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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo- and Active-controlled Trial to Evaluate the Efficacy of Brexpiprazole Monotherapy for the Treatment in Adolescents (13-17 Years old) With Schizophrenia

    Summary
    EudraCT number
    		 2017-001447-12
    Trial protocol
    		 HU   ES   PL   BG   FR   IT   RO  
    Global end of trial date
    03 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2023
    First version publication date
    15 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    331-10-234
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03198078
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, 20850
    Public contact
    Clinical Transparency, Otsuka Pharmaceutical Development & Commercialization, Inc., clinicaltransparency@otsuka-us.com
    Scientific contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., clinicaltransparency@otsuka-us.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001185-PIP01-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the short-term efficacy and safety of brexpiprazole monotherapy in the treatment of adolescents with schizophrenia.
    Protection of trial subjects
    Written informed consent, assent, or both were obtained from a legally acceptable representative (eg, guardian) or subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Mexico: 95
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Serbia: 31
    Country: Number of subjects enrolled
    Ukraine: 102
    Country: Number of subjects enrolled
    United States: 43
    Worldwide total number of subjects
    316
    EEA total number of subjects
    34
    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)
    315
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at investigational sites in the United States, Mexico, France, Italy, Poland, Romania, Serbia, Spain, Ukraine, and Russia from 30 June 2017 to 03 April 2023.

    Pre-assignment
    Screening details
    		 A total of 376 subjects were screened, of which 316 subjects were enrolled and randomised to brexpiprazole, aripiprazole, or placebo groups in 1:1:1 ratio.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brexpiprazole
    Arm description
    		 Subjects were administered with brexpiprazole oral tablets, daily, dose titrated up to 0.5 mg by Day 4, 1 mg by Day 7, 2 mg by Day 14, then between 2-4 mg after Day 21 up to Week 6 with a 1 mg increase or decrease, based on the Investigator's decision.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    OPC-34712
    Other name
    Rexulti®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole tablets, flexible dosing from 0.5 to 4 mg/day administered orally up to Week 6.

    Arm title
    		 Aripiprazole
    Arm description
    		 Subjects were administered with aripiprazole oral tablets, daily, dose titrated up to 2 mg by Day 4, 5 mg by Day 7, 10 mg by Day 14, then 10, 15 or 20 mg after Day 21 up to Week 6 with a 5 mg increase or decrease, based on the Investigator's decision.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aripiprazole tablets, flexible dosing from 2 to 20 mg/day administered orally up to Week 6.

    Arm title
    		 Placebo
    Arm description
    		 Subjects were administered with brexpiprazole or aripiprazole matching placebo oral tablets, daily up to Week 6.
    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
    Matching placebo tablets were administered orally up to Week 6.

    Number of subjects in period 1
    		Brexpiprazole Aripiprazole Placebo
    Started
    110
    102
    104
    Completed
    107
    97
    92
    Not completed
    3
    5
    12
         Adverse Event
    -
    1
    2
         Pregnancy
    -
    1
    -
         Withdrawal by Subject
    1
    -
    2
         Lost to follow-up
    1
    -
    -
         Withdrawal by Caregiver
    1
    3
    5
         Lack of efficacy
    -
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Subjects were administered with brexpiprazole oral tablets, daily, dose titrated up to 0.5 mg by Day 4, 1 mg by Day 7, 2 mg by Day 14, then between 2-4 mg after Day 21 up to Week 6 with a 1 mg increase or decrease, based on the Investigator's decision.

    Reporting group title
    Aripiprazole
    Reporting group description
    		 Subjects were administered with aripiprazole oral tablets, daily, dose titrated up to 2 mg by Day 4, 5 mg by Day 7, 10 mg by Day 14, then 10, 15 or 20 mg after Day 21 up to Week 6 with a 5 mg increase or decrease, based on the Investigator's decision.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered with brexpiprazole or aripiprazole matching placebo oral tablets, daily up to Week 6.

    Reporting group values
    		 Brexpiprazole Aripiprazole Placebo Total
    Number of subjects
    		 110 102 104 316
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.3 ( 1.5 ) 15.3 ( 1.4 ) 15.2 ( 1.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 57 51 166
        Male
    		 52 45 53 150
    Race
    Units: Subjects
        White
    		 70 66 68 204
        Black or African American
    		 8 7 6 21
        American Indian or Alaska Native
    		 2 1 4 7
        Asian
    		 1 1 0 2
        Other
    		 29 27 25 81
        Missing
    		 0 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 34 32 34 100
        Not Hispanic or Latino
    		 75 70 68 213
        Other
    		 1 0 1 2
        Missing
    		 0 0 1 1
    Positive and Negative Syndrome Scale (PANSS) Total Score
    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) to 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 ranges from 30 (best possible outcome) to 210 (worst possible outcome). Higher scores indicate worsening of symptoms.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 101.1 ( 14.9 ) 101.0 ( 13.0 ) 102.1 ( 16.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Subjects were administered with brexpiprazole oral tablets, daily, dose titrated up to 0.5 mg by Day 4, 1 mg by Day 7, 2 mg by Day 14, then between 2-4 mg after Day 21 up to Week 6 with a 1 mg increase or decrease, based on the Investigator's decision.

    Reporting group title
    Aripiprazole
    Reporting group description
    		 Subjects were administered with aripiprazole oral tablets, daily, dose titrated up to 2 mg by Day 4, 5 mg by Day 7, 10 mg by Day 14, then 10, 15 or 20 mg after Day 21 up to Week 6 with a 5 mg increase or decrease, based on the Investigator's decision.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered with brexpiprazole or aripiprazole matching placebo oral tablets, daily up to Week 6.

    Primary: Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score

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    End point title
    		 Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score
    End point description
    The PANSS consisted of three subscales: 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) to 7 (extremely severe symptoms). PANSS total score was sum of rating scores for 7 positive scale items, 7 negative scale items, & 16 general psychopathology scale items from PANSS panel. PANSS total score ranges from 30 (best possible outcome) to 210 (worst possible outcome). Higher scores indicate worsening of symptoms. Least squares (LS) mean was determined by Mixed-effect model repeated measures (MMRM) method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value and baseline visit interaction as a covariate, & with an unstructured covariance. Efficacy sample included all randomised subjects who received at least 1 dose of investigational medicinal product (IMP),had a baseline assessment, & at least one post-baseline assessment of the PANSS Total Score.
    End point type
    Primary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
        least squares mean (standard error)
    -22.75 ( 1.49 )
    -23.95 ( 1.57 )
    -17.42 ( 1.58 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0136 [1]
    Method
    		 MMRM
    Parameter type
    		 Least squares (LS) mean Difference
    Point estimate
    -5.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.55
         upper limit
    		 -1.1
    Notes
    [1] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032 [2]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -6.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.8
         upper limit
    		 -2.21
    Notes
    [2] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.

    Secondary: Change From Baseline to Week 6 in PANSS Positive and Negative Sub-scales Scores

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    End point title
    		 Change From Baseline to Week 6 in PANSS Positive and Negative Sub-scales Scores
    End point description
    PANSS has 7 positive symptom constructs: delusions, conceptual disorganisation, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility; and 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. Each item`s severity was rated on 7-point scale, with score of 1 (absence of symptoms) to 7 (extremely severe symptoms). PANSS positive & negative subscale scores were the sum of rating scores for 7 positive & 7 negative items respectively. Both scores range from 7 (best possible outcome) to 49 (worst possible outcome). Higher scores denote worsening of symptoms. LS mean was determined by MMRM method. Efficacy sample included all randomised subjects who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
    least squares mean (standard error)
        Change From Baseline in PANSS Positive Score
    -6.58 ( 0.43 )
    -7.29 ( 0.45 )
    -5.14 ( 0.46 )
        Change From Baseline in PANSS Negative Score
    -4.70 ( 0.41 )
    -4.77 ( 0.43 )
    -3.82 ( 0.44 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Statistical analysis description
    PANSS positive sub-scale score
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0205 [3]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.65
         upper limit
    		 -0.22
    Notes
    [3] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Statistical analysis description
    PANSS positive sub-scale score
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008 [4]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -2.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 -0.91
    Notes
    [4] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Statistical analysis description
    PANSS negative sub-scale score
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.136 [5]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.04
         upper limit
    		 0.28
    Notes
    [5] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Statistical analysis description
    PANSS negative sub-scale score
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1158 [6]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 0.24
    Notes
    [6] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.

    Secondary: Percentage of Subjects Achieving Response

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    End point title
    		 Percentage of Subjects Achieving Response
    End point description
    Response was defined as at least 30% improvement from baseline in PANSS Total Score or CGI score of 1 or 2. 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, and ranges from 30 (best possible outcome) to 210 (worst possible outcome). The CGI scale is an investigator-rated evaluation that assesses the severity of a subject’s illness on a 7-point scale, ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill subjects). Percentage of subjects achieving response was determined by Last Observation Carried Forward (LOCF) method. Efficacy sample included all randomised subjects who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score. Percentages are rounded off to the nearest decimal point.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: percentage of subjects
        number (not applicable)
    43.64
    43.56
    28.16
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0111 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response rate
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 2.2
    Notes
    [7] - P-value was analysed by Cochran-Mantel-Haenszel (CMH) general association test controlling for (pooled) centers.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0224 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response rate
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 2.16
    Notes
    [8] - P-value was analysed by CMH general association test controlling for (pooled) centers.

    Secondary: Percentage of Subjects Achieving Remission

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    End point title
    		 Percentage of Subjects Achieving Remission
    End point description
    Remission was defined as a score of ≤ 3 on each of the following specific PANSS items: delusions (positive scale item [P] 1), unusual thought content (general scale item [G] 9), hallucinatory behavior (P3), conceptual disorganisation (P2), mannerisms/posturing (G5), blunted affect (negative scale item [N] 1), passive/apathetic social withdrawal (N4), and lack of spontaneity and conversation flow (N6). Each item`s severity was rated on 7-point scale, with score of 1 (absence of symptoms) to 7 (extremely severe symptoms). Percentage of subjects achieving remission was determined by LOCF method. Efficacy sample included all randomised subjects who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score. Percentages are rounded off to the nearest decimal point.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: percentage of subjects
        number (not applicable)
    29.09
    35.64
    23.30
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4415 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Remission Rate
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.81
    Notes
    [9] - P-value was analysed by CMH general association test controlling for (pooled) centers.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0472 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Remission Rate
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.16
    Notes
    [10] - P-value was analysed by CMH general association test controlling for (pooled) centers.

    Secondary: Change From Baseline to Week 6 in Children’s Global Assessment Scale (CGAS) Total Score

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    End point title
    		 Change From Baseline to Week 6 in Children’s Global Assessment Scale (CGAS) Total Score
    End point description
    The CGAS is a 100-point rating scale measuring psychological, social, and school functioning for children aged 6-17 years and provides a global measure of the severity of disturbance. The scale is separated into 10-point sections that are headed with a description of the level of functioning and followed by examples matching the interval. The score ranges from 0-100, 1 to 10 indicates the need for constant supervision and 91 to 100 indicates superior functioning in all areas. Higher scores indicate better functioning. LS mean was determined by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance. Efficacy sample included all randomised subjects who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
        least squares mean (standard error)
    10.56 ( 1.00 )
    12.07 ( 1.05 )
    8.08 ( 1.06 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0854 [11]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 5.31
    Notes
    [11] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0072 [12]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    3.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 6.88
    Notes
    [12] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.

    Secondary: Change From Baseline to Week 6 in Clinical Global Impression Severity (CGI-S) Score

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    End point title
    		 Change From Baseline to Week 6 in Clinical Global Impression Severity (CGI-S) Score
    End point description
    The CGI-S scale is an investigator-rated evaluation that assesses the severity of a subject’s illness on a 7-point scale, ranging from 1 to 7. The investigator answered the question: “Considering your total clinical experience with this particular population, how mentally ill is the subject at this time?”. Response choices were: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill subjects. Higher scores indicate worse condition. LS mean was determined by the MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance. Efficacy sample included all randomised subjects who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
        least squares mean (standard error)
    -0.92 ( 0.09 )
    -1.01 ( 0.09 )
    -0.80 ( 0.09 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3589 [13]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.13
    Notes
    [13] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1118 [14]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 0.05
    Notes
    [14] - P-value was analysed by MMRM method with fixed effect of treatment, (pooled) clinical center visit, treatment visit interaction, baseline value, and baseline visit interaction as a covariate, and with an unstructured covariance.

    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 brexpiprazole in the treatment was rated for each subject using the CGI-I. The investigator rated the subject’s total improvement whether or not it was entirely due to drug treatment on a 7-point scale, ranging from 0 to 7. Response choices were: 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. Higher scores indicate worse condition. Mean CGI-I scale score was determined by LOCF method. Efficacy sample included all randomised subjects who received at least 1 dose of IMP, had a baseline assessment, and at least one post-baseline assessment of the PANSS Total Score.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
        arithmetic mean (standard deviation)
    2.86 ( 0.95 )
    2.79 ( 0.97 )
    3.17 ( 1.08 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0287 [15]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.03
    Notes
    [15] - P-value was analysed by CMH row mean scores differ test controlling for study center.
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0184 [16]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 -0.06
    Notes
    [16] - P-value was analysed by CMH row mean scores differ test controlling for study center.

    Secondary: Number of Subjects With Adverse Events (AEs) and Trial Discontinuations Due to AEs

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Trial Discontinuations Due to AEs
    End point description
    An AE was defined as any untoward medical occurrence in a subject administered with a medicinal product that does not necessarily have a causal relationship with the treatment. Safety sample included all randomised subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to 21 days after the last dose of study drug (up to approximately 9 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    102
    104
    Units: subjects
        AEs
    46
    56
    44
        Trial Discontinuation Due to AEs
    0
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent AEs (TEAEs), Serious TEAEs, and TEAEs Graded by Severity

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    End point title
    		 Number of Subjects With Treatment-emergent AEs (TEAEs), Serious TEAEs, and TEAEs Graded by Severity
    End point description
    AE is any untoward medical occurrence in subject administered with medicinal product that does not necessarily have a causal relationship with treatment. An SAE is any AE that results in appearance of (or worsening of any pre-existing) undesirable signs, symptoms/medical conditions which is fatal, life-threatening, result in persistent/significant disability/incapacity, constitutes congenital anomaly/birth defect, and requires inpatient hospitalisation/prolongation of existing hospitalisation. TEAE is AE after start of treatment/if event was continuous from baseline, medicinal product related, or resulted in death, discontinuation, interruption/reduction of medicinal product. TEAEs were graded on a 3-point scale: 1(Mild:Discomfort noticed, but no disruption to daily activity), 2(Moderate:Discomfort sufficient to reduce/affect normal daily activity), 3(Severe:Inability to work/perform normal daily activity). Safety sample=all randomized participants who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to 21 days after the last dose of study drug (up to approximately 9 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    102
    104
    Units: subjects
        Serious TEAEs
    1
    1
    3
        Mild TEAEs
    33
    47
    32
        Moderate TEAEs
    17
    16
    13
        Severe TEAEs
    2
    0
    1
        TEAEs
    44
    53
    42
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Relevant Abnormalities in Vital Signs 

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    End point title
    		 Number of Subjects With Potentially Clinically Relevant Abnormalities in Vital Signs 
    End point description
    Vital sign measurements included body weight measured in kilograms (kg), systolic blood pressure (SBP), and diastolic blood pressure (DBP), measured in millimetres of mercury (mmHg). Blood pressure measurements were made in the supine, sitting, and standing positions after the subject had been in each position for at least 3 minutes. Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed' indicates the number of subjects with at least one post-baseline result for the specified vital signs.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: subjects
        SBP Sitting (mmHg): Low
    0
    0
    1
        SBP Standing (mmHg): Low
    1
    1
    0
        SBP Supine (mmHg): Low
    0
    0
    1
        DBP Standing (mmHg): Low
    1
    0
    0
        DBP Supine (mmHg): Low
    0
    1
    0
        Weight (kg): Low
    5
    2
    4
        Weight (kg): High
    9
    5
    5
        Orthostatic Hypotension (mmHg): Low
    2
    1
    2
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Weight

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    End point title
    		 Mean Change From Baseline in Weight
    End point description
    Change in weight was reported, in kg. Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed’ indicates the number of subjects with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to last visit (approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: kg
        arithmetic mean (standard deviation)
    0.8 ( 2.6 )
    0.5 ( 2.7 )
    0.0 ( 2.2 )
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Height

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    End point title
    		 Mean Change From Baseline in Height
    End point description
    Change in height was reported in centimeters (cm). Safety sample included all randomised subjects who received at least 1 dose of IMP. 'Number of subjects analysed' indicates the number of subjects with data available for the endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to last visit (approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    108
    99
    96
    Units: cm
        arithmetic mean (standard deviation)
    0.2 ( 1.1 )
    0.2 ( 2.9 )
    0.3 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Body Mass Index (BMI)

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    End point title
    		 Mean Change From Baseline in Body Mass Index (BMI)
    End point description
    Change in BMI was reported in kilograms per square metre (kg/m^2). Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed' indicates the number of subjects with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to last visit (approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    108
    99
    96
    Units: kg/m^2
        arithmetic mean (standard deviation)
    0.2 ( 1.1 )
    0.3 ( 1.5 )
    0.0 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Waist Circumference

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    End point title
    		 Mean Change From Baseline in Waist Circumference
    End point description
    Change in waist circumference was reported in ‘cm’. Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed’ indicates the number of subjects with data available for endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to last visit (approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: cm
        arithmetic mean (standard deviation)
    0.6 ( 3.9 )
    -0.3 ( 4.3 )
    0.0 ( 5.1 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With At Least One Occurrence of Suicidal Behavior or Suicidal Ideation as Recorded on Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Subjects With At Least One Occurrence of Suicidal Behavior or Suicidal Ideation as Recorded on Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    C-SSRS is a scale used to report at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any of the following items: actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior. The suicidal ideation total score is the sum of intensity scores of 5 items (frequency, duration, controllability, deterrents, and reasons for ideation). The score of each intensity item ranges from 0 (none) to 5 (worst) and the total score ranges from 0 to 25. Lower scores indicate improvement. Safety sample included all randomised subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    102
    104
    Units: subjects
    1
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Relevant Laboratory Test Values

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    End point title
    		 Number of Subjects With Potentially Clinically Relevant Laboratory Test Values
    End point description
    Potentially clinically relevant laboratory values assessed included - serum chemistry [including blinded prolactin], hematology, and urinalysis. Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed’ indicates the number of subjects with data available for the endpoint analysis. ‘Number analysed (n)’ indicates the number of subjects with at least one post-baseline numeric result for the specified parameter.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    105
    98
    99
    Units: subjects
        Alanine aminotransferase (U/L): High (n=105,98,98)
    1
    2
    0
        Bilirubin (mg/dL): High (n=105, 96, 91)
    0
    1
    0
        Cholesterol, Fasting (mg/dL): High (n=102, 98, 96)
    2
    3
    0
        Creatine kinase (U/L): High (n=105, 98, 98)
    5
    4
    1
        Glucose, Fasting (mg/dL): High (n=102, 98, 96)
    16
    15
    9
        HDL Cholesterol, Fasting (mg/dL):Low(n=100,96,94)
    12
    10
    13
        LDL Cholesterol, Fasting (mg/dL):High(n=100,96,94)
    2
    3
    0
        Triglycerides Fasting (mg/dL):High(n=102, 98, 96)
    13
    7
    10
        Urate (mg/dL): High (n=105, 98, 98)
    0
    0
    1
        Hematocrit (%): Low (n=104, 97, 98)
    4
    0
    1
        Hemoglobin (g/dL): Low (n=104, 98, 99)
    2
    0
    0
        Leukocytes (10^9/L): Low (n=104, 98, 99)
    0
    1
    0
        Leukocytes (10^9/L): High (n=104, 98, 99)
    0
    0
    1
        Protein, Urine: High (n=105, 98, 97)
    2
    2
    0
        Eosinophils/Leukocytes (%): High (n=104,98,99)
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Potentially Clinically Significant Electrocardiogram (ECG) Parameters

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Electrocardiogram (ECG) Parameters
    End point description
    Twelve-lead ECG recordings were obtained after the subject was supine and at rest for at least 5 minutes. Safety sample included all randomised subjects who received at least 1 dose of IMP. 'Number of subjects analysed' indicates the number of subjects with data available for the endpoint analysis. ‘Number analysed (n)’ indicates the number of subjects with at least one post-baseline numeric result for the specified parameter.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    107
    97
    94
    Units: subjects
        Rate: Bradycardia (n=107, 97, 93)
    0
    0
    1
        Rhythm: Sinus Bradycardia (n=107, 97, 93)
    0
    0
    1
        Rhythm: SupraventricularPrematureBeat(n=107,97,94)
    0
    1
    1
        Rhythm: Ventricular Premature Beat (n=106, 97, 93)
    1
    0
    0
        ST/T Morphology: QTcF (n=107, 97, 93)
    0
    1
    0
        ST/T Morphology: QTcN (n=107, 97, 93)
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Simpson Angus Scale (SAS) Total Score

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    End point title
    		 Change From Baseline in Simpson Angus Scale (SAS) Total Score
    End point description
    The SAS consists of a list of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Severity of each item was rated on a 5-point scale, with a score of 0 (absence of symptoms) to 4 (severe condition). The SAS total score is the sum of the scores of all 10 items, ranging from 0 to 40 where lower scores indicate less severe condition. LS mean was determined by Analysis of Covariance (ANCOVA) model with treatment and study center as main effects and baseline value as covariate. Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed’ indicates the number of subjects with data available for the endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to last visit (approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
    least squares mean (standard error)
        Change From Baseline to Last Visit
    0.04 ( 0.12 )
    0.15 ( 0.12 )
    -0.03 ( 0.13 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Statistical analysis description
    LS mean difference was analysed by ANCOVA model, with treatment and study center as main effects and baseline value as covariate.
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.39
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Statistical analysis description
    LS mean difference was analysed by ANCOVA model, with treatment and study center as main effects and baseline value as covariate.
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.51

    Secondary: Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score

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    End point title
    		 Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score
    End point description
    The AIMS assessment consists of 12 items rating the involuntary movements: Facial and oral movements (4 items), extremity movements (2 items), and trunk movements (1 item) were observed unobtrusively while the subject is at rest and the investigator also made global judgments on the subject’s dyskinesias (2 items), and dental status (2 items). Severity of each item was rated on a 5-point scale, with a score of 0 (absence of symptoms) to 4 (severe condition). Total Score is the sum of the scores of all 12 items, ranging from 0 to 48, higher scores indicate severe condition. LS mean was determined by ANCOVA model with treatment and study center as main effects and baseline value as covariate. Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed’ indicates the number of subjects with data available for the endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to last visit (approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
        least squares mean (standard error)
    -0.12 ( 0.09 )
    0.05 ( 0.09 )
    -0.06 ( 0.09 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Statistical analysis description
    LS mean difference was analysed by ANCOVA model, with treatment and study center as main effects and baseline value as covariate.
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.18
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Statistical analysis description
    LS mean difference was analysed by ANCOVA model, with treatment and study center as main effects and baseline value as covariate.
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.36

    Secondary: Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score

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    End point title
    		 Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score
    End point description
    The BARS consists of 4 items related to akathisia: objective observation of akathisia by the investigator, subjective feelings of restlessness by the subject, subjective distress due to akathisia, and global clinical assessment of akathisia. The first 3 items were rated on a 4-point scale, with a score of 0 (absence of symptoms) to 3 (severe condition) and the global clinical assessment was rated on a 6-point scale, with a score of 0 (absence of symptoms) to 5 (severe akathisia). Total score is the sum of the scores of all 4 items, ranging from 0 to 14, higher scores indicate severe condition. LS mean was determined by ANCOVA model with treatment and study center as main effects and baseline value as covariate. Safety sample included all randomised subjects who received at least 1 dose of IMP. ‘Number of subjects analysed’ indicates the number of subjects with data available for the endpoint analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to last visit (approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    101
    103
    Units: score on a scale
        least squares mean (standard error)
    0.01 ( 0.03 )
    0.06 ( 0.03 )
    0.01 ( 0.03 )
    Statistical analysis title
    		 Brexpiprazole vs Placebo
    Statistical analysis description
    LS mean difference was analysed by ANCOVA model, with treatment and study center as main effects and baseline value as covariate.
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.09
    Statistical analysis title
    		 Aripiprazole vs Placebo
    Statistical analysis description
    LS mean difference was analysed by ANCOVA model, with treatment and study center as main effects and baseline value as covariate.
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.14

    Secondary: Number of Subjects With Severe Psychotropic Side Effects as Assessed by Udvalg for Kliniske Undersogelser (UKU) Rating Scale

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    End point title
    		 Number of Subjects With Severe Psychotropic Side Effects as Assessed by Udvalg for Kliniske Undersogelser (UKU) Rating Scale
    End point description
    The UKU rating scale is a semi-structured interview used to assess the side effects of subjects being treated with antipsychotic drugs. The scale is divided into 6 sub-scales: Psychic, neurological, autonomic, other, global assessment by subject, and global assessment by doctor. The scale has a total of 48 items, each item is rated on a 4-point scale (0=not present; 1=mild; 2=moderate; 3=severe), and the total score ranges from 0 to 144. Higher ratings indicate greater impairment. The severe side effects are reported in this endpoint. Safety sample included all randomised subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    102
    104
    Units: subjects
        Psychic: Concentration Difficulties
    7
    10
    8
        Psychic: Asthenia/Lassitude
    6
    3
    1
        Psychic: Failing Memory
    2
    2
    4
        Psychic: Depression
    0
    2
    1
        Psychic: Tension/Inner Unrest
    4
    3
    9
        Psychic: Increased Duration of Sleep
    0
    1
    0
        Psychic: Reduced Duration of Sleep
    4
    1
    1
        Psychic: Increased Dream Activity
    0
    2
    0
        Psychic: Emotional Indifference
    3
    6
    6
        Neurologic: Akathisia
    1
    1
    0
        Autonomic: Nausea/Vomiting
    0
    0
    1
        Autonomic: Micturition Disturbances
    0
    1
    0
        Autonomic: Palpitations/Tachycardia
    1
    0
    1
        Autonomic: Increased Tendency to Sweating
    1
    0
    0
        Other: Weight Gain
    0
    1
    0
        Other: Amenorrhoea
    0
    1
    0
        Other: Migraine
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Cognitive Adverse Effects Assessed by New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)

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    End point title
    		 Number of Subjects With Cognitive Adverse Effects Assessed by New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)
    End point description
    The NY-AACENT is used to detect changes in cognitive function subsequent to pharmacological or similar treatments for neurological or psychiatric problems, specifically designed to be used in pediatric population (ages 12 to 17), but could have been utilised with other age groups, as appropriate. Number of subjects with at least one occurrence of the corresponding signs/symptoms are reported in this endpoint. Safety sample included all randomised subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to last dose of study drug (up to approximately 6 weeks)
    End point values
    		 Brexpiprazole Aripiprazole Placebo
    Number of subjects analysed
    110
    102
    104
    Units: subjects
        Working Memory
    88
    79
    83
        Attention/Vigilance
    98
    90
    91
        Verbal Learning
    71
    70
    69
        Visual Learning
    46
    46
    44
        Reasoning
    97
    86
    83
        Speed of Processing
    88
    84
    82
        Social Cognition
    91
    87
    84
        Any Signs/Symptoms
    100
    91
    92
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to 21 days after the last dose of study drug (up to approximately 9 weeks)
    Adverse event reporting additional description
    Safety sample included all randomised subjects who received at least 1 dose of IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Subjects were administered with brexpiprazole oral tablets, daily, dose titrated up to 0.5 mg by Day 4, 1 mg by Day 7, 2 mg by Day 14, then between 2-4 mg after Day 21 up to Week 6 with a 1 mg increase or decrease, based on the Investigator's decision.

    Reporting group title
    Aripiprazole
    Reporting group description
    		 Subjects were administered with aripiprazole oral tablets, daily, dose titrated up to 2 mg by Day 4, 5 mg by Day 7, 10 mg by Day 14, then 10, 15 or 20 mg after Day 21 up to Week 6 with a 5 mg increase or decrease, based on the Investigator's decision.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were administered with brexpiprazole or aripiprazole matching placebo oral tablets, daily up to Week 6.

    Serious adverse events
    		 Brexpiprazole Aripiprazole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 102 (0.98%)
    3 / 104 (2.88%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Psychiatric disorders
    Psychotic Disorder
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 102 (0.98%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 102 (0.00%)
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Brexpiprazole Aripiprazole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 110 (17.27%)
    28 / 102 (27.45%)
    16 / 104 (15.38%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    4 / 110 (3.64%)
    7 / 102 (6.86%)
    3 / 104 (2.88%)
         occurrences all number
    4
    9
    3
    Headache
         subjects affected / exposed
    7 / 110 (6.36%)
    5 / 102 (4.90%)
    5 / 104 (4.81%)
         occurrences all number
    7
    6
    5
    Somnolence
         subjects affected / exposed
    5 / 110 (4.55%)
    11 / 102 (10.78%)
    5 / 104 (4.81%)
         occurrences all number
    6
    12
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 110 (1.82%)
    8 / 102 (7.84%)
    0 / 104 (0.00%)
         occurrences all number
    3
    9
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 110 (6.36%)
    4 / 102 (3.92%)
    4 / 104 (3.85%)
         occurrences all number
    7
    4
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2018
    • Revised EudraCT ID • Clarified that adequately trained clinician is psychiatrist/local medical equivalent “who is experienced in treating adolescents with schizophrenia” • Clarified that subjects must be between 13 and 17 years of age, inclusive, at time of baseline(Day 1), in addition to time of informed consent/assent • Clarified that subjects must have a PANSS Total Score ≥80 at screening and baseline(Day 1) • Removed inclusion criteria for previous response to antipsychotic treatment (other than clozapine), for history of relapse/exacerbation of symptoms when not receiving antipsychotic treatment • Clarified exclusion criterion on diagnosis to exclude all subjects with Diagnostic and Statistical Manual of Mental Disorders -5th Edition (DSM-5) diagnosis other than schizophrenia that has been primary focus of treatment within 3 months of screening • Updated possible sample size to 160/arm • Modified exclusion criteria for subjects considered treatment resistant to antipsychotic medication • Added exclusion criteria for subjects known to have medication compliance issues that lead to intramuscular (IM) depot medication use and who report a true allergic response to aripiprazole or brexpiprazole • Removed exclusion of subjects exposed to brexpiprazole • Modified exclusion criteria for subjects who have been exposed to “IM depot therapy” to on IM depot therapy within 5×half-life of medication • Added: recording of lifetime antipsychotic use to screening procedure, recording of height to screening & Week 6, body temperature to vital sign measurements, dispensing of IMP at Weeks 1, 2, 3, 4, and 5 to schedule of assessments • Modified maximum allowable dose of clonazepam as rescue therapy during trial to 1.5 mg/day throughout trial • Corrected description & basis of PANSS scales rating • Modified ‘Hy’s Law’ and drug-induced liver injury to potential serious hepatotoxicity.
    16 Jun 2020
    • Deleted text stating that translation of ICFs with back translation for confirmation will be utilised. • Clarified that stimulants are prohibited within 28 days (instead of 1 month) prior to dosing for subjects with a diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), for consistency. • Deleted the footnote superscript note from all assessment time points for serum pregnancy test and urine pregnancy test. • Added a single footnote superscript note next to the urine pregnancy assessment. The footnote for the urine pregnancy assessment was updated to state that if the urine pregnancy test is positive, the result should be confirmed with a serum pregnancy test if a serum pregnancy test is not being performed during that visit. • Deleted text stating that the methods of follow-up for complete withdrawal of consent will also be noted in the trial ICF.
    05 Jul 2022
    • Reduced sample size to 315 subjects (105 subjects per arm). • Deleted text “To ensure that trial is adequately powered, the estimate of the trial variability will be obtained at the blinded interim analysis. The variability will be estimated based on a blinded and pooled analysis of all treatment arms. Sample size may be adjusted up to the maximum of 160 subjects per arm.” describing SD re-estimation. • Replaced the new power calculated based on the reduced sample size (80%). No changes were made to assumptions in calculation (nominal 2-sided alpha level of 0.05 to detect a −7.4-point reduction in PANSS Total Score change from baseline to Week 6 for brexpiprazole vs placebo assuming a SD of 19%). • Replaced the requirement for at least 1 post-randomisation to postbaseline efficacy evaluation for the PANSS Total Score. • Added a description of the estimand to expand on the primary efficacy analysis text. • Added a statement regarding the primary endpoint analysis that the comparison between brexpiprazole 2 – 4 mg and placebo would be tested at a significance level of 0.05 (2-sided). • Added definition for remission to the secondary efficacy endpoint that is based on the aripiprazole and brexpiprazole trials. • Deleted the use of log rank test for testing differences in time from randomisation to remission to be consistent with the analysis method used in other brexpiprazole studies. • Changed Efficacy sample to Randomisation Sample which is conventional for analysis of demographics and baseline characteristics.

    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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