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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Brexpiprazole (OPC-34712) as Maintenance Treatment in Adults with Schizophrenia.

    Summary
    EudraCT number
    2011-005766-38
    Trial protocol
    RO  
    Global end of trial date
    12 Feb 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    331-10-232
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01668797
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, Maryland, United States, 20850
    Public contact
    Mary Hobart, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 240-683-3194, Mary.Hobart@otsuka-us.com
    Scientific contact
    Mary Hobart, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 240-683-3194, Mary.Hobart@otsuka-us.com
    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
    Interim
    Date of interim/final analysis
    26 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of brexpiprazole compared with placebo as maintenance treatment in adults with schizophrenia.
    Protection of trial subjects
    This trial was conducted in compliance with the protocol, ICH-GCP and applicable local laws and regulatory requirements. Written informed consent was obtained from all participants (or their guardian or legal representative, as applicable according to local laws). Informed consent was obtained and 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). Participants were asked to sign a separate ICF designed for the purpose of collecting a onetime blood sample for assessment of cytochrome P450 (CYP) 2D6 metabolizer genotype. Participants were informed that they would not be excluded from the treatment trial if they did not wish to participate in the pharmacogenomic assessments.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Oct 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
    Turkey: 18
    Country: Number of subjects enrolled
    Ukraine: 147
    Country: Number of subjects enrolled
    United States: 204
    Country: Number of subjects enrolled
    Colombia: 61
    Country: Number of subjects enrolled
    Malaysia: 47
    Country: Number of subjects enrolled
    Puerto Rico: 38
    Country: Number of subjects enrolled
    Romania: 73
    Country: Number of subjects enrolled
    Serbia: 78
    Worldwide total number of subjects
    666
    EEA total number of subjects
    73
    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)
    666
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 753 participants were screened at 49 trial sites.

    Pre-assignment
    Screening details
    Trial had Phase A (Conversion) (N= 406), Phase B (Oral Stabilization) (N= 464; 346 rolled over from Phase A and 118 entered directly into Phase B ) and Phase C (Double-Blind Maintenance) with (N= 202 rolled over from Phase B). Participants were randomized in to Phase C in a 1:1 ratio (brexpiprazole: placebo) to receive treatment for up to 52 weeks.

    Period 1
    Period 1 title
    Phase A and Phase B
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase A (Conversion Phase)
    Arm description
    The purpose of the open-label conversion phase was 2-fold: 1) to cross-titrate the participants current antipsychotic treatment to brexpiprazole monotherapy over a period of 1 to 4 weeks and 2) to allow washout of prohibited medications in preparation for the stabilization phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants in the Conversion phase received brexpiprazole 1 mg/day as a starting dose and the dose was adjusted within the range of brexpiprazole 1 to 4 mg/day according to the study physician's judgment.

    Arm title
    Phase B (Stabilization Phase)
    Arm description
    This single-blind stabilization phase was to titrate participants to a dose of brexpiprazole (1 to 4 mg/day) that would maintain stability of psychotic symptoms over 12 consecutive weeks (within a maximum of 36 weeks), while minimizing tolerability issues.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants in this stabilization phase were titrated to a dose of brexpiprazole (1 to 4 mg/day) that would maintain stability of psychotic symptoms over 12 consecutive weeks (within a maximum of 36 weeks), while minimizing tolerability issues.

    Number of subjects in period 1
    Phase A (Conversion Phase) Phase B (Stabilization Phase)
    Started
    406
    464
    Completed
    346
    202
    Not completed
    60
    262
         Protocol deviation
    2
    3
         Physician decision
    2
    11
         Met withdrawal criteria
    3
    22
         Terminated Study on Interim Analysis
    19
    86
         Lack of efficacy
    7
    21
         Consent withdrawn by subject
    16
    60
         Adverse Event Without Impending Relapse
    8
    43
         Lost to follow-up
    3
    16
    Period 2
    Period 2 title
    Phase C
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The randomized treatments were administered in a double-blind fashion with blocks of randomization numbers assigned to trial centers by the Interactive voice response system (IVRS)/ Interactive web response system (IWRS).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase)
    Arm description
    Participants received maintenance treatment daily with brexpiprazole (at the final dose achieved during the stabilization phase) for up to 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received maintenance treatment daily with brexpiprazole (at the final dose achieved during the stabilization phase) for up to 52 weeks.

    Arm title
    Phase C - Placebo (Double-Blind Maintenance Phase)
    Arm description
    Participants received placebo orally once daily for 52 weeks.
    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
    Participants received placebo orally once daily for 52 weeks.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is not baseline period as it consisted of Phase A and Phase B. Phase A was for conversion from other antipsychotics to oral brexpiprazole and washout of prohibited concomitant medications, if applicable. In addition, Phase B was a single-blind treatment phase to stabilize participants on oral brexpiprazole.
    Number of subjects in period 2 [2] [3]
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Started
    97
    105
    Completed
    14
    9
    Not completed
    83
    96
         Protocol deviation
    2
    -
         Physician decision
    5
    2
         Met withdrawal criteria
    3
    3
         Terminated Study on Interim Analysis
    49
    38
         Lack of efficacy
    2
    10
         Lack of Efficacy without AE
    11
    30
         Consent withdrawn by subject
    3
    5
         Adverse Event Without Impending Relapse
    4
    2
         Lost to follow-up
    4
    6
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All participants who signed the informed consent for the trial and entered the conversion phase or stabilization phase were included in the subjects enrolled per country table. However, the baseline period (Phase C) are those participants who were randomized to receive at least one dose of double-blind study medication in the maintenance phase.
    [3] - 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: 346 participants entered Phase B; 346 rolled over from Phase A and 118 new patients entered into Phase B directly.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase)
    Reporting group description
    Participants received maintenance treatment daily with brexpiprazole (at the final dose achieved during the stabilization phase) for up to 52 weeks.

    Reporting group title
    Phase C - Placebo (Double-Blind Maintenance Phase)
    Reporting group description
    Participants received placebo orally once daily for 52 weeks.

    Reporting group values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase) Total
    Number of subjects
    97 105 202
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    97 105 202
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.8 ± 10.7 41.6 ± 10.6 -
    Gender categorical
    Units: Subjects
        Female
    39 40 79
        Male
    58 65 123

    End points

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    End points reporting groups
    Reporting group title
    Phase A (Conversion Phase)
    Reporting group description
    The purpose of the open-label conversion phase was 2-fold: 1) to cross-titrate the participants current antipsychotic treatment to brexpiprazole monotherapy over a period of 1 to 4 weeks and 2) to allow washout of prohibited medications in preparation for the stabilization phase.

    Reporting group title
    Phase B (Stabilization Phase)
    Reporting group description
    This single-blind stabilization phase was to titrate participants to a dose of brexpiprazole (1 to 4 mg/day) that would maintain stability of psychotic symptoms over 12 consecutive weeks (within a maximum of 36 weeks), while minimizing tolerability issues.
    Reporting group title
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase)
    Reporting group description
    Participants received maintenance treatment daily with brexpiprazole (at the final dose achieved during the stabilization phase) for up to 52 weeks.

    Reporting group title
    Phase C - Placebo (Double-Blind Maintenance Phase)
    Reporting group description
    Participants received placebo orally once daily for 52 weeks.

    Primary: Time From Randomization to Exacerbation of Psychotic Symptoms/Impending Relapse in Phase C.

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    End point title
    Time From Randomization to Exacerbation of Psychotic Symptoms/Impending Relapse in Phase C.
    End point description
    The primary efficacy variable was time to impending relapse from randomization, as assessed by Clinical Global Impression of Improvement (CGI-I) score ≥5, Positive and Negative Syndrome Scale (PANSS) scores for hostility or uncooperativeness ≥5, or ≥20% increase in PANSS Total Score. Impending relapse was defined as meeting any of the following 5 criteria: 1) CGI-I score of ≥ 5 (minimally worse) and increase in individual PANSS items to a score > 4 with an absolute increase of ≥ 2 on that specific item or absolute increase of ≥ 4 on the combined 4 PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content). OR 2) CGI-I score of 6 or 7 (much or very much worse) OR 3) Hospitalization due to worsening of illness OR 4) Any suicidal behavior or answers of "yes" to Questions 4 or 5 on the suicidal ideation section of the C-SSRS OR 5) Violent or aggressive behavior resulting in clinically significant injury.
    End point type
    Primary
    End point timeframe
    From randomization to time of exacerbation of psychotic symptoms/impending relapse - up to 52 weeks
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Days
        number (not applicable)
    169
    111
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The total number of exacerbation of psychotic symptoms/impending relapse was estimated using a 1:1 (brexpiprazole: placebo) randomization ratio. For the primary endpoint, a 95% confidence interval for the hazard ratio (brexpiprazole vs. placebo) was provided using the Cox Proportional Hazard model with term of treatment in the model.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.292
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.156
         upper limit
    0.548
    Notes
    [1] - The log-rank test was based on time to exacerbation of psychotic symptoms/impending relapse.

    Secondary: Percentage of Participants Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria in the Double-blind Maintenance Phase

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    End point title
    Percentage of Participants Meeting Exacerbation of Psychotic Symptoms/Impending Relapse Criteria in the Double-blind Maintenance Phase
    End point description
    Impending relapse was defined as meeting any of the following 5 criteria: 1) CGI-I score of ≥ 5 (minimally worse) and increase in individual PANSS items to a score > 4 with an absolute increase of ≥ 2 on that specific item or an increase on any of the following individual PANSS items (conceptual disorganization, hallucinatory behavior, suspiciousness, unusual though content) to a score of >4 and an absolute increase of ≥ 4 on the combined 4 PANSS items. OR 2) CGI-I score of 6 or 7 (much or very much worse) OR 3) Hospitalization due to worsening of illness OR 4) Current suicidal behavior as assessed by the C-SSRS (ie, an answer of "yes" to any of the questions on the suicidal behavior section of the C-SSRS 5) Violent or aggressive behavior resulting in clinically significant self-injury to another person, or property damage.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52/Early Termination
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: percentage of participants
        number (not applicable)
    13.54
    38.46
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The percentage of participants with impending relapse in treatment groups (Brexpiprazole and placebo) in final analysis for participants meeting at least one of the criteria.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Chi-squared
    Confidence interval

    Secondary: Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - MMRM Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    0.19 ± 0.25
    0.66 ± 0.24
        Week 12 (N= 73, 68)
    0.54 ± 0.29
    0.78 ± 0.29
        Week 24 (N= 50, 36)
    0.61 ± 0.28
    0.58 ± 0.32
        Week 36 (N= 33, 24)
    0.46 ± 0.33
    0.71 ± 0.39
        Week 52 (N= 15, 9)
    0.04 ± 0.43
    0.28 ± 0.56
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.164
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.14
         upper limit
    0.19
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5466
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.04
         upper limit
    0.55
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9417
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.81
         upper limit
    0.87
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6257
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.25
         upper limit
    0.76
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7437
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.68
         upper limit
    1.21
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4506
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    0.28

    Other pre-specified: Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase

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    End point title
    Percentage of Participants Meeting Stability Criteria in Double Blind Maintenance Phase
    End point description
    Participants were assessed for stability using the following criteria:1) Outpatient status AND 2) Positive and Negative Syndrome Scale (PANSS) Total Score ≤ 70 AND 3) A score of ≤ 4 (moderate) on each of the following PANSS items (possible scores of 1 to 7 for each item): conceptual disorganization, suspiciousness hallucinatory behavior, unusual thought content, AND 4) Clinical Global Impression - Severity of Illness scale(CGI-S) score ≤ 4 (moderately ill) AND 5) No current suicidal behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), defined as the following: An answer of "no" to each question on the Suicidal Behavior section of the C-SSRS AND an answer of "no" to Questions 4 and 5 on the Suicidal Ideation section of the C-SSRS, if completed, AND 6) No evidence of aggressive or violent behavior resulting in clinically significant self-injury, injury to another person, property damage.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: percentage of participants
    number (not applicable)
        Week 6 (N= 81, 84)
    92.59
    86.9
        Week 12 (N= 73, 68)
    93.15
    86.76
        Week 24 (N= 50, 36)
    96
    94.44
        Week 36 (N= 33, 24)
    93.94
    83.33
        Week 52 (N= 15, 9)
    86.67
    88.89
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2296
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2051
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7354
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1977
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8734
    Method
    Chi-squared
    Confidence interval

    Other pre-specified: Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score - MMRM Analysis
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    0.79 ± 1.31
    4.09 ± 1.27
        Week 12 (N= 73, 68)
    0.84 ± 1.73
    6.15 ± 1.74
        Week 24 (N= 50, 36)
    -1.88 ± 1.39
    2.89 ± 1.55
        Week 36 (N= 33, 24)
    -2.71 ± 1.48
    3.33 ± 1.7
        Week 52 (N= 15, 9)
    0.61 ± 3.34
    6.92 ± 4.53
    Statistical analysis title
    Statistical analysis at Week 6
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0664
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.82
         upper limit
    0.23
    Statistical analysis title
    Statistical analysis at Week 12
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0301
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -5.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.1
         upper limit
    -0.52
    Statistical analysis title
    Statistical analysis at Week 24
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0226
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.86
         upper limit
    -0.68
    Statistical analysis title
    Statistical analysis at Week 36
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0086
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.5
         upper limit
    -1.59
    Statistical analysis title
    Statistical analysis at Week 52
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.28
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.1
         upper limit
    5.46
    Statistical analysis title
    Statistical analysis at across visits
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.01
         upper limit
    -1.82

    Other pre-specified: Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis

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    End point title
    Mean Change From Baseline in PANSS Total Score - Last-observation-carried-forward (LOCF) Analysis
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    0.51 ± 1.4
    3.56 ± 1.28
        Week 12
    1.55 ± 1.77
    6.6 ± 1.62
        Week 24
    1.58 ± 1.88
    9.17 ± 1.72
        Week 36
    2.49 ± 1.89
    10.51 ± 1.73
        Week 52
    3.25 ± 1.94
    11.2 ± 1.77
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0683
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.31
         upper limit
    0.23
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0174
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -5.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.2
         upper limit
    -0.9
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12
         upper limit
    -3.18
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -8.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.4
         upper limit
    -3.59
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.5
         upper limit
    -3.41

    Other pre-specified: Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Positive Subscale Score - MMRM Analysis
    End point description
    PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    0.17 ± 0.42
    1.28 ± 0.41
        Week 12 (N= 73, 68)
    -0.06 ± 0.5
    1.81 ± 0.51
        Week 24 (N= 50, 36)
    -0.84 ± 0.46
    0.72 ± 0.51
        Week 36 (N= 33, 24)
    -0.97 ± 0.44
    0.91 ± 0.51
        Week 52 (N= 15, 9)
    -1.21 ± 0.73
    1.5 ± 0.99
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Placebo (Double-Blind Maintenance Phase) v Phase C - Brexpiprazole (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0507
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.23
         upper limit
    0
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.008
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.24
         upper limit
    -0.5
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0215
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.89
         upper limit
    -0.24
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0053
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.19
         upper limit
    -0.58
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0339
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.2
         upper limit
    -0.22
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.32
         upper limit
    -0.88

    Other pre-specified: Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PANSS Positive Subscale Score - LOCF Analysis
    End point description
    PANSS consisted of three subscales: a total of 30 symptom constructs. For each construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS positive subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    0.3 ± 0.49
    1.25 ± 0.45
        Week 12
    0.38 ± 0.59
    2.24 ± 0.54
        Week 24
    0.49 ± 0.64
    3.23 ± 0.59
        Week 36
    0.97 ± 0.63
    3.91 ± 0.58
        Week 52
    0.99 ± 0.64
    4.17 ± 0.59
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1093
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    0.21
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0089
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.25
         upper limit
    -0.47
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.26
         upper limit
    -1.22
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.43
         upper limit
    -1.44
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.7
         upper limit
    -1.66

    Other pre-specified: Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Negative Subscale Score - MMRM Analysis
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    -0.04 ± 0.37
    0.65 ± 0.35
        Week 12 (N= 73, 68)
    -0.22 ± 0.43
    0.55 ± 0.44
        Week 24 (N= 50, 36)
    -0.78 ± 0.39
    0.18 ± 0.42
        Week 36 (N= 33, 24)
    -1.03 ± 0.47
    0.02 ± 0.53
        Week 52 (N= 15, 9)
    1.3 ± 1.37
    0.87 ± 1.71
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.165
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.66
         upper limit
    0.29
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.97
         upper limit
    0.42
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0939
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.07
         upper limit
    0.16
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1396
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.44
         upper limit
    0.35
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.847
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.14
         upper limit
    5
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2258
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.24
         upper limit
    0.3

    Other pre-specified: Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PANSS Negative Subscale Score - LOCF Analysis
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS negative subscale score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    -0.12 ± 0.39
    0.63 ± 0.35
        Week 12
    -0.17 ± 0.46
    1.06 ± 0.42
        Week 24
    -0.08 ± 0.49
    1.47 ± 0.44
        Week 36
    -0.14 ± 0.51
    1.44 ± 0.46
        Week 52
    0.39 ± 0.54
    1.63 ± 0.49
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0981
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.65
         upper limit
    0.14
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0264
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    -0.15
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0078
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.69
         upper limit
    -0.42
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0101
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.77
         upper limit
    -0.38
    Statistical analysis title
    Statistical analysis at Week 52
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0516
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    0.01

    Other pre-specified: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis

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    End point title
    Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at Endpoint - MMRM Analysis
    End point description
    The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 2, 12, 24, 26 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    -0.01 ± 0.09
    0.26 ± 0.09
        Week 12 (N= 73, 68)
    -0.01 ± 0.11
    0.37 ± 0.11
        Week 24 (N= 50, 36)
    -0.16 ± 0.1
    0.21 ± 0.1
        Week 36 (N= 33, 24)
    -0.31 ± 0.11
    0.25 ± 0.12
        Week 52 (N= 15, 9)
    -0.23 ± 0.17
    0.28 ± 0.22
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0279
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    -0.03
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0117
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    -0.09
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0105
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.64
         upper limit
    -0.09
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.87
         upper limit
    -0.25
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.078
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.09
         upper limit
    0.06
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.54
         upper limit
    -0.15

    Other pre-specified: Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis

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    End point title
    Change From Baseline in CGI-S Score at Endpoint - LOCF Analysis
    End point description
    The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the study physician answered the following question: "Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?" Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    -0.08 ± 0.09
    0.17 ± 0.09
        Week 12
    -0.04 ± 0.11
    0.32 ± 0.1
        Week 24
    -0.03 ± 0.11
    0.47 ± 0.1
        Week 36
    0 ± 0.11
    0.56 ± 0.1
        Week 52
    0.02 ± 0.11
    0.55 ± 0.11
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0284
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.47
         upper limit
    -0.03
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Placebo (Double-Blind Maintenance Phase) v Phase C - Brexpiprazole (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0056
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    -0.11
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.76
         upper limit
    -0.24
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.82
         upper limit
    -0.3
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0002
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.79
         upper limit
    -0.26

    Other pre-specified: Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis

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    End point title
    Clinical Global Impression - Improvement Score (CGI-I) at Endpoint - LOCF Analysis
    End point description
    The rater or investigator would rate the participant's total improvement whether or not it is due entirely to study treatment. During Phase B, responses were compared to the participant's condition at Baseline of Phase B (for participants who entered Phase B directly after screening) or to the End of Phase A visit (for participants who participated in Phase A). During Phase C, responses were compared to the participant's condition at the End of Phase B visit. 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
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 6
    3.68 ± 0.98
    4 ± 1.14
        Week 12
    3.66 ± 1.19
    4.1 ± 1.3
        Week 24
    3.67 ± 1.27
    4.3 ± 1.32
        Week 36
    3.71 ± 1.27
    4.39 ± 1.3
        Week 52
    3.77 ± 1.26
    4.4 ± 1.32
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0387
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.2
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0185
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.75
         upper limit
    -0.07
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.97
         upper limit
    -0.24
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.02
         upper limit
    -0.3
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.96
         upper limit
    -0.25

    Other pre-specified: Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in Personal and Social Performance (PSP) Scale Score - MMRM Analysis
    End point description
    The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains is rated as absent, mild, manifest, marked, severe, or very severe. These ratings are then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment to determine the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 are considered to have mild functional difficulty. Scores of 31 to 70 represent manifest disabilities of various degrees and ratings of 1 to 30 indicate minimal functioning that requires intense support and/or supervision. The PSP score ranges from 0 to 100, with higher scores indicating higher levels of social functioning.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 24 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 24 (N= 50, 36)
    18.85 ± 1.51
    17.84 ± 1.82
        Week 52 (N= 15, 9)
    18.63 ± 2.76
    12.55 ± 3.48
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6525
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.47
         upper limit
    5.49
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1677
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    6.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.71
         upper limit
    14.87
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2347
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    3.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.41
         upper limit
    9.5

    Other pre-specified: Mean Change From Baseline in PSP Scale Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PSP Scale Score - LOCF Analysis
    End point description
    The PSP is a validated clinician-rated scale that measures personal and social functioning in four domains: socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment in each of these domains is rated as absent, mild, manifest, marked, severe, or very severe. These ratings are then converted to a total score based on a 100-point scale using algorithms to identify the appropriate 10-point interval, and the rater's judgment to determine the total score within the 10-point interval. Participants with a PSP total score of 71 to 100 are considered to have mild functional difficulty. Scores of 31 to 70 represent manifest disabilities of various degrees and ratings of 1 to 30 indicate minimal functioning that requires intense support and/or supervision. The PSP score ranges from 0 to 100, with higher scores indicating higher levels of social functioning.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 24 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    94
    100
    Units: Units on a scale
    least squares mean (standard error)
        Week 24
    15.2 ± 1.41
    11.41 ± 1.32
        Week 52
    15.06 ± 1.43
    10.31 ± 1.34
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0285
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    7.17
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0071
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    4.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.31
         upper limit
    8.18

    Other pre-specified: Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in Global Assessment of Functioning (GAF) Scale Score - MMRM Analysis
    End point description
    The GAF is a clinician-rated scale that assesses the participant's psychological, social, and occupational functioning on a hypothetical continuum of mental health-illness using a scale that ranges from 1 to 100 score, where lower values indicate worst outcome. From among 10 descriptive anchors, investigators will choose the anchor which is the most representative of the participant's level of functioning at the time of the assessment and will assign a single score within the point range given for the selected anchor.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 12 (N= 73, 68)
    1.59 ± 1.27
    -0.03 ± 1.29
        Week 24 (N= 50, 36)
    3.74 ± 1.42
    1.09 ± 1.57
        Week 36 (N= 33, 24)
    4.71 ± 1.5
    0.21 ± 1.67
        Week 52 (N= 15, 9)
    5.72 ± 1.87
    -0.16 ± 2.37
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.329
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.65
         upper limit
    4.88
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1756
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.22
         upper limit
    6.54
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0331
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    8.63
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0522
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    5.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.06
         upper limit
    11.82
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0281
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    3.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    6.92

    Other pre-specified: Mean Change From Baseline in GAF Scale Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in GAF Scale Score - LOCF Analysis
    End point description
    The GAF is a clinician-rated scale that assesses the participant's psychological, social, and occupational functioning on a hypothetical continuum of mental health-illness using a scale that ranges from 1 to 100 score, where lower values indicate worst outcome. From among 10 descriptive anchors, investigators will choose the anchor which is the most representative of the participant's level of functioning at the time of the assessment and will assign a single score within the point range given for the selected anchor.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    95
    102
    Units: Units on a scale
    least squares mean (standard error)
        Week 12
    0.44 ± 1.26
    -3.44 ± 1.17
        Week 24
    0.85 ± 1.37
    -4.51 ± 1.27
        Week 36
    0.97 ± 1.35
    -5.84 ± 1.25
        Week 52
    0.55 ± 1.38
    -6.01 ± 1.28
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0111
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    6.86
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    5.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.1
         upper limit
    8.62
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    6.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.61
         upper limit
    10
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    6.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.28
         upper limit
    9.83

    Other pre-specified: Percentage of Participants Who Discontinued Due to All Causes

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    End point title
    Percentage of Participants Who Discontinued Due to All Causes
    End point description
    Analysis of the percentage of participants who discontinued due to all causes was based on all participants who have been randomized and taken one dose of IMP in the Double-blind Maintenance phase. The trial was completed by sponsor when efficacy was demonstrated at the first pre-specified interim analysis (45 impending relapse events) performed by an independent (unblinded) statistician.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Percentage of participants
        number (not applicable)
    34.38
    54.81
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Statistical analysis for participants who discontinued due to all causes.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014
    Method
    Logrank
    Confidence interval

    Other pre-specified: Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Excited Component (PEC) Score - MMRM Analysis
    End point description
    The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    0.32 ± 0.23
    0.74 ± 0.22
        Week 12 (N= 73, 68)
    0.5 ± 0.34
    1.16 ± 0.35
        Week 24 (N= 50, 36)
    -0.06 ± 0.31
    0.45 ± 0.36
        Week 36 (N= 33, 24)
    0.1 ± 0.33
    1.25 ± 0.4
        Week 52 (N= 15, 9)
    -0.04 ± 0.46
    1 ± 0.59
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1577
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.02
         upper limit
    0.17
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1685
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.61
         upper limit
    0.28
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2815
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.43
         upper limit
    0.42
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0286
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.16
         upper limit
    -0.12
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1803
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.58
         upper limit
    0.51
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0077
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.12
         upper limit
    -0.17

    Other pre-specified: Mean Change From Baseline in PEC Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PEC Score - LOCF Analysis
    End point description
    The PEC score consisted of five PANSS items: excitement (P4), hostility (P7), tension (G4), uncooperativeness (G8), and poor impulse control (G14). Each of the items were rated on a scale of 1 (absent) to 7 (extreme). The PEC scores ranged from 5 (not present) to 35 (extremely severe).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    0.38 ± 0.27
    0.81 ± 0.25
        Week 12
    0.73 ± 0.36
    1.36 ± 0.33
        Week 24
    0.78 ± 0.42
    1.86 ± 0.38
        Week 36
    0.89 ± 0.41
    2.23 ± 0.38
        Week 52
    0.82 ± 0.41
    2.35 ± 0.38
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1852
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.06
         upper limit
    0.21
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.143
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.47
         upper limit
    0.21
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0323
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.06
         upper limit
    -0.09
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0071
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.31
         upper limit
    -0.37
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0023
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.52
         upper limit
    -0.56

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - MMRM Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    -0.1 ± 0.45
    1.24 ± 0.44
        Week 12 (N= 73, 68)
    -0.18 ± 0.58
    1.83 ± 0.58
        Week 24 (N= 50, 36)
    -0.82 ± 0.54
    0.77 ± 0.6
        Week 36 (N= 33, 24)
    -1.35 ± 0.57
    0.93 ± 0.63
        Week 52 (N= 15, 9)
    -1.62 ± 0.83
    1.78 ± 1.05
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0288
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.54
         upper limit
    -0.14
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0128
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    -0.44
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0462
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.15
         upper limit
    0.03
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0074
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.94
         upper limit
    -0.64
    Statistical analysis title
    Statistical analysis at Week 52
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0136
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.05
         upper limit
    -0.75
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.84
         upper limit
    -0.97

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Positive Symptoms Score - LOCF Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The positive factor score is the sum of the 8 components of the positive symptoms scale (range: 8 - best possible outcome to 56 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    0.05 ± 0.5
    1.13 ± 0.46
        Week 12
    0.1 ± 0.61
    2.03 ± 0.56
        Week 24
    0.25 ± 0.66
    3.08 ± 0.61
        Week 36
    0.6 ± 0.66
    3.69 ± 0.6
        Week 52
    0.58 ± 0.66
    4.02 ± 0.6
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Placebo (Double-Blind Maintenance Phase) v Phase C - Brexpiprazole (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0695
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.26
         upper limit
    0.09
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0089
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.38
         upper limit
    -0.49
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.39
         upper limit
    -1.27
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.63
         upper limit
    -1.54
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.99
         upper limit
    -1.89

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - MMRM Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    0.02 ± 0.38
    0.68 ± 0.36
        Week 12 (N= 73, 68)
    -0.01 ± 0.45
    0.8 ± 0.45
        Week 24 (N= 50, 36)
    -0.71 ± 0.4
    0.46 ± 0.43
        Week 36 (N= 33, 24)
    -0.8 ± 0.5
    0.7 ± 0.56
        Week 52 (N= 15, 9)
    1.37 ± 1.39
    1.06 ± 1.77
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1969
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.66
         upper limit
    0.35
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2007
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.04
         upper limit
    0.43
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0436
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    -0.03
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0444
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.97
         upper limit
    -0.04
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8927
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.4
         upper limit
    5.02
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2154
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.34
         upper limit
    0.31

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Negative Symptoms Score - LOCF Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The negative factor score is the sum of the 7 items of the negative subscale (range: 8 - best possible outcome to 56 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    -0.24 ± 0.4
    0.61 ± 0.36
        Week 12
    -0.15 ± 0.48
    1.09 ± 0.43
        Week 24
    -0.09 ± 0.49
    1.5 ± 0.44
        Week 36
    -0.07 ± 0.52
    1.56 ± 0.47
        Week 52
    0.34 ± 0.56
    1.57 ± 0.5
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0707
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.78
         upper limit
    0.07
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0276
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.35
         upper limit
    -0.14
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0065
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.72
         upper limit
    -0.45
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0085
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.84
         upper limit
    -0.42
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.063
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.52
         upper limit
    0.07

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - MMRM Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    -0.18 ± 0.31
    0.32 ± 0.3
        Week 12 (N= 73, 68)
    -0.44 ± 0.38
    0.69 ± 0.39
        Week 24 (N= 50, 36)
    -1.26 ± 0.34
    0.27 ± 0.38
        Week 36 (N= 33, 24)
    -1.31 ± 0.44
    0.17 ± 0.5
        Week 52 (N= 15, 9)
    -0.37 ± 0.99
    -0.3 ± 1.24
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Placebo (Double-Blind Maintenance Phase) v Phase C - Brexpiprazole (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2251
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.33
         upper limit
    0.31
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0368
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.19
         upper limit
    -0.07
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0024
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.51
         upper limit
    -0.56
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0293
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    -0.15
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9632
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.32
         upper limit
    3.17
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0029
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.63
         upper limit
    -0.34

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Disorganized Thought Score - LOCF Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The disorganized thoughts factor score is the sum of score from the 7 items on the disorganized thoughts subscale (range: 7 - best possible outcome to 49 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    -0.32 ± 0.34
    0.33 ± 0.31
        Week 12
    -0.19 ± 0.41
    1.19 ± 0.38
        Week 24
    -0.29 ± 0.44
    1.76 ± 0.41
        Week 36
    0 ± 0.45
    1.95 ± 0.42
        Week 52
    0.29 ± 0.48
    1.97 ± 0.45
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1062
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.44
         upper limit
    0.14
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0051
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.33
         upper limit
    -0.42
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.08
         upper limit
    -1.01
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3
         upper limit
    -0.89
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0035
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.81
         upper limit
    -0.56

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - MMRM Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6 (N= 81, 84)
    0.19 ± 0.19
    0.55 ± 0.18
        Week 12 (N= 73, 68)
    0.33 ± 0.28
    0.82 ± 0.29
        Week 24 (N= 50, 36)
    -0.26 ± 0.27
    0.81 ± 0.31
        Week 36 (N= 33, 24)
    -0.13 ± 0.29
    0.94 ± 0.34
        Week 52 (N= 15, 9)
    -0.2 ± 0.4
    0.94 ± 0.5
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1465
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.85
         upper limit
    0.13
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2154
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.27
         upper limit
    0.29
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2696
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.23
         upper limit
    0.35
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0179
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.95
         upper limit
    -0.19
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0875
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.46
         upper limit
    0.18
    Statistical analysis title
    Statistical analysis at across visits.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.08
         upper limit
    -0.24

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis

    Close Top of page
    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Uncontrolled Hostility/Excitement Score - LOCF Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The uncontrolled hostility/excitement factor score is the sum of score from the 4 items on the uncontrolled hostility/excitement subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    0.32 ± 0.22
    0.65 ± 0.21
        Week 12
    0.52 ± 0.3
    0.94 ± 0.28
        Week 24
    0.5 ± 0.36
    1.31 ± 0.33
        Week 36
    0.57 ± 0.36
    1.63 ± 0.33
        Week 52
    0.49 ± 0.37
    1.75 ± 0.34
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2135
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.86
         upper limit
    0.19
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2437
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.13
         upper limit
    0.29
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0635
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.66
         upper limit
    0.05
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0144
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.92
         upper limit
    -0.22
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0046
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.12
         upper limit
    -0.39

    Other pre-specified: Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis

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    End point title
    Mean Change From Baseline in PANSS Marder Factor Scores: Anxiety/Depression Score - LOCF Analysis
    End point description
    Retrospective factor analyses have been performed in recent decades using scores for the 30 individual PANSS items to categorize symptoms into 5 dimensions. Collectively, these dimensions are referred to as the PANSS Marder Factor scores and include positive symptoms score, negative symptoms score, thought score, uncontrolled hostility/excitement, anxiety depression score. The anxiety/depression factor score is the sum of score from the 4 items on the anxiety/depression subscale (range: 4 - best possible outcome to 28 - worst possible outcome).
    End point type
    Other pre-specified
    End point timeframe
    Weeks 6, 12, 24, 36 and 52
    End point values
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects analysed
    96
    104
    Units: Units on a scale
    least squares mean (standard error)
        Week 6
    0.19 ± 0.27
    0.85 ± 0.25
        Week 12
    0.86 ± 0.32
    1.41 ± 0.3
        Week 24
    1.07 ± 0.32
    1.64 ± 0.3
        Week 36
    1.09 ± 0.32
    1.79 ± 0.3
        Week 52
    1.17 ± 0.31
    1.88 ± 0.29
    Statistical analysis title
    Statistical analysis at Week 6.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0467
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.32
         upper limit
    -0.06
    Statistical analysis title
    Statistical analysis at Week 12.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1599
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.33
         upper limit
    0.22
    Statistical analysis title
    Statistical analysis at Week 24.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1417
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.35
         upper limit
    0.19
    Statistical analysis title
    Statistical analysis at Week 36.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0724
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.47
         upper limit
    0.06
    Statistical analysis title
    Statistical analysis at Week 52.
    Comparison groups
    Phase C - Brexpiprazole (Double-Blind Maintenance Phase) v Phase C - Placebo (Double-Blind Maintenance Phase)
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0608
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.47
         upper limit
    0.03

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events reported from the signing of the informed consent throughout the stabilization and treatment period followed by a follow-up phone call or clinic visit (study physician's discretion) of 30 (+2) days after last dose of study medication.
    Adverse event reporting additional description
    AEs were collected for participants who received brexpiprazole in the stabilization phase and for participants were randomized to double-blind treatment (brexpiprazole or placebo) and received at least one dose of double-blind study medication in Double-Blind Maintenance Phase.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Single Blind Stabilization Phase
    Reporting group description
    This single-blind stabilization phase was to titrate participants to a dose of brexpiprazole (1 to 4 mg/day) that would maintain stability of psychotic symptoms over 12 consecutive weeks (within a maximum of 36 weeks), while minimizing tolerability issues.

    Reporting group title
    Brexpiprazole (Double-blind Maintenance Phase)
    Reporting group description
    Participants received maintenance treatment daily with brexpiprazole (at the final dose achieved during the stabilization phase) for up to 52 weeks.

    Reporting group title
    Placebo (Double-blnd Maintenance Phase)
    Reporting group description
    Participants received placebo orally once daily for 52 weeks.

    Serious adverse events
    Single Blind Stabilization Phase Brexpiprazole (Double-blind Maintenance Phase) Placebo (Double-blnd Maintenance Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 464 (7.33%)
    3 / 97 (3.09%)
    11 / 104 (10.58%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 464 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 464 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (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
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 464 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 464 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    3 / 464 (0.65%)
    1 / 97 (1.03%)
    4 / 104 (3.85%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    22 / 464 (4.74%)
    1 / 97 (1.03%)
    5 / 104 (4.81%)
         occurrences causally related to treatment / all
    3 / 23
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    3 / 464 (0.65%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 464 (0.22%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Single Blind Stabilization Phase Brexpiprazole (Double-blind Maintenance Phase) Placebo (Double-blnd Maintenance Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    148 / 464 (31.90%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
    Investigations
    Weight increased
         subjects affected / exposed
    24 / 464 (5.17%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    27
    1
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    42 / 464 (9.05%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    57
    1
    1
    Headache
         subjects affected / exposed
    23 / 464 (4.96%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    42
    6
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    56 / 464 (12.07%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    90
    9
    8
    Schizophrenia
         subjects affected / exposed
    28 / 464 (6.03%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    7
    2
    2
    Agitation
         subjects affected / exposed
    30 / 464 (6.47%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    42
    1
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    As the interim analysis results were positive, the trial was completed as it achieved the primary endpoint of a significant delay in time to impending relapse for participants randomized to brexpiprazole when compared to participants in placebo.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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