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    Clinical Trial Results:
    A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo controlled, 2 Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability of Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer’s Type

    Summary
    EudraCT number
    		 2017-003940-19
    Trial protocol
    		 BG   ES   HU   SK  
    Global end of trial date
    01 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2023
    First version publication date
    30 Sep 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    331-14-213
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03548584
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Blvd, Rockville, Maryland, United States, 20850
    Public contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 609 524-6788, clinicaltransparency@otsuka-us.com
    Scientific contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 609 524-6788, clinicaltransparency@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
    01 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study compares the efficacy of 2 doses of brexpiprazole with placebo in subjects with agitation associated with dementia of the Alzheimer’s type.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2018
    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
    Slovakia: 13
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Bulgaria: 37
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Serbia: 19
    Country: Number of subjects enrolled
    Ukraine: 107
    Country: Number of subjects enrolled
    United States: 152
    Worldwide total number of subjects
    345
    EEA total number of subjects
    67
    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)
    37
    From 65 to 84 years
    283
    85 years and over
    25

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 345 subjects were randomised, and participated in the study from 16 May 2018 to 1 June 2022.

    Pre-assignment
    Screening details
    		 The enrolled subjects were randomised to, brexpiprazole or placebo group in a ratio of 2:1. Within the brexpiprazole arm group, subjects were further randomised in a 1:2 ratio to 2 milligrams per day (mg/day) or 3 mg/day.

    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 2 mg
    Arm description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15. Subjects continued to receive brexpiprazole 2 milligrams (mg), once daily until Week 12.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole was administered orally in gradually increasing doses starting from 0.5 mg/day to 2 mg/day from Day 15. Brexpiprazole 2 mg was then given once daily until Week 12.

    Arm title
    		 Brexpiprazole 3 mg
    Arm description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Subjects continued to receive brexpiprazole 3 mg, once daily until Week 12.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    OPC-34712
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole was administered orally in gradually increasing doses starting from 0.5 mg/day in the starting to 3 mg/day from Day 29. Brexpiprazole 3 mg was then given, once daily until Week 12.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo, once daily for 12 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
    Matching placebo, once daily for 12 weeks.

    Number of subjects in period 1
    		Brexpiprazole 2 mg Brexpiprazole 3 mg Placebo
    Started
    75
    153
    117
    Intent-to-treat Population
    73
    153
    116
    Completed
    68
    130
    104
    Not completed
    7
    23
    13
         Reason not specified (unrelated to COVID-19)
    -
    2
    2
         Site terminated by sponsor
    1
    3
    2
         Adverse event
    1
    11
    5
         Non-compliance with study drug
    -
    1
    -
         Lost to follow-up
    -
    -
    1
         Subject withdrew consent to participate
    5
    5
    3
         Lack of efficacy
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole 2 mg
    Reporting group description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15. Subjects continued to receive brexpiprazole 2 milligrams (mg), once daily until Week 12.

    Reporting group title
    Brexpiprazole 3 mg
    Reporting group description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Subjects continued to receive brexpiprazole 3 mg, once daily until Week 12.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo, once daily for 12 weeks.

    Reporting group values
    		 Brexpiprazole 2 mg Brexpiprazole 3 mg Placebo Total
    Number of subjects
    		 75 153 117 345
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.3 ± 7.3 74.6 ± 8.0 73.0 ± 7.0 -
    Gender categorical
    Units: Subjects
        Female
    		 43 92 60 195
        Male
    		 32 61 57 150
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 25 46 37 108
        Not Hispanic or Latino
    		 50 107 80 237
    Race
    Units: Subjects
        Asian
    		 0 3 1 4
        Black or African American
    		 5 6 1 12
        White
    		 70 144 115 329
    Cohen-Mansfield Agitation Inventory (CMAI) Total Score
    The CMAI assesses frequency of agitated behaviours in elderly persons. The scale consists of 29 agitated behaviours that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. Each of the agitated behaviours are scored 1 (never) to 7 (several times an hours), with the total scale score ranging from 29 to 203. Higher score indicates greater frequency of agitated behaviour.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 78.6 ± 15.5 81.2 ± 17.2 79.4 ± 17.6 -

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole 2 mg
    Reporting group description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15. Subjects continued to receive brexpiprazole 2 milligrams (mg), once daily until Week 12.

    Reporting group title
    Brexpiprazole 3 mg
    Reporting group description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Subjects continued to receive brexpiprazole 3 mg, once daily until Week 12.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo, once daily for 12 weeks.

    Subject analysis set title
    Brexpiprazole 2 and 3 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Subjects continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.

    Primary: Change From Baseline to Week 12 in the CMAI Total Score

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    End point title
    		 Change From Baseline to Week 12 in the CMAI Total Score [1]
    End point description
    The CMAI score is used to assess the frequency of manifestations of agitated behaviours in subjects. The CMAI consists of 29 agitated behaviours, rated on a 7-point scale of frequency across four subscales of aggressive behaviour, physically nonaggressive behaviour, verbally agitated behaviour and hiding and hoarding ranging from 1=never to 7=several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. Mixed model repeated measures (MMRM) was used for the analysis. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of investigational medical product (IMP) and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: score on a scale
        least squares mean (standard error)
    -17.3 ± 1.44
    -22.6 ± 1.08
    Statistical analysis title
    		 Change From Baseline in the CMAI Total Score
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0026 [3]
    Method
    		 MMRM
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -5.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.77
         upper limit
    		 -1.87
    Notes
    [2] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [3] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.

    Secondary: Change From Baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Agitation

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    End point title
    		 Change From Baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Agitation [4]
    End point description
    CGI-S was used to rate the severity of agitation. The score ranges from 0 to 7 with response choices as, 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 subjects. The higher the value, the more severe the agitation. A negative change from baseline indicates improvement. MMRM was used for the analysis. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: score on a scale
        least squares mean (standard error)
    -0.93 ± 0.08
    -1.20 ± 0.06
    Statistical analysis title
    		 Change From Baseline to Week 12 in the CGI-S Score
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0078 [6]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 -0.07
    Notes
    [5] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [6] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.

    Secondary: Change From Baseline to Week 12 in CMAI Subscale Scores

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    End point title
    		 Change From Baseline to Week 12 in CMAI Subscale Scores [7]
    End point description
    The CMAI score is used to assess the frequency of manifestations of agitated behaviours in subjects. The CMAI consists of 29 agitated behaviours that are rated on a 7-point scale of frequency across four subscales of aggressive behaviour, physically nonaggressive behaviour, verbally agitated behaviour and hiding and hoarding as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. MMRM was used for the analysis. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: score on a scale
    least squares mean (standard error)
        Aggressive Behaviour
    -7.13 ± 0.56
    -9.09 ± 0.42
        Physically Nonaggressive Behaviour
    -5.04 ± 0.53
    -6.45 ± 0.40
        Verbally Agitated Behaviour
    -3.14 ± 0.40
    -4.39 ± 0.31
        Hiding and Hoarding
    -1.14 ± 0.23
    -1.50 ± 0.17
    Statistical analysis title
    		 Change From Baseline in CMAI Subscale Scores
    Statistical analysis description
    Aggressive Behaviour
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.004 [9]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 -0.63
    Notes
    [8] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [9] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Subscale Scores
    Statistical analysis description
    Physically Nonaggressive Behaviour
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0296 [11]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.68
         upper limit
    		 -0.14
    Notes
    [10] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [11] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Subscale Scores
    Statistical analysis description
    Verbally Agitated Behaviour
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.0113 [13]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.21
         upper limit
    		 -0.28
    Notes
    [12] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [13] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Subscale Scores
    Statistical analysis description
    Hiding and Hoarding
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.1941 [15]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.18
    Notes
    [14] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [15] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.

    Secondary: Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period

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    End point title
    		 Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period [16]
    End point description
    The CMAI score is used to assess the frequency of manifestations of agitated behaviours in subjects. The CMAI consists of 29 agitated behaviours, rated on a 7-point scale of frequency across four subscales of aggressive behaviour, physically nonaggressive behaviour, verbally agitated behaviour and hiding and hoarding ranging from 1=never to 7=several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. MMRM was used for the analysis. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 8, 10, and 12
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the Statistical Analysis Plan (SAP), data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: score on a scale
    least squares mean (standard error)
        Change From Baseline at Week 2
    -6.61 ± 0.90
    -5.76 ± 0.71
        Change From Baseline at Week 4
    -11.0 ± 1.06
    -12.1 ± 0.82
        Change From Baseline at Week 6
    -13.9 ± 1.19
    -16.2 ± 0.91
        Change From Baseline at Week 8
    -14.4 ± 1.28
    -19.4 ± 0.96
        Change From Baseline at Week 10
    -15.7 ± 1.29
    -22.2 ± 0.97
        Change From Baseline at Week 12
    -17.3 ± 1.44
    -22.6 ± 1.08
    Statistical analysis title
    		 Change From Baseline in CMAI Total Score - Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.4242 [18]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.24
         upper limit
    		 2.93
    Notes
    [17] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [18] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Total Score - Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.3665 [20]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.63
         upper limit
    		 1.34
    Notes
    [19] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [20] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Total Score - Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.1065 [22]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.15
         upper limit
    		 0.5
    Notes
    [21] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [22] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Total Score - Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.0011 [24]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -5.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.12
         upper limit
    		 -2.05
    Notes
    [23] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [24] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Total Score - Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.0001 [26]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -6.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.54
         upper limit
    		 -3.4
    Notes
    [25] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [26] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CMAI Total Score - Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.0026 [28]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -5.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.77
         upper limit
    		 -1.87
    Notes
    [27] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [28] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.

    Secondary: Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period

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    End point title
    		 Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period [29]
    End point description
    CGI-S was used to rate the severity of agitation. The score ranges from 0 to 7 with response choices as, 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 subjects. The higher the value, the more severe the agitation. A negative change from baseline indicates improvement. MMRM was used for the analysis. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 8, 10, and 12
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: score on a scale
    least squares mean (standard error)
        Change From Baseline at Week 2
    -0.27 ± 0.04
    -0.21 ± 0.03
        Change From Baseline at Week 4
    -0.50 ± 0.06
    -0.53 ± 0.05
        Change From Baseline at Week 6
    -0.68 ± 0.07
    -0.74 ± 0.05
        Change From Baseline at Week 8
    -0.70 ± 0.08
    -0.97 ± 0.06
        Change From Baseline at Week 10
    -0.86 ± 0.08
    -1.14 ± 0.06
        Change From Baseline at Week 12
    -0.93 ± 0.08
    -1.20 ± 0.06
    Statistical analysis title
    		 Change From Baseline in CGI-S Score at Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.3048 [31]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.16
    Notes
    [30] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [31] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CGI-S Score at Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.7058 [33]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.12
    Notes
    [32] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [33] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CGI-S Score at Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.4516 [35]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.1
    Notes
    [34] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [35] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CGI-S Score at Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 0.0052 [37]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 -0.08
    Notes
    [36] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [37] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CGI-S Score at Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.006 [39]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 -0.08
    Notes
    [38] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [39] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.
    Statistical analysis title
    		 Change From Baseline in CGI-S Score at Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.0078 [41]
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 -0.07
    Notes
    [40] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    [41] - MMRM method with model terms of treatment, trial site, visit, treatment-by-visit and baseline-by-visit interaction were used for analysis.

    Secondary: Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period

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    End point title
    		 Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period [42]
    End point description
    CGI-I is a 7-point scale that requires the clinician to assess whether a subject’s condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Higher scores indicate worse condition. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses. 'n' indicates number analysed is the number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 8, 10, and 12
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 2 (n=114, 221)
    3.57 ± 0.69
    3.70 ± 0.75
        Week 4 (n=116, 225)
    3.39 ± 0.87
    3.19 ± 0.85
        Week 6 (n=116, 225)
    3.19 ± 0.95
    2.92 ± 0.94
        Week 8 (n=116, 225)
    3.16 ± 1.01
    2.80 ± 1.00
        Week 10 (n=116, 225)
    2.97 ± 1.00
    2.62 ± 0.99
        Week 12 (n=116, 225)
    2.97 ± 1.12
    2.66 ± 1.09
    Statistical analysis title
    		 CGI-I Score at Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.1975
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.26
    Notes
    [43] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Score at Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [44]
    P-value
    		 = 0.0084
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 -0.06
    Notes
    [44] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Score at Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.0101
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 -0.06
    Notes
    [45] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Score at Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 = 0.0008
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 -0.15
    Notes
    [46] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Score at Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 0.0023
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 -0.12
    Notes
    [47] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Score at Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 = 0.007
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 -0.09
    Notes
    [48] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.

    Secondary: CMAI Response Rate Assessed as Percentage of Subjects With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period

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    End point title
    		 CMAI Response Rate Assessed as Percentage of Subjects With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period [49]
    End point description
    The CMAI assesses frequency of agitated behaviours in elderly persons. The scale consists of 29 agitated behaviours that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. Each of the agitated behaviours are scored 1 (never) to 7 (several times an hours), with the total scale score ranging from 29 to 203. Higher score indicates greater frequency of agitated behaviour. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses. 'n' indicates number analysed is the number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 6, 8, 10, and 12
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: percentage of subjects
    number (not applicable)
        >/= 20%: Week 2 (n=114, 221)
    13.2
    11.3
        >/= 20%: Week 4 (n=116, 225)
    27.6
    29.3
        >/= 20%: Week 6 (n=116, 225)
    37.9
    43.1
        >/= 20%: Week 8 (n=116, 225)
    38.8
    59.6
        >/= 20%: Week 10 (n=116, 225)
    45.7
    65.8
        >/= 20%: Week 12 (n=116, 225)
    47.4
    68.4
        >/= 30%: Week 2 (n=114, 221)
    3.51
    3.62
        >/= 30%: Week 4 (n=116, 225)
    10.3
    10.7
        >/= 30%: Week 6 (n=116, 225)
    20.7
    22.7
        >/= 30%: Week 8 (n=116, 225)
    19.0
    32.9
        >/= 30%: Week 10 (n=116, 225)
    24.1
    38.2
        >/= 30%: Week 12 (n=116, 225)
    25.9
    42.7
        >/= 40%: Week 2 (n=114, 221)
    1.75
    1.81
        >/= 40%: Week 4 (n=116, 225)
    5.17
    4.89
        >/= 40%: Week 6 (n=116, 225)
    8.62
    10.7
        >/= 40%: Week 8 (n=116, 225)
    8.62
    16.9
        >/= 40%: Week 10 (n=116, 225)
    11.2
    20.9
        >/= 40%: Week 12 (n=116, 225)
    14.7
    23.1
    Statistical analysis title
    		 CMAI Response Rate- >/= 20%: Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [50]
    P-value
    		 = 0.729
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.91
    Notes
    [50] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 20%: Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.6196
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.52
    Notes
    [51] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 20%: Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [52]
    P-value
    		 = 0.2718
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.53
    Notes
    [52] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 20%: Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 0.0004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 1.93
    Notes
    [53] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 20%: Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [54]
    P-value
    		 = 0.0006
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 1.76
    Notes
    [54] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 20%: Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 = 0.0004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 1.72
    Notes
    [55] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 30%: Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [56]
    P-value
    		 = 0.7211
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 3.85
    Notes
    [56] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 30%: Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 = 0.7606
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 2.14
    Notes
    [57] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 30%: Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [58]
    P-value
    		 = 0.5902
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.68
    Notes
    [58] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 30%: Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 = 0.0054
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 2.54
    Notes
    [59] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 30%: Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [60]
    P-value
    		 = 0.0066
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 2.26
    Notes
    [60] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 30%: Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 = 0.0017
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 2.23
    Notes
    [61] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 40%: Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [62]
    P-value
    		 = 0.9074
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 5.97
    Notes
    [62] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 40%: Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 = 0.9625
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 2.64
    Notes
    [63] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 40%: Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [64]
    P-value
    		 = 0.512
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 2.53
    Notes
    [64] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 40%: Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 = 0.0244
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 3.79
    Notes
    [65] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 40%: Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [66]
    P-value
    		 = 0.0161
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 3.18
    Notes
    [66] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate- >/= 40%: Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [67]
    P-value
    		 = 0.0347
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.61
    Notes
    [67] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.

    Secondary: CMAI Response Rate Assessed as Percentage of Subjects With CMAI Response Based on Improvement From Baseline in Agitation Status at Every Scheduled Trial Visit in the Double-Blind Treatment Period

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    End point title
    		 CMAI Response Rate Assessed as Percentage of Subjects With CMAI Response Based on Improvement From Baseline in Agitation Status at Every Scheduled Trial Visit in the Double-Blind Treatment Period [68]
    End point description
    The CMAI assesses frequency of agitated behaviours in elderly persons. The scale consists of 29 agitated behaviours that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. Each of the agitated behaviours are scored 1 (never) to 7 (several times an hours), with the total scale score ranging from 29 to 203. Higher score indicates greater frequency of agitated behaviour. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses. 'n' indicates number analysed is the number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 8, 10, and 12
    Notes
    [68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: percentage of subjects
    number (not applicable)
        Week 2 (n=114, 221)
    14.0
    8.14
        Week 4 (n=116, 225)
    19.0
    20.4
        Week 6 (n=116, 225)
    26.7
    33.8
        Week 8 (n=116, 225)
    31.0
    44.0
        Week 10 (n=116, 225)
    34.5
    50.2
        Week 12 (n=116, 225)
    37.1
    52.4
    Statistical analysis title
    		 CMAI Response Rate at Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [69]
    P-value
    		 = 0.1503
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.16
    Notes
    [69] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate at Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [70]
    P-value
    		 = 0.7559
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.67
    Notes
    [70] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate at Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [71]
    P-value
    		 = 0.2246
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.72
    Notes
    [71] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate at Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [72]
    P-value
    		 = 0.0276
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.87
    Notes
    [72] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate at Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [73]
    P-value
    		 = 0.0031
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 1.89
    Notes
    [73] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CMAI Response Rate at Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [74]
    P-value
    		 = 0.0017
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 1.89
    Notes
    [74] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.

    Secondary: CGI-I Response Rate Assessed as Percentage of Subjects With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period

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    End point title
    		 CGI-I Response Rate Assessed as Percentage of Subjects With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period [75]
    End point description
    CGI-I is a 7-point scale that requires the clinician to assess whether a subject’s condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Higher scores indicate worse condition. The ITT Population consisted of all subjects in the randomised sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Number of subjects analysed is the number of subjects with data available for analyses. 'n' indicates number analysed is the number of subjects with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 6, 8, 10, and 12
    Notes
    [75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As prespecified in the SAP, data for this endpoint was analysed and reported in a combined way for brexpiprazole 2 and 3 mg.
    End point values
    		 Placebo Brexpiprazole 2 and 3 mg
    Number of subjects analysed
    116
    225
    Units: percentage of subjects
    number (not applicable)
        Week 2 (n=114, 221)
    5.26
    4.98
        Week 4 (n=116, 225)
    12.1
    21.8
        Week 6 (n=116, 225)
    23.3
    35.1
        Week 8 (n=116, 225)
    24.1
    44.4
        Week 10 (n=116, 225)
    33.6
    52.4
        Week 12 (n=116, 225)
    40.5
    52.4
    Statistical analysis title
    		 CGI-I Response Rate at Week 2
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [76]
    P-value
    		 = 0.8549
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 3.03
    Notes
    [76] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Response Rate at Week 4
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [77]
    P-value
    		 = 0.0093
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 3.32
    Notes
    [77] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Response Rate at Week 6
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [78]
    P-value
    		 = 0.0083
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 2.22
    Notes
    [78] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Response Rate at Week 8
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [79]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.32
         upper limit
    		 2.58
    Notes
    [79] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Response Rate at Week 10
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [80]
    P-value
    		 = 0.0005
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 2.09
    Notes
    [80] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.
    Statistical analysis title
    		 CGI-I Response Rate at Week 12
    Comparison groups
    Placebo v Brexpiprazole 2 and 3 mg
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [81]
    P-value
    		 = 0.016
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Ratio of Response Rate
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.69
    Notes
    [81] - Comparison groups are Brexpiprazole 2 and 3 mg v Placebo. Point estimate and confidence interval are based on Brexpiprazole 2 and 3 mg v Placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent up to end of study (Week 16)
    Adverse event reporting additional description
    Randomised Sample was used to assess all-cause deaths. It consisted of all subjects who were randomised into this trial. Safety Sample was used to assess serious adverse events (SAEs) and non-serious adverse events (NSAEs) and consisted of all subjects who were administered at least one 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 2 mg
    Reporting group description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15. Subjects continued to receive brexpiprazole 2 mg, once daily until Week 12.

    Reporting group title
    Brexpiprazole 3 mg
    Reporting group description
    		 Subjects followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Subjects continued to receive brexpiprazole 3 mg, once daily until Week 12.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo, once daily for 12 weeks.

    Serious adverse events
    		 Brexpiprazole 2 mg Brexpiprazole 3 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 73 (0.00%)
    6 / 153 (3.92%)
    3 / 116 (2.59%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 153 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 153 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 153 (1.31%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 153 (0.65%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Brexpiprazole 2 mg Brexpiprazole 3 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 73 (6.85%)
    10 / 153 (6.54%)
    8 / 116 (6.90%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 73 (6.85%)
    10 / 153 (6.54%)
    8 / 116 (6.90%)
         occurrences all number
    5
    12
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2019
    The following changes were implemented as per Amendment 1: 1. Sample size was increased from 225 subjects to 255 subjects. 2. The number of trial sites was increased from 60 to 80 sites.
    06 Aug 2020
    The following change was implemented as per Amendment 2: A Coronavirus disease 2019 (COVID-19) addendum was introduced for any protocol specified activities that were not able to be performed or could not be performed due to COVID-19 considerations.
    14 Sep 2020
    The following changes were implemented as per Amendment 3: 1. Sample size was increased from approximately 255 subjects to approximately 330 subjects. 2. References to German sites were removed. 3. Trial duration was increased. 4. Details were added regarding the interim analysis and possible rollover of subjects.

    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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