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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Fixed dose OPC-34712 (4, 2, and 1 mg/day) in the Treatment of Adults With Acute Schizophrenia

    Summary
    EudraCT number
    2011-002513-11
    Trial protocol
    SK  
    Global end of trial date
    29 Jan 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    331-10-230
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01393613
    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
    Final
    Date of interim/final analysis
    13 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to compare the efficacy of each of 3 fixed doses of brexpiprazole with placebo in the treatment of acute schizophrenia in adults. The secondary objective was to compare the safety and tolerability.
    Protection of trial subjects
    This trial was conducted in compliance with the protocol, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline and the applicable local laws and regulatory requirements of the countries in which the trial was conducted, copies of the protocol, amendments, and informed consent form (ICF) were reviewed and approved by the governing institutional review board (IRB) or independent ethics committee (IEC) for each investigational site or country, as appropriate, prior to trial start or prior to implementation of the amendment at that site or country.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jul 2011
    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
    Colombia: 57
    Country: Number of subjects enrolled
    Croatia: 38
    Country: Number of subjects enrolled
    Mexico: 37
    Country: Number of subjects enrolled
    Philippines: 11
    Country: Number of subjects enrolled
    Russian Federation: 266
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    United States: 243
    Worldwide total number of subjects
    674
    EEA total number of subjects
    43
    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)
    672
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This trial was conducted in 674 participants from 68 trial sites in 8 countries.

    Pre-assignment
    Screening details
    Adults with schizophrenia as defined by Diagnostic and Statistical Manual of Mental Health Disorders 4th Edition Text Revision criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI) for schizophrenia and psychotic disorders studies were included.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Sponsor personnel, including those involved in monitoring, data management, and data analysis, did not have access to the treatment code during the trial. Access to the treatment codes was to have been restricted to personnel charged with generating and maintaining randomization files, packaging study medication, operating the interactive voice response system (IVRS)/ interactive web response system (IWRS), and reporting serious treatment-emergent adverse event (TEAEs) to regulatory agencies.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Brexpiprazole 1 mg
    Arm description
    Participants were administered oral brexpiprazole 1 milligram (mg) tablet once daily for 6 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    OPC-34712
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole 1 mg tablet once daily for 6 weeks.

    Arm title
    Brexpiprazole 2 mg
    Arm description
    Participants were administered oral brexpiprazole 2 mg tablet once daily for 6 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    OPC-34712
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole 2 mg tablet once daily for 6 weeks.

    Arm title
    Brexpiprazole 4 mg
    Arm description
    Participants were administered oral brexpiprazole 4 mg tablet once daily for 6 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    OPC-34712
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole 4 mg tablet once daily for 6 weeks.

    Arm title
    Placebo
    Arm description
    Participants were administered oral placebo tablet once daily for 6 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet once daily for 6 weeks.

    Number of subjects in period 1
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Started
    120
    186
    184
    184
    Completed
    81
    129
    130
    118
    Not completed
    39
    57
    54
    66
         Protocol deviation
    2
    1
    -
    -
         Met withdrawal criteria
    -
    -
    2
    1
         Physician decision
    2
    -
    -
    1
         Adverse event
    11
    11
    13
    22
         Lack of efficacy
    9
    20
    16
    21
         Consent withdrawn by subject
    15
    25
    23
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole 1 mg
    Reporting group description
    Participants were administered oral brexpiprazole 1 milligram (mg) tablet once daily for 6 weeks.

    Reporting group title
    Brexpiprazole 2 mg
    Reporting group description
    Participants were administered oral brexpiprazole 2 mg tablet once daily for 6 weeks.

    Reporting group title
    Brexpiprazole 4 mg
    Reporting group description
    Participants were administered oral brexpiprazole 4 mg tablet once daily for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants were administered oral placebo tablet once daily for 6 weeks.

    Reporting group values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo Total
    Number of subjects
    120 186 184 184 674
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    119 185 184 184 672
        From 65-84 years
    1 1 0 0 2
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.1 ± 11.9 36.9 ± 10.9 38.6 ± 11 39.3 ± 10.8 -
    Gender categorical
    Units: Subjects
        Female
    43 64 71 73 251
        Male
    77 122 113 111 423

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole 1 mg
    Reporting group description
    Participants were administered oral brexpiprazole 1 milligram (mg) tablet once daily for 6 weeks.

    Reporting group title
    Brexpiprazole 2 mg
    Reporting group description
    Participants were administered oral brexpiprazole 2 mg tablet once daily for 6 weeks.

    Reporting group title
    Brexpiprazole 4 mg
    Reporting group description
    Participants were administered oral brexpiprazole 4 mg tablet once daily for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants were administered oral placebo tablet once daily for 6 weeks.

    Primary: Mean change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score.

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    End point title
    Mean change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score.
    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). Efficacy sample consisted of all participants who received at least one dose of study medication and had Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Primary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: Units on a scale
        least squares mean (standard error)
    -16.9 ± 1.86
    -16.61 ± 1.49
    -20 ± 1.48
    -13.53 ± 1.52
    Statistical analysis title
    Statistical analysis 1 at Week 6
    Statistical analysis description
    Difference between the average effect of brexpiprazole 2 and 4 mg/day and placebo was tested first at alpha level of 0.05. If statistically significant, then comparisons for each group (brexpiprazole 2 and 4 mg/day) versus placebo were performed at a significance level of 0.05. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    540
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0093
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Statistical analysis 2 at Week 6
    Statistical analysis description
    The primary statistical analysis was to compare brexpiprazole 1mg/day and placebo performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 1 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1588
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.06
         upper limit
    1.32
    Statistical analysis title
    Statistical analysis 3 at Week 6
    Statistical analysis description
    The primary statistical analysis was to compare brexpiprazole 2mg/day and placebo performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 2 mg
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1448
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.23
         upper limit
    1.07
    Statistical analysis title
    Statistical analysis 4 at Week 6
    Statistical analysis description
    The primary statistical analysis was to compare brexpiprazole 2mg/day and placebo performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 4 mg
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0022
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.6
         upper limit
    -2.35

    Secondary: Mean change from Baseline to Week 6 in Clinical Global Impression-Severity of Illness Scale (CGI-S) Score.

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    End point title
    Mean change from Baseline to Week 6 in Clinical Global Impression-Severity of Illness Scale (CGI-S) Score.
    End point description
    This is the key secondary endpoint. The severity of illness for each participant was rated using the CGI-S. To perform this assessment, 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 at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    120
    180
    183
    181
    Units: Units on a scale
        least squares mean (standard error)
    -0.91 ± 0.11
    -0.99 ± 0.09
    -1.19 ± 0.08
    -0.81 ± 0.09
    Statistical analysis title
    Statistical analysis 1 at Week 6
    Statistical analysis description
    Statistical analysis to compare the average effect analysis for brexpiprazole 2 mg/day and 4 mg/day combined treatment groups at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo v Brexpiprazole 2 mg
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0069
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Statistical analysis 2 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 1 mg
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4449
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    0.16
    Statistical analysis title
    Statistical analysis 3 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 2 mg
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1269
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.42
         upper limit
    -0.05
    Statistical analysis title
    Statistical analysis 4 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 4 mg
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0015
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    -0.15

    Secondary: Mean change from Baseline to Week 6 in Personal and Social Performance (PSP) Score.

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    End point title
    Mean change from Baseline to Week 6 in Personal and Social Performance (PSP) Score.
    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 was rated as absent, mild, manifest, marked, severe, or very severe. These ratings were 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 were considered to have mild functional difficulty. Scores of 31 to 70 represented manifest disabilities of various degrees and ratings of 1 to 30 indicated minimal functioning that required intense support and/or supervision. All participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    105
    170
    174
    163
    Units: Units on a scale
        least squares mean (standard error)
    11.73 ± 1.19
    10.52 ± 0.95
    13.11 ± 0.94
    8.52 ± 0.97
    Statistical analysis title
    Statistical analysis 1 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0332
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    3.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    6.16
    Statistical analysis title
    Statistical analysis 2 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1286
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.58
         upper limit
    4.59
    Statistical analysis title
    Statistical analysis 3 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. MMRM analysis fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    4.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.02
         upper limit
    7.17

    Secondary: Mean change from Baseline to Week 6 in PANSS Positive Subscale score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Positive Subscale score.
    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 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). Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: Units on a scale
        least squares mean (standard error)
    -5.63 ± 0.62
    -5.42 ± 0.5
    -6.65 ± 0.5
    -4.95 ± 0.51
    Statistical analysis title
    Statistical analysis 1 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3938
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.26
         upper limit
    0.89
    Statistical analysis title
    Statistical analysis 2 at Week 6
    Statistical analysis description
    The primary statistical analysis was to compare brexpiprazole 2mg/day and placebo performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5101
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.86
         upper limit
    0.93
    Statistical analysis title
    Statistical analysis 3 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0166
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.08
         upper limit
    -0.31

    Secondary: Mean change from Baseline to Week 6 in PANSS Negative Subscale score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Negative Subscale score.
    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). Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    81
    130
    128
    119
    Units: Units on a scale
        least squares mean (standard error)
    -2.92 ± 0.48
    -2.91 ± 0.38
    -3.36 ± 0.38
    -2.14 ± 0.39
    Statistical analysis title
    Statistical analysis 1 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2004
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.98
         upper limit
    0.42
    Statistical analysis title
    Statistical analysis 2 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1547
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.83
         upper limit
    0.29
    Statistical analysis title
    Statistical analysis 3 at Week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0231
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.28
         upper limit
    -0.17

    Secondary: Mean Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 6.

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    End point title
    Mean Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 6.
    End point description
    The efficacy of trial medication was rated for each participant using the CGI-I. The study physician would rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at Baseline prior to the first dose of double-blind study medication. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    120
    180
    183
    181
    Units: Units on a scale
        arithmetic mean (standard deviation)
    3.2 ± 1.45
    3.17 ± 1.34
    2.95 ± 1.33
    3.48 ± 1.46
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. Last observation carried forward (LOCF) dataset was to include data recorded at a scheduled visit, ie, all observed cases (OC) data, or, if no observation is recorded at that visit, data carried forward from the previously scheduled visit. Baseline data were not be carried forward to impute missing values for the LOCF dataset.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1358 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    0.08
    Notes
    [1] - CMH row mean scores differ test controlling for study center.
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. LOCF dataset was to include data recorded at a scheduled visit, ie, all OC data, or, if no observation is recorded at that visit, data carried forward from the previously scheduled visit. Baseline data were not be carried forward to impute missing values for the LOCF dataset.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0422 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.01
    Notes
    [2] - CMH row mean scores differ test controlling for study center.
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. LOCF dataset was to include data recorded at a scheduled visit, ie, all OC data, or, if no observation is recorded at that visit, data carried forward from the previously scheduled visit. Baseline data were not be carried forward to impute missing values for the LOCF dataset.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    -0.2
    Notes
    [3] - CMH row mean scores differ test controlling for study center.

    Secondary: Percentage of participants with response at Week 6.

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    End point title
    Percentage of participants with response at Week 6.
    End point description
    The response rate was defined as reduction of ≥30% from Baseline in PANSS Total Score or CGI-I score of 1 or 2. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: percentage of participants
        number (not applicable)
    43.6
    38.5
    49.7
    31.7
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. LOCF dataset was to include data recorded at a scheduled visit, ie, all OC data, or, if no observation is recorded at that visit, data carried forward from the previously scheduled visit. Baseline data were not be carried forward to impute missing values for the LOCF dataset.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0433 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Relative Risk
    Point estimate
    1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    1.79
    Notes
    [4] - CMH row mean scores differ test controlling for study center.
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. LOCF dataset was to include data recorded at a scheduled visit, ie, all OC data, or, if no observation is recorded at that visit, data carried forward from the previously scheduled visit. Baseline data were not be carried forward to impute missing values for the LOCF dataset.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.168
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Relative Risk
    Point estimate
    1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    1.62
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. LOCF dataset was to include data recorded at a scheduled visit, ie, all OC data, or, if no observation is recorded at that visit, data carried forward from the previously scheduled visit. Baseline data were not be carried forward to impute missing values for the LOCF dataset.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Relative Risk
    Point estimate
    1.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    2
    Notes
    [5] - CMH row mean scores differ test controlling for study center.

    Secondary: Percentage of participants with discontinuation rate for lack of efficacy at Week 6.

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    End point title
    Percentage of participants with discontinuation rate for lack of efficacy at Week 6.
    End point description
    Participants discontinued for lack of efficacy during the trial were reported here. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: percentage of participants
        number (not applicable)
    7.69
    11.2
    8.84
    11.7
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4586 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Relative Risk
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    1.59
    Notes
    [6] - CMH row mean scores differ test controlling for study center.
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9894 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Relative Risk
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.85
    Notes
    [7] - CMH row mean scores differ test controlling for study center.
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5202 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Relative Risk
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.51
    Notes
    [8] - CMH row mean scores differ test controlling for study center.

    Secondary: Mean change from Baseline to Week 6 in PANSS Excited Component (PEC) Score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Excited Component (PEC) Score.
    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). Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: Units on a scale
        least squares mean (standard error)
    -1.94 ± 0.41
    -1.9 ± 0.33
    -2.86 ± 0.33
    -1.47 ± 0.34
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 1 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3646
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.51
         upper limit
    0.56
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3559
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.34
         upper limit
    0.48
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0029
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    -0.48

    Secondary: Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Positive Symptoms Score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Positive Symptoms Score.
    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 (range: 8 to 56): sum of select scores from positive, negative, and general psychopathology subscales. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: Units on a scale
        least squares mean (standard error)
    -6.56 ± 0.66
    -6.26 ± 0.53
    -7.05 ± 0.53
    -5.91 ± 0.54
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4423
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.32
         upper limit
    1.01
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.64
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.83
         upper limit
    1.12
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1273
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.61
         upper limit
    0.33

    Secondary: Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Negative Symptoms Score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Negative Symptoms Score.
    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 (range: 7 to 49): sum of select scores from negative and general psychopathology subscales. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: Units on a scale
        least squares mean (standard error)
    -3.55 ± 0.48
    -3.53 ± 0.39
    -3.84 ± 0.39
    -2.55 ± 0.4
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.108
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.22
         upper limit
    0.22
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0754
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.06
         upper limit
    0.1
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0194
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.36
         upper limit
    -0.21

    Secondary: Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Disorganized Thought Score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Disorganized Thought Score.
    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 (range: 7 to 49): sum of select scores from positive, negative, and general psychopathology subscales. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: Units on a scale
        least squares mean (standard error)
    -3.46 ± 0.43
    -2.94 ± 0.35
    -3.98 ± 0.34
    -2.59 ± 0.35
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 1 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.115
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.96
         upper limit
    0.21
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4753
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.31
         upper limit
    0.61
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0045
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.34
         upper limit
    -0.43

    Secondary: Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Uncontrolled Hostility and Excitement Score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Uncontrolled Hostility and Excitement Score.
    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 (range: 4 to 28): sum of select scores from positive and general psychopathology subscales. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    81
    130
    128
    119
    Units: Units on a scale
        least squares mean (standard error)
    -0.9 ± 0.36
    -0.81 ± 0.29
    -1.89 ± 0.29
    -0.64 ± 0.3
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5752
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.16
         upper limit
    0.65
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 2 mg
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6792
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.97
         upper limit
    0.63
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.05
         upper limit
    -0.46

    Secondary: Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Anxiety and Depression Score.

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    End point title
    Mean change from Baseline to Week 6 in PANSS Marder Factor Scores: Anxiety and Depression Score.
    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 (range: 4 to 28): sum of select scores from general psychopathology subscale. Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Number of subjects analysed
    117
    179
    181
    180
    Units: Units on a scale
        least squares mean (standard error)
    -3.57 ± 0.3
    -3.62 ± 0.24
    -3.78 ± 0.24
    -2.93 ± 0.24
    Statistical analysis title
    Statistical analysis 1 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 1mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 1 mg v Placebo
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.089
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.39
         upper limit
    0.1
    Statistical analysis title
    Statistical analysis 2 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 2mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 2 mg v Placebo
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0373
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.35
         upper limit
    -0.04
    Statistical analysis title
    Statistical analysis 3 at week 6
    Statistical analysis description
    Statistical analysis to compare brexpiprazole 4mg/day and placebo was performed at Week 6. With fixed effect of treatment, clinical visit, treatment visit interaction, Baseline value, and Baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0104
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.51
         upper limit
    -0.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from signing of the informed consent until follow-up for up to 30 (+2) days after the last dose of study medication.
    Adverse event reporting additional description
    A serious adverse event (SAE) was an untoward medical occurrence that resulted in death or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or a new problem experienced by a participant when enrolled in a trial whether or not it was considered drug related by study physician.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Brexpiprazole 1 mg
    Reporting group description
    Participants were administered oral brexpiprazole 1 mg tablet once daily for 6 weeks.

    Reporting group title
    Brexpiprazole 2 mg
    Reporting group description
    Participants were administered oral brexpiprazole 2 mg tablet once daily for 6 weeks.

    Reporting group title
    Brexpiprazole 4 mg
    Reporting group description
    Participants were administered oral brexpiprazole 4 mg tablet once daily for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants were administered oral placebo tablets once daily for 6 weeks.

    Serious adverse events
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 120 (2.50%)
    4 / 186 (2.15%)
    4 / 184 (2.17%)
    10 / 184 (5.43%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 186 (0.00%)
    0 / 184 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 186 (0.00%)
    0 / 184 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 186 (0.00%)
    0 / 184 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 120 (0.83%)
    2 / 186 (1.08%)
    1 / 184 (0.54%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 120 (0.83%)
    2 / 186 (1.08%)
    3 / 184 (1.63%)
    8 / 184 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 186 (0.00%)
    1 / 184 (0.54%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brexpiprazole 1 mg Brexpiprazole 2 mg Brexpiprazole 4 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 120 (30.83%)
    65 / 186 (34.95%)
    66 / 184 (35.87%)
    71 / 184 (38.59%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    5 / 120 (4.17%)
    9 / 186 (4.84%)
    12 / 184 (6.52%)
    13 / 184 (7.07%)
         occurrences all number
    8
    10
    14
    13
    Headache
         subjects affected / exposed
    9 / 120 (7.50%)
    20 / 186 (10.75%)
    19 / 184 (10.33%)
    27 / 184 (14.67%)
         occurrences all number
    12
    27
    20
    40
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    10 / 120 (8.33%)
    16 / 186 (8.60%)
    13 / 184 (7.07%)
    13 / 184 (7.07%)
         occurrences all number
    11
    29
    17
    22
    Insomnia
         subjects affected / exposed
    15 / 120 (12.50%)
    25 / 186 (13.44%)
    28 / 184 (15.22%)
    27 / 184 (14.67%)
         occurrences all number
    18
    32
    44
    44
    Schizophrenia
         subjects affected / exposed
    4 / 120 (3.33%)
    6 / 186 (3.23%)
    7 / 184 (3.80%)
    10 / 184 (5.43%)
         occurrences all number
    4
    6
    7
    11
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    7 / 120 (5.83%)
    7 / 186 (3.76%)
    6 / 184 (3.26%)
    6 / 184 (3.26%)
         occurrences all number
    9
    8
    8
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jul 2012
    A formal amendment to the original protocol was to change the primary method for statistical analysis from an analysis of covariance (ANCOVA) model based on the last observation carried forward (LOCF) to MMRM and to add additional clarity to some trial procedures. Clarify that every effort was made to complete efficacy scales prior to administering rescue medication at the last trial (or early termination) visit and that efficacy scales were not done if a new antipsychotic was given before the scales were completed. Add change from Baseline in PANSS Excited Component and PANSS Marder Factor scores as secondary efficacy variables. Clarify that participants who were sterile (ie, women who have had an oophorectomy and/or hysterectomy or have been postmenopausal for at least 12 consecutive months; or men who have had orchidectomy) were not required to use two different methods of birth control and add “other approved birth control device” to the list of acceptable birth control methods. Clarify instructions for preparation of whole blood sample for metabolic profiling. Clarify that participants may remain on stable doses of propranolol during the trial if the propranolol is being taken for an indication other than akathisia. Revise Appendix 9 to include the correct version of the PANSS (ie, 2006). The 2006 version of the PANSS was the version that was distributed to the sites at the start of the trial and was used by raters throughout the trial. In addition, administrative changes were made and typographical errors identified during review of the protocol amendment were corrected.
    20 Dec 2013
    A second formal amendment to the original protocol was done to change the primary and secondary efficacy analysis used the Hochberg procedure to control multiplicity. This testing scheme was replaced by the Average Method to be carried out in 2 steps to control the family-wise error rate. In addition, administrative changes were made.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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