applicable according to local laws) and was documented prior to initiation of any procedures that were performed solely for the purpose of determining eligibility for this trial, including withdrawal from current medication(s).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Nov 2012
    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
    United States: 239
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    Poland: 53
    Country: Number of subjects enrolled
    Russian Federation: 165
    Country: Number of subjects enrolled
    Serbia: 6
    Worldwide total number of subjects
    503
    EEA total number of subjects
    93
    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)
    501
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Trial was conducted at 75 trial sites in 7 countries (United States, Russia, Poland, France, Serbia, Germany & Canada). Of the screened 3001 subjects (with major depressive disorder), 2182 entered Phase A, 503 (non-responders) were randomized into Phase B (brexpiprazole/Seroquel/placebo +ADT) and 1394 entered Phase A+ (continued Phase A therapy)

    Pre-assignment
    Screening details
    Screening period ranged from a minimum of 7 days to a maximum of 28 days and began when informed consent was signed. The purpose was to assess eligibility criteria at 1 or more visits (as necessary to complete screening assessments) and to washout (minimum of 24 hours) prohibited concomitant pharmacotherapy, if applicable.

    Period 1
    Period 1 title
    Phase B (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Investigational medicinal product (placebo, brexpiprazole, or Seroquel XR) other than ADT was double-blind at any given visit. Personnel at trial sites were blinded to details of randomization criteria & dosing schedule. Except in cases of emergency unblinding, subjects, investigational site personnel, sponsor employees, and all other trial personnel remained blinded to the identity of the treatment assignments until every subject had completed trial treatment and the database had been locked

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Brexpiprazole + Antidepressant therapy (ADT)
    Arm description
    Subjects received orally brexpiprazole 1 mg tablet per day and assigned ADT at randomization, and then the dose was increased to 2 mg/day at Day 7 (± 2 days). Subjects remained at the target dose (2 mg/day) unless the investigator requested an increase to a higher dose. Change in the dose was done based on a clinical assessment of the benefit and the subject’s tolerance of the investigational medicinal product (IMP). The choice of ADT was determined by considering each subject's antidepressant treatment history.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    OPC-34712
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orally brexpiprazole 1 mg tablet per day at randomization, and then the dose was increased to 2 mg/day at Day 7 (± 2 days).

    Arm title
    Quetiapine (Seroquel) extended release (XR) + ADT
    Arm description
    Randomized subjects received orally quetiapine XR tablets at a dose of 50 mg/day and assigned ADT therapy on Day 1 and Day 2, and then the dose was increased to 150 mg/day on Day 3 through Day 14. Subjects remained at the target dose (150 mg/day) unless the investigator requested an increase to a higher dose.
    Arm type
    Active comparator

    Investigational medicinal product name
    Quetiapine XR tablet
    Investigational medicinal product code
    Other name
    Seroquel XR
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Orally quetiapine 50 mg XR tablet per day on Day 1 and Day 2, and then the dose was increased to 150 mg/day on Day 3 through Day 14.

    Arm title
    Placebo + ADT
    Arm description
    Randomized subjects received orally brexpiprazole or quetiapine matching placebo tablets with the open-label ADT (Phase A) at the final dose reached during the prospective treatment phase.
    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
    Orally brexpiprazole or quetiapine matching placebo tablets with the open-label ADT final dose reached during the prospective treatment phase (Phase A).

    Number of subjects in period 1
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Started
    197
    100
    206
    Completed
    171
    86
    186
    Not completed
    26
    14
    20
         Protocol deviation
    2
    -
    1
         Lack of efficacy
    1
    2
    4
         Adverse events
    2
    4
    2
         Subject met protocol specified withdrawal criteria
    9
    2
    3
         Subject participation withdrawn - by investigator
    1
    1
    -
         Subject withdrew consent to participate
    10
    3
    9
         Lost to follow-up
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole + Antidepressant therapy (ADT)
    Reporting group description
    Subjects received orally brexpiprazole 1 mg tablet per day and assigned ADT at randomization, and then the dose was increased to 2 mg/day at Day 7 (± 2 days). Subjects remained at the target dose (2 mg/day) unless the investigator requested an increase to a higher dose. Change in the dose was done based on a clinical assessment of the benefit and the subject’s tolerance of the investigational medicinal product (IMP). The choice of ADT was determined by considering each subject's antidepressant treatment history.

    Reporting group title
    Quetiapine (Seroquel) extended release (XR) + ADT
    Reporting group description
    Randomized subjects received orally quetiapine XR tablets at a dose of 50 mg/day and assigned ADT therapy on Day 1 and Day 2, and then the dose was increased to 150 mg/day on Day 3 through Day 14. Subjects remained at the target dose (150 mg/day) unless the investigator requested an increase to a higher dose.

    Reporting group title
    Placebo + ADT
    Reporting group description
    Randomized subjects received orally brexpiprazole or quetiapine matching placebo tablets with the open-label ADT (Phase A) at the final dose reached during the prospective treatment phase.

    Reporting group values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT Total
    Number of subjects
    197 100 206 503
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    197 100 206 503
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.6 ± 11.5 44.6 ± 11.6 41.8 ± 11.7 -
    Gender categorical
    Units: Subjects
        Female
    128 66 149 343
        Male
    69 34 57 160

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole + Antidepressant therapy (ADT)
    Reporting group description
    Subjects received orally brexpiprazole 1 mg tablet per day and assigned ADT at randomization, and then the dose was increased to 2 mg/day at Day 7 (± 2 days). Subjects remained at the target dose (2 mg/day) unless the investigator requested an increase to a higher dose. Change in the dose was done based on a clinical assessment of the benefit and the subject’s tolerance of the investigational medicinal product (IMP). The choice of ADT was determined by considering each subject's antidepressant treatment history.

    Reporting group title
    Quetiapine (Seroquel) extended release (XR) + ADT
    Reporting group description
    Randomized subjects received orally quetiapine XR tablets at a dose of 50 mg/day and assigned ADT therapy on Day 1 and Day 2, and then the dose was increased to 150 mg/day on Day 3 through Day 14. Subjects remained at the target dose (150 mg/day) unless the investigator requested an increase to a higher dose.

    Reporting group title
    Placebo + ADT
    Reporting group description
    Randomized subjects received orally brexpiprazole or quetiapine matching placebo tablets with the open-label ADT (Phase A) at the final dose reached during the prospective treatment phase.

    Primary: Mean Change From Randomization (End of Phase A) to End of Phase B in montgomery asberg depression rating scale (MADRS) Total Score - Efficacy Sample

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    End point title
    Mean Change From Randomization (End of Phase A) to End of Phase B in montgomery asberg depression rating scale (MADRS) Total Score - Efficacy Sample
    End point description
    To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS was used to asses the subject’s level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) each with 7 defined grades of severity. If a subject discontinued early, every effort was made to complete the “End of Week 18/ET” evaluations.
    End point type
    Primary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ early termination (ET) Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Number
        least squares mean (standard error)
    -6.04 ± 0.43
    -4.86 ± 0.57
    -4.57 ± 0.41
    Statistical analysis title
    Bbrexpiprazole+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Placebo + ADT v Brexpiprazole + Antidepressant therapy (ADT)
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0078
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -1.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.56
         upper limit
    -0.39
    Statistical analysis title
    Seroquel XR+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6642
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.63
         upper limit
    1.04

    Secondary: Mean change from randomization (End of Phase A) to end of Phase B in Sheehan Disability Scale (SDS) score

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    End point title
    Mean change from randomization (End of Phase A) to end of Phase B in Sheehan Disability Scale (SDS) score
    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. It was a visual analogue scale which used spatio-visual, numeric, and verbal descriptive anchors to assess disability across 3 domains and the symptom was marked along the line from 0 (not at all) to 10 (extreme). Scores of 5 and above was associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.
    End point type
    Secondary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ ET Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Number
        least squares mean (standard error)
    -0.97 ± 0.12
    -0.32 ± 0.16
    -0.74 ± 0.11
    Statistical analysis title
    Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1334
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.52
         upper limit
    0.07
    Statistical analysis title
    Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Placebo + ADT v Quetiapine (Seroquel) extended release (XR) + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0237
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.78

    Secondary: Mean Change From Randomization (End of Phase A) to Phase B by Trial Week in MADRS Total Score at Week 2 visit and Week 4 visit

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    End point title
    Mean Change From Randomization (End of Phase A) to Phase B by Trial Week in MADRS Total Score at Week 2 visit and Week 4 visit
    End point description
    To determine the efficacy of brexpiprazole (flexible dose) with placebo as adjunctive therapy by assessment of MADRS total score. The MADRS was used to asses the subject’s level of depression by utilizing the structured interview guide for the MADRS (SIGMA). The MADRS consisted of 10 items (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts) each with 7 defined grades of severity. If a subject discontinued early, every effort was made to complete the “End of Week 18/ET” evaluations.
    End point type
    Secondary
    End point timeframe
    Treatment Phase: At Week 2 visit and Week 4 visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Number
    least squares mean (standard error)
        Week 2 visit (N = 188, 99, 203)
    -2.57 ± 0.32
    -2.26 ± 0.41
    -1.04 ± 0.31
        Week 4 visit (N = 178, 94, 192)
    -4.39 ± 0.39
    -3.30 ± 0.51
    -3.22 ± 0.37
    Statistical analysis title
    Week 2 visit: Brexpiprazole+ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.29
         upper limit
    -0.76
    Statistical analysis title
    Week 2 visit: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0103
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.15
         upper limit
    -0.29
    Statistical analysis title
    Week 4 visit: Brexpiprazole+ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0185
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.15
         upper limit
    -0.2
    Statistical analysis title
    Week 4 visit: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8949
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.27
         upper limit
    1.11

    Secondary: Mean Change from End of Phase A to Phase B by Study Week in Clinical Global Impression Severity of Illness (CGI-S) Scale

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    End point title
    Mean Change from End of Phase A to Phase B by Study Week in Clinical Global Impression Severity of Illness (CGI-S) Scale
    End point description
    The severity of illness for each subject was rated using the CGI-S. To perform this assessment, the rater or investigator answered the following question: “Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?” Response choices include: 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 patients.
    End point type
    Secondary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ ET Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Number
    least squares mean (standard error)
        Week 2 (N = 188, 99, 203)
    -0.26 ± 0.04
    -0.22 ± 0.05
    -0.15 ± 0.04
        Week 4 (N = 178, 94, 192)
    -0.49 ± 0.05
    -0.36 ± 0.06
    -0.37 ± 0.05
        Week 6 (N = 178, 87, 194)
    -0.70 ± 0.05
    -0.60 ± 0.07
    -0.55 ± 0.05
    Statistical analysis title
    Week 2: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0369
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.21
         upper limit
    -0.01
    Statistical analysis title
    Week 2: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2468
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.05
    Statistical analysis title
    Week 4: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0764
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.23
         upper limit
    0.01
    Statistical analysis title
    Week 4: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8258
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.13
         upper limit
    0.17
    Statistical analysis title
    Week 6: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.035
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    -0.01
    Statistical analysis title
    Week 6: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5601
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.22
         upper limit
    0.12

    Secondary: Mean Clinical Global Impression Improvement Scale (CGI-I) Score by Study Week in Phase B Relative to End of Phase A

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    End point title
    Mean Clinical Global Impression Improvement Scale (CGI-I) Score by Study Week in Phase B Relative to End of Phase A
    End point description
    The improvement of each subject’s condition was rated for each subject using the CGI-I. The rater or investigator rated the subject’s total improvement whether or not it was due entirely to drug treatment. To perform this assessment, the rater or investigator answered the following question: “Compared to his/her condition at baseline, how much has the patient changed?” Response choices include: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
    End point type
    Secondary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ ET Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Mean score
    arithmetic mean (standard deviation)
        Week 2 (N = 188, 99, 203)
    2.94 ± 0.81
    3.01 ± 0.75
    3.10 ± 0.71
        Week 4 (N = 191, 99, 205)
    2.72 ± 0.80
    2.89 ± 0.83
    2.88 ± 0.76
        Week 6 (N = 191, 99, 205)
    2.55 ± 0.84
    2.71 ± 0.87
    2.74 ± 0.83
    Statistical analysis title
    Week 2: Bbrexpiprazole+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0156
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    -0.03
    Statistical analysis title
    Week 2: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2053
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.27
         upper limit
    0.06
    Statistical analysis title
    Week 4: Bbrexpiprazole+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0222
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    -0.02
    Statistical analysis title
    Week 4: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9403
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.18
         upper limit
    0.17
    Statistical analysis title
    Week 6: Bbrexpiprazole+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0146
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.35
         upper limit
    -0.04
    Statistical analysis title
    Week 6: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7127
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.23
         upper limit
    0.15

    Secondary: MADRS Response Rate (>= 50% reduction in total score) for every trial week visit during double-blind randomized Phase B treatment

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    End point title
    MADRS Response Rate (>= 50% reduction in total score) for every trial week visit during double-blind randomized Phase B treatment
    End point description
    The rating was based on a clinical interview moving from broadly phrased questions about symptoms to more detailed ones which allowed a precise rating of severity. The rater decided whether the rating lies on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5).
    End point type
    Secondary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ ET Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Participants
        week 2 (N = 188, 99, 203)
    3
    0
    3
        Week 4 (N = 191, 99, 205)
    8
    3
    6
        Week 6 (N = 191, 99, 205)
    20
    8
    14
    Statistical analysis title
    Week 2: Bbrexpiprazole+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8396
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.22
         upper limit
    6.31
    Statistical analysis title
    Week 2: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2413
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Week 4: Bbrexpiprazole+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4131
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ration of response rate
    Point estimate
    1.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    4.62
    Statistical analysis title
    Week 4: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6976
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    5.22
    Statistical analysis title
    Week 6: Bbrexpiprazole+ADT Vs Placebo+ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2242
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    2.84
    Statistical analysis title
    Week 6: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5998
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    2.98

    Secondary: MADRS Remission Rate(<=10 and >=50% reduction in total score) for every trial week visit during double-blind randomized Phase B treatment

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    End point title
    MADRS Remission Rate(<=10 and >=50% reduction in total score) for every trial week visit during double-blind randomized Phase B treatment
    End point description
    The rating was based on a clinical interview moving from broadly phrased questions about symptoms to more detailed ones which allowed a precise rating of severity. The rater decided whether the rating lies on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5).
    End point type
    Secondary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ ET Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Participants
        Week 2 (N = 188, 99, 203)
    1
    0
    1
        Week 4 (N = 191, 99, 205)
    4
    0
    4
        Week 6 (N = 191, 99, 205)
    13
    2
    9
    Statistical analysis title
    Week 2: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8711
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    43.6
    Statistical analysis title
    Week 2: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4795
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Week 4: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8117
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    5.45
    Statistical analysis title
    Week 4: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2169
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Week 6: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3321
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    3.49
    Statistical analysis title
    Week 6: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3917
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    2.46

    Secondary: CGI-I Response rate for every trial week visit during double-blind randomized Phase B treatment

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    End point title
    CGI-I Response rate for every trial week visit during double-blind randomized Phase B treatment
    End point description
    The response was defined as a CGI-I score of 1 or 2 (very much improved or much improved). The improvement of each subject’s condition was rated for each subject using the CGI-I. The rater or investigator rated the subject’s total improvement whether or not it was due entirely to drug treatment. To perform this assessment, the rater or investigator answered the following question: “Compared to his/her condition at baseline, how much has the patient changed?” Response choices include: 1 = very much improved and 2 = much improved.
    End point type
    Secondary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ ET Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191
    99
    205
    Units: Participants
        Week 2 (N = 188, 99, 203)
    54
    24
    35
        Week 4 (N = 191, 99, 205)
    78
    35
    62
        Week 6 (N = 191, 99, 205)
    100
    48
    79
    Statistical analysis title
    Week 2: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0072
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.13
         upper limit
    2.31
    Statistical analysis title
    Week 2: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1501
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    2.15
    Statistical analysis title
    Week 4: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0194
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    1.74
    Statistical analysis title
    Week 4: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Placebo + ADT v Quetiapine (Seroquel) extended release (XR) + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2934
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.63
    Statistical analysis title
    Week 6: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0032
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    1.66
    Statistical analysis title
    Week 6: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0898
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Ratio of response rate
    Point estimate
    1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.59

    Secondary: The safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with major depressive disorder (MDD)

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    End point title
    The safety and tolerability of brexpiprazole (flexible dose) as adjunctive therapy to ADT in the proposed subject population with major depressive disorder (MDD)
    End point description
    Assessment of safety and tolerability included adverse events (AEs), clinical laboratory tests (hematology, serum chemistry [including prolactin and glycosylated hemoglobin (HbA1c)], and urinalysis), physical examinations, vital sign measurements, and ECGs. Body weight, height, and waist circumference were also measured.
    End point type
    Secondary
    End point timeframe
    At treatment phase (Week 8 or 10 to Week 18/ET visit) and post-treatment follow-up
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    197
    100
    206
    Units: Participants
        Death
    0
    0
    0
        Serious treatment emergent AE (TEAE)
    0
    1
    1
        Discontinuation due to TEAE
    2
    4
    1
        Any TEAE
    100
    58
    107
    No statistical analyses for this end point

    Secondary: Mean Change from End of Phase A to Phase B in SDS scores for all 3 individual item

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    End point title
    Mean Change from End of Phase A to Phase B in SDS scores for all 3 individual item
    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. It was a visual analogue scale which used spatio-visual, numeric, and verbal descriptive anchors to assess disability across 3 domains and the symptom was marked along the line from 0 (not at all) to 10 (extreme). Scores of 5 and above was associated with significant functional impairment. Additionally, SDS included 2 questions related to productivity losses due to the psychiatric symptoms and impairment.
    End point type
    Secondary
    End point timeframe
    Treatment phase: From Week 8/10 Visit to Week 18/ ET Visit
    End point values
    Brexpiprazole + Antidepressant therapy (ADT) Quetiapine (Seroquel) extended release (XR) + ADT Placebo + ADT
    Number of subjects analysed
    191 [1]
    99 [2]
    205 [3]
    Units: Mean score
    least squares mean (standard error)
        Work/School (N = 109, 55, 125)
    -0.59 ± 0.16
    -0.22 ± 0.21
    -0.74 ± 0.16
        Social life (N = 178, 87, 194)
    -1.03 ± 0.13
    -0.26 ± 0.17
    -0.70 ± 0.12
        Family life (N = 178, 87, 194)
    -1.02 ± 0.13
    -0.34 ± 0.18
    -0.67 ± 0.13
    Notes
    [1] - For work/school, number of subjects analyzed was 125
    [2] - For work/school, number of subjects analyzed was 67
    [3] - For work/school, number of subjects analyzed was 136
    Statistical analysis title
    Work/School: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.448
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.25
         upper limit
    0.56
    Statistical analysis title
    Work/School: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.038
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    1.02
    Statistical analysis title
    Social life: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Placebo + ADT v Brexpiprazole + Antidepressant therapy (ADT)
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0436
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.66
         upper limit
    -0.01
    Statistical analysis title
    Social life: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Placebo + ADT v Quetiapine (Seroquel) extended release (XR) + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.035
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    0.84
    Statistical analysis title
    Family life: Brexpiprazole +ADT Vs Palcebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Brexpiprazole + Antidepressant therapy (ADT) v Placebo + ADT
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0424
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    -0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.69
         upper limit
    -0.01
    Statistical analysis title
    Family life: Quetiapine +ADT Vs Placebo + ADT
    Statistical analysis description
    Efficacy Sample: All participants in the Safety Sample who had an end of Phase A (i.e., Week 8 or 10) value and at least one post-randomization efficacy evaluation for MADRS Total Score in Phase B.
    Comparison groups
    Quetiapine (Seroquel) extended release (XR) + ADT v Placebo + ADT
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.123
    Method
    Mixed models analysis
    Parameter type
    LS mean difference
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.09
         upper limit
    0.75

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At treatment phase (Week 8 or 10 to Week 18/ET visit) and post-treatment follow-up
    Adverse event reporting additional description
    In the safety sample (who received at least 1 dose of double-blind study drug), all AEs with an onset date on or after the start of double-blind treatment; or if the events was continuous from end of phase A and was worsening serious, study drug related, or resulted in death, discontinuation, interruption or reduction of trial therapy.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Brexpiprazole + ADT
    Reporting group description
    Subjects received orally brexpiprazole 1 mg tablet per day and assigned ADT at randomization, and then the dose was increased to 2 mg/day at Day 7 (± 2 days). Subjects remained at the target dose (2 mg/day) unless the investigator requested an increase to a higher dose. Change in the dose was done based on a clinical assessment of the benefit and the subject’s tolerance of the investigational medicinal product (IMP).

    Reporting group title
    Quetiapine (Seroquel) XR + ADT
    Reporting group description
    Randomized subjects received orally quetiapine XR tablets at a dose of 50 mg/day and assigned ADT therapy on Day 1 and Day 2, and then the dose was increased to 150 mg/day on Day 3 through Day 14. Subjects remained at the target dose (150 mg/day) unless the investigator requested an increase to a higher dose.

    Reporting group title
    Placebo + ADT
    Reporting group description
    Randomized subjects received orally brexpiprazole or quetiapine matching placebo tablets with the open-label ADT (Phase A) at the final dose reached during the prospective treatment phase.

    Serious adverse events
    Brexpiprazole + ADT Quetiapine (Seroquel) XR + ADT Placebo + ADT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 100 (1.00%)
    1 / 206 (0.49%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 100 (1.00%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 100 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brexpiprazole + ADT Quetiapine (Seroquel) XR + ADT Placebo + ADT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 197 (20.30%)
    27 / 100 (27.00%)
    19 / 206 (9.22%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    12 / 197 (6.09%)
    3 / 100 (3.00%)
    4 / 206 (1.94%)
         occurrences all number
    14
    3
    4
    Headache
         subjects affected / exposed
    11 / 197 (5.58%)
    1 / 100 (1.00%)
    10 / 206 (4.85%)
         occurrences all number
    14
    1
    13
    Somnolence
         subjects affected / exposed
    11 / 197 (5.58%)
    18 / 100 (18.00%)
    2 / 206 (0.97%)
         occurrences all number
    11
    22
    2
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    2 / 197 (1.02%)
    6 / 100 (6.00%)
    1 / 206 (0.49%)
         occurrences all number
    2
    6
    1
    Metabolism and nutrition disorders
    Increased Appetite
         subjects affected / exposed
    5 / 197 (2.54%)
    5 / 100 (5.00%)
    2 / 206 (0.97%)
         occurrences all number
    5
    5
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2014
    Amendment 1: Clarified necessary trial procedures, inclusion/exclusions criteria and provided updated contact information. Updated to revise the randomization criteria in the blinded addendum, and to make minor administrative changes to the protocol.

    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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