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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Three Fixed Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia

    Summary
    EudraCT number
    		 2011-002538-38
    Trial protocol
    		 LV   PL  
    Global end of trial date
    05 Dec 2013

    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
    331-10-231
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01396421
    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
    16 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy, safety and tolerability of each of three fixed doses of OPC-34712 with placebo in the treatment of acute schizophrenia in adults.
    Protection of trial subjects
    This trial was conducted in compliance with the protocol, International Conference on Harmonization (ICH) Good Clinical Practice (GCP), and 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
    09 Aug 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
    Ukraine: 115
    Country: Number of subjects enrolled
    United States: 228
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 15
    Country: Number of subjects enrolled
    Latvia: 31
    Country: Number of subjects enrolled
    Malaysia: 21
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Romania: 109
    Country: Number of subjects enrolled
    Serbia: 75
    Worldwide total number of subjects
    636
    EEA total number of subjects
    156
    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)
    634
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 636 participants from 65 trial sites in 10 countries.

    Pre-assignment
    Screening details
    		 Participants entered a pre-treatment screening phase of up to 14 days before enrollment to assess eligibility criteria and to washout from prior antipsychotic medications and other prohibited concomitant medications, followed by a 6-week double blinded treatment phase.

    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 4 mg
    Arm description
    		 Brexpiprazole 4 milligram (mg) tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 1-week period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose the day after the Week 1 visit (ie, the beginning of Week 2).
    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 4mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 1-week period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose the day after the Week 1 visit (ie, the beginning of Week 2).

    Arm title
    		 Brexpiprazole 2mg
    Arm description
    		 Brexpiprazole 2mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 5 day period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose by Day 5.
    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 2mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 5 day period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose by Day 5.

    Arm title
    		 Brexpiprazole 0.25mg
    Arm description
    		 Brexpiprazole 0.25mg 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 0.25mg tablet once daily for 6 weeks.

    Arm title
    		 Placebo
    Arm description
    		 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 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Started
    180
    182
    90
    184
    Completed
    121
    124
    56
    109
    Not completed
    59
    58
    34
    75
         Physician decision
    1
    1
    -
    3
         Consent withdrawn by subject
    31
    24
    13
    21
         Adverse event
    17
    15
    12
    32
         Lost to follow-up
    -
    -
    -
    1
         Participant met withdrawal criteria
    1
    -
    1
    -
         Protocol deviation
    2
    1
    1
    -
         Lack of efficacy
    7
    17
    7
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole 4 mg
    Reporting group description
    		 Brexpiprazole 4 milligram (mg) tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 1-week period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose the day after the Week 1 visit (ie, the beginning of Week 2).

    Reporting group title
    Brexpiprazole 2mg
    Reporting group description
    		 Brexpiprazole 2mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 5 day period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose by Day 5.

    Reporting group title
    Brexpiprazole 0.25mg
    Reporting group description
    		 Brexpiprazole 0.25mg tablet once daily for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet once daily for 6 weeks.

    Reporting group values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo Total
    Number of subjects
    		 180 182 90 184 636
    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)
    		 180 181 89 184 634
        From 65-84 years
    		 0 1 1 0 2
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.8 ( 11 ) 39.6 ( 10.2 ) 40.5 ( 11.4 ) 39.7 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 69 71 29 66 235
        Male
    		 111 111 61 118 401

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole 4 mg
    Reporting group description
    		 Brexpiprazole 4 milligram (mg) tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 1-week period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose the day after the Week 1 visit (ie, the beginning of Week 2).

    Reporting group title
    Brexpiprazole 2mg
    Reporting group description
    		 Brexpiprazole 2mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 5 day period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose by Day 5.

    Reporting group title
    Brexpiprazole 0.25mg
    Reporting group description
    		 Brexpiprazole 0.25mg tablet once daily for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet once daily for 6 weeks.

    Primary: Mean change from Baseline to Week 6 Positive and Negative Syndrome Scale (PANSS) total score.

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    End point title
    		 Mean change from Baseline to Week 6 Positive and Negative Syndrome Scale (PANSS) total score.
    End point description
    The PANSS consists of 3 subscales (positive subscale, negative subscale and general psychopathology subscale) containing a total of 30 symptom constructs and was administered using the Structured Clinical Interview (SCI)-PANSS. 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 ranged from 30 (best possible outcome) to 210 (worst possible outcome). Efficacy dataset consists 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
    Primary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Units on a scale
        least squares mean (standard error)
    -19.65 ( 1.54 )
    -20.73 ( 1.55 )
    -14.9 ( 2.23 )
    -12.01 ( 1.6 )
    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. With fixed effect of treatment, (pooled) clinical center, visit, treatment visit interaction, baseline value, and baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Brexpiprazole 2mg v Placebo
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -8.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 -4.4
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The primary efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 4 mg
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -7.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 -3.3
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The primary efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -8.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.1
         upper limit
    		 -4.37
    Statistical analysis title
    		 Statistical analysis 4 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The primary efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.291
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.27
         upper limit
    		 2.49

    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 was rated using the CGI-S. To perform this assessment, the rater or 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 participant. Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 124, 56 and 109 participants in the Brexpiprazole 4mg, Brexpiprazole 2mg, Brexpiprazole 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    181
    89
    178
    Units: Units on a scale
        least squares mean (standard error)
    -1.2 ( 0.08 )
    -1.15 ( 0.08 )
    -0.85 ( 0.12 )
    -0.82 ( 0.09 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    The analysis of the key secondary endpoint was conducted if both comparisons of brexpiprazole 2 mg/day versus placebo and brexpiprazole 4 mg/day versus placebo of the primary endpoint were statistically significant under the procedure described for the primary efficacy analysis. With fixed effect of treatment, (pooled) clinical center, visit, treatment visit interaction, baseline value, and baseline visit interaction as covariates.
    Comparison groups
    Brexpiprazole 4 mg v Brexpiprazole 2mg v Placebo
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.15
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    The analysis of the key secondary endpoint was conducted if both comparisons of brexpiprazole 2 mg/day versus placebo and brexpiprazole 4 mg/day versus placebo of the primary endpoint were statistically significant under the procedure described for the primary efficacy analysis. With fixed effect of treatment, (pooled) clinical center, 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
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 -0.15
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    The analysis of the key secondary endpoint was conducted if both comparisons of brexpiprazole 2 mg/day versus placebo and brexpiprazole 4 mg/day versus placebo of the primary endpoint were statistically significant under the procedure described for the primary efficacy analysis. With fixed effect of treatment, (pooled) clinical center, visit, treatment visit interaction, baseline value, and baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0056
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.1
    Statistical analysis title
    		 Statistical analysis 4 at Week 6
    Statistical analysis description
    The analysis of the key secondary endpoint was conducted if both comparisons of brexpiprazole 2 mg/day versus placebo and brexpiprazole 4 mg/day versus placebo of the primary endpoint were statistically significant under the procedure described for the primary efficacy analysis. With fixed effect of treatment, (pooled) clinical center, visit, treatment visit interaction, baseline value, and baseline visit interaction as covariates.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8491
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.26

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

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    End point title
    		 Mean change from Baseline to Week 6 in Personal and Social Performance Scale (PSP)
    End point description
    The PSP is a clinician-rated scale that measures personal and social functioning in 4 domains: socially useful activities (eg, 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. Efficacy: consists 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 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    168
    173
    86
    170
    Units: Units on a scale
        least squares mean (standard error)
    12.72 ( 0.93 )
    13.15 ( 0.93 )
    11.84 ( 1.33 )
    10.26 ( 0.98 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0557
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 4.98
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 5.42
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3264 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.58
         upper limit
    		 4.74
    Notes
    [1] - With fixed effect of treatment, (pooled) clinical center, visit, treatment visit interaction, baseline value, baseline visit interaction as covariates.

    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
    For each symptom construct of the PANSS Positive Subscale, 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 symptom constructs were as follows: delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome). Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brexpiprazole 4mg, Brexpiprazole 2mg, Brexpiprazole 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    180
    Units: Units on a scale
        least squares mean (standard error)
    -6.78 ( 0.51 )
    -6.57 ( 0.52 )
    -5.46 ( 0.74 )
    -4.35 ( 0.54 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.88
         upper limit
    		 -0.99
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.67
         upper limit
    		 -0.77
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2227
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -0.68

    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
    For each symptom construct of the PANSS Negative Subscale, 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 symptom constructs were as follows: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome). Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brexpiprazole 4mg, Brexpiprazole 2mg, Brexpiprazole 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Units on a scale
        least squares mean (standard error)
    -3.65 ( 0.36 )
    -4.02 ( 0.36 )
    -3.31 ( 0.53 )
    -2.24 ( 0.38 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0069
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.44
         upper limit
    		 0.39
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 2mg v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.81
         upper limit
    		 -0.76
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0996
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.33
         upper limit
    		 0.2

    Secondary: Clinical Global Impression- Improvement scale (CGI-I) score at Week 6

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    End point title
    		 Clinical Global Impression- Improvement scale (CGI-I) score at Week 6
    End point description
    The participant’s overall improvement was rated using the CGI-I. The rater or study physician rated the participant’s total improvement whether or not it was due entirely to drug treatment. All responses were compared with the participant’s condition at screening/baseline. 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. Efficacy dataset consists 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 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    181
    89
    178
    Units: Units on a scale
        arithmetic mean (standard deviation)
    2.94 ( 1.29 )
    2.94 ( 1.34 )
    3.37 ( 1.46 )
    3.48 ( 1.47 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    The same analysis model as described for the primary analysis was applied.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 -0.22
    Notes
    [2] - The CMH row mean scores differ test controlling for trial center was applied to CGI-I score.
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    The same analysis model as described for the primary analysis was applied.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 -0.26
    Notes
    [3] - The CMH row mean scores differ test controlling for trial center was applied to CGI-I score.
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    The same analysis model as described for the primary analysis was applied.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4505 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Treatment difference
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.22
    Notes
    [4] - The CMH row mean scores differ test controlling for trial center was applied to CGI-I score.

    Secondary: Response rate at Week 6

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    End point title
    		 Response rate at Week 6
    End point description
    Response rate was defined as improvement in mean change of ≥30% from baseline in PANSS Total Score at Week 6 or CGI-I score of 1 (very much improved) or 2 (much improved) at Week 6. Efficacy dataset consists 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 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Percentage of participants
        number (not applicable)
    46.07
    47.78
    39.08
    30.34
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Comparison groups
    Placebo v Brexpiprazole 4 mg
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative risk
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.91
    Notes
    [5] - CMH general association test controlling for trial was applied to the analysis of response rate.
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative risk
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 2.05
    Notes
    [6] - CMH general association test controlling for trial was applied to the analysis of response rate.
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1576 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative risk
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.76
    Notes
    [7] - CMH general association test controlling for trial was applied to the analysis of response rate.

    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 consists of 5 PANSS items (excitement [P4], hostility [P7], tension [G4], uncooperativeness [G8], and poor impulse control [G14]). Each rated on a scale of 1 (absent) to 7 (extreme). The PEC for participants was calculated as the sum of the rating assigned to each of the 5 items, and ranged from 5 to 35 with a higher score indicating greater severity of symptoms. Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brexpiprazole 4mg, Brexpiprazole 2mg, Brexpiprazole 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Units on a scale
        least squares mean (standard error)
    -2.75 ( 0.34 )
    -2.87 ( 0.34 )
    -1.99 ( 0.49 )
    -1.64 ( 0.36 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 0.25mg v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5706
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 0.85
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0131
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.19
         upper limit
    		 -0.26
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 4 mg
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0246
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.06
         upper limit
    		 -0.14

    Secondary: Discontinuation rate for lack of efficacy at Week 6

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    End point title
    		 Discontinuation rate for lack of efficacy at Week 6
    End point description
    Discontinuation rate for lack of efficacy during the trial at Week 6 is reported below. Efficacy dataset consists 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 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Percentage of participants
        number (not applicable)
    3.93
    9.44
    8.05
    10.11
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0143 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative risk
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.85
    Notes
    [8] - CMH general association test controlling for trial center was applied to the analysis of discontinuation rate.
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6606 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative risk
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.65
    Notes
    [9] - CMH general association test controlling for trial center was applied to the analysis of discontinuation rate.
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5115 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative risk
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.68
    Notes
    [10] - CMH general association test controlling for trial center was applied to the analysis of discontinuation rate.

    Secondary: Change from Baseline to Week 6 in PANSS Marder Factor score - Positive Symptoms Score

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    End point title
    		 Change from Baseline to Week 6 in PANSS Marder Factor score - Positive Symptoms Score
    End point description
    The PANSS Marder Factor score - Positive Symptoms Score consists of 8 PANSS items (delusions [P1], hallucinatory behaviour [P3], grandiosity [P5], suspiciousness [P6], stereotyped thinking [N7], somatic concern [G1], unusual thought content [G9], lack of judgment and insight [G10]. Each was rated on a scale of 1 (absent) to 7 (extreme). The PANSS Marder Factor score - Positive Symptoms Score for participants was calculated as the sum of the rating assigned to each of the 8 items, and ranged from 8 to 42 with a higher score indicating greater severity of symptoms. Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brexpiprazole 4mg, Brexpiprazole 2mg, Brexpiprazole 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Units on a scale
        least squares mean (standard error)
    -7.23 ( 0.51 )
    -7.37 ( 0.51 )
    -5.78 ( 0.73 )
    -4.89 ( 0.53 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.77
         upper limit
    		 -0.91
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -2.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.91
         upper limit
    		 -1.04
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3263
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.66
         upper limit
    		 0.89

    Secondary: Change from Baseline to Week 6 in PANSS Marder Factor score - Negative Symptoms Score

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    End point title
    		 Change from Baseline to Week 6 in PANSS Marder Factor score - Negative Symptoms Score
    End point description
    The PANSS Marder Factor score - Negative Symptoms Score consists of 7 PANSS items (blunted effect [N1], emotional withdrawal [N2], poor rapport [N3], passive/apathetic social withdrawal [N4], lack of spontaneity and conversation flow [N6], motor retardation [G7], active social avoidance [G16]). The PANSS Marder Factor score - Negative Symptoms Score for participants was calculated as the sum of the rating assigned to each of the 7 items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brexpiprazole 4mg, Brexpiprazole 2mg, Brexpiprazole 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Units on a scale
        least squares mean (standard error)
    -4.1 ( 0.37 )
    -4.48 ( 0.37 )
    -3.66 ( 0.54 )
    -2.8 ( 0.39 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 4 mg
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0155
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.35
         upper limit
    		 -0.25
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.73
         upper limit
    		 -0.62
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1956
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.17
         upper limit
    		 -0.44

    Secondary: Change from Baseline to Week 6 in PANSS Marder Disorganised Thought Score

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    End point title
    		 Change from Baseline to Week 6 in PANSS Marder Disorganised Thought Score
    End point description
    The PANSS Marder Factor score -Disorganized Thought Score consists of 7 PANSS items (conceptual disorganization [P2], difficulty in abstract thinking [N5], mannerisms and posturing [G5], disorientation [G10], poor attention [G11], disturbance of violation [G13], preoccupation [G15]). The PANSS Marder Factor score - Disorganized Thought Score for participants was calculated as the sum of the rating assigned to each of the 7 items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brexpiprazole 4mg, Brexpiprazole 2mg, Brexpiprazole 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    180
    Units: Units on a scale
        least squares mean (standard error)
    -3.72 ( 0.36 )
    -3.94 ( 0.36 )
    -2.69 ( 0.52 )
    -1.97 ( 0.37 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.76
         upper limit
    		 -0.75
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.98
         upper limit
    		 -0.97
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2572
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.96
         upper limit
    		 0.52

    Secondary: Change from Baseline to Week 6 in PANSS Marder Uncontrolled Hostility/Excitement Score

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    End point title
    		 Change from Baseline to Week 6 in PANSS Marder Uncontrolled Hostility/Excitement Score
    End point description
    The PANSS Marder Factor score - Uncontrolled Hostility/Excitement Score consists of 4 PANSS items (excitement [P4], hostility [P7], uncooperativeness [G8], poor impulse control [G14]). The PANSS Marder Factor score - Uncontrolled Hostility/Excitement Score for participants was calculated as the sum of the rating assigned to each of the 4 items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Efficacy: consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brex 4mg, Brex 2mg, Brex 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Units on a scale
        least squares mean (standard error)
    -1.9 ( 0.28 )
    -1.91 ( 0.28 )
    -1.15 ( 0.41 )
    -0.82 ( 0.3 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0085
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 -0.28
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 2mg v Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0081
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.88
         upper limit
    		 -0.28
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5172
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 0.66

    Secondary: Change from Baseline to Week 6 in PANSS Marder Anxiety Depression Score

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    End point title
    		 Change from Baseline to Week 6 in PANSS Marder Anxiety Depression Score
    End point description
    The PANSS Marder Factor score - Anxiety/Depression Score consists of 4 PANSS items (anxiety [G2], guilt feelings [G3], tension [G4], depression [G6]). The PANSS Marder Factor score - Anxiety/Depression Score for participants was calculated as the sum of the rating assigned to each of the 4 items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Efficacy: consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. At Week 6, 121, 123, 56 and 108 participants in the Brex 4mg, Brex 2mg, Brex 0.25 mg and placebo group, respectively had data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6
    End point values
    		 Brexpiprazole 4 mg Brexpiprazole 2mg Brexpiprazole 0.25mg Placebo
    Number of subjects analysed
    178
    180
    87
    178
    Units: Units on a scale
        least squares mean (standard error)
    -3.4 ( 0.25 )
    -3.7 ( 0.25 )
    -3.27 ( 0.35 )
    -3.05 ( 0.26 )
    Statistical analysis title
    		 Statistical analysis 1 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Brexpiprazole 4 mg v Placebo
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3284
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 0.35
    Statistical analysis title
    		 Statistical analysis 2 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 2mg
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0655
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 0.04
    Statistical analysis title
    		 Statistical analysis 3 at Week 6
    Statistical analysis description
    Efficacy dataset consists of all participants who received at least one dose of study medication and have baseline and at least one post-baseline efficacy evaluation. The efficacy endpoint was analyzed using a mixed model repeated measures (MMRM) analysis. The model included treatment, visit, site, and treatment interacting with visit as fixed effects and the covariate baseline PANSS Total Score and its interaction with visit.
    Comparison groups
    Placebo v Brexpiprazole 0.25mg
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6251
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.07
         upper limit
    		 0.64

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time the participant signs the informed consent form until 30 days after the last dose of study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Brexpiprazole 4mg
    Reporting group description
    		 Brexpiprazole 4mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 1-week period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose the day after the Week 1 visit (ie, the beginning of Week 2).

    Reporting group title
    Brexpiprazole 2 mg
    Reporting group description
    		 Brexpiprazole 2mg tablet once daily for 6 weeks. Participants were titrated to the target dose of brexpiprazole over a 5-day period beginning at the randomization (Day 1), and all participants were to have achieved the assigned dose by Day 5.

    Reporting group title
    Brexpiprazole 0.25 mg
    Reporting group description
    		 Brexpiprazole 0.25mg tablet once daily for 6 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet once daily for 6 weeks.

    Serious adverse events
    		 Brexpiprazole 4mg Brexpiprazole 2 mg Brexpiprazole 0.25 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 180 (1.11%)
    4 / 182 (2.20%)
    4 / 90 (4.44%)
    7 / 184 (3.80%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 180 (0.00%)
    0 / 182 (0.00%)
    1 / 90 (1.11%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Grand mal convulsion
         subjects affected / exposed
    0 / 180 (0.00%)
    0 / 182 (0.00%)
    0 / 90 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    0 / 180 (0.00%)
    0 / 182 (0.00%)
    0 / 90 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 182 (0.55%)
    1 / 90 (1.11%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    2 / 180 (1.11%)
    2 / 182 (1.10%)
    2 / 90 (2.22%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    0 / 180 (0.00%)
    0 / 182 (0.00%)
    0 / 90 (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
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 182 (0.55%)
    0 / 90 (0.00%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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 4mg Brexpiprazole 2 mg Brexpiprazole 0.25 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 180 (35.56%)
    53 / 182 (29.12%)
    25 / 90 (27.78%)
    65 / 184 (35.33%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    13 / 180 (7.22%)
    8 / 182 (4.40%)
    0 / 90 (0.00%)
    4 / 184 (2.17%)
         occurrences all number
    14
    8
    0
    4
    Headache
         subjects affected / exposed
    22 / 180 (12.22%)
    17 / 182 (9.34%)
    9 / 90 (10.00%)
    15 / 184 (8.15%)
         occurrences all number
    28
    18
    10
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 180 (3.89%)
    3 / 182 (1.65%)
    5 / 90 (5.56%)
    3 / 184 (1.63%)
         occurrences all number
    8
    3
    5
    4
    Nausea
         subjects affected / exposed
    6 / 180 (3.33%)
    10 / 182 (5.49%)
    1 / 90 (1.11%)
    8 / 184 (4.35%)
         occurrences all number
    6
    10
    1
    9
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    13 / 180 (7.22%)
    11 / 182 (6.04%)
    4 / 90 (4.44%)
    19 / 184 (10.33%)
         occurrences all number
    15
    15
    5
    23
    Insomnia
         subjects affected / exposed
    15 / 180 (8.33%)
    16 / 182 (8.79%)
    8 / 90 (8.89%)
    18 / 184 (9.78%)
         occurrences all number
    17
    20
    10
    20
    Schizophrenia
         subjects affected / exposed
    10 / 180 (5.56%)
    7 / 182 (3.85%)
    6 / 90 (6.67%)
    18 / 184 (9.78%)
         occurrences all number
    11
    7
    8
    18

    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 done to change the primary efficacy analysis used from an Analysis of Covariance (ANCOVA) model based on the LOCF dataset. The MMRM model was included as a sensitivity analysis. Based on regulatory feedback, the MMRM approach was the primary analysis method, with the ANCOVA LOCF used as the sensitivity analysis. Clarified 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. Clarified that participants may remain on stable doses of propranolol during the trial if the propranolol was being taken for an indication other than akathisia. Updated wording of select standard exclusion criteria for consistency with other protocols in the brexpiprazole clinical program. Clarified instructions for preparation of whole blood sample for metabolic profiling. Clarified 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. Added change from Baseline in PANSS Excited Component and PANSS Marder Factor scores as secondary efficacy variables. Revised 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 has been used by raters throughout the trial. In addition, administrative changes were made and typographical errors identified during review of the protocol amendment were corrected.
    05 Dec 2013
    The second formal amendment to the original protocol was to change the statistical method for controlling multiplicity from the Hochberg procedure to the family-wise error rate. The actual protocol amendment was dated 20-Dec-2013 which was after the trial completed but before database lock.

    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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