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    Clinical Trial Results:
    Country-specific protocol amendment for Germany entitled: A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of 2 Fixed Doses of Brexpiprazole (OPC-34712) in the Treatment of Subjects with Agitation Associated with Dementia of the Alzheimer’s Type

    Summary
    EudraCT number
    		 2013-000504-41
    Trial protocol
    		 DE   ES   HR  
    Global end of trial date
    15 Mar 2017

    Results information
    Results version number
    		 v1
    This version publication date
    14 Jun 2018
    First version publication date
    14 Jun 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    331-12-283
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    Laura Beth Duncan, Otsuka Pharmaceutical Development & Commercialization, Inc., 001 240780 4286, LauraBeth.Duncan@otsuka-us.com
    Scientific contact
    Laura Beth Duncan, Otsuka Pharmaceutical Development & Commercialization, Inc., 001 240780 4286, LauraBeth.Duncan@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
    15 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of 2 fixed doses (1 mg/day, and 2 mg/day) of brexpiprazole with placebo in subjects with agitation associated with Alzhemier's dementia, as assessed by the Cohen-Mansfield Agitation Inventory (CMAI) after 12 weeks of treatment
    Protection of trial subjects
    This trial was conducted in compliance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines for conducting, recording, and reporting trials, as well as for archiving essential documents. Consistent with ethical principles for the protection of human research subjects, no trial procedures were performed on trial candidates until written consent or assent had been obtained from them and/or their legally acceptable representative. The informed consent form, protocol, and amendments for this trial were submitted to and approved by the Institutional Review Board or Independent Ethics Committee at each respective trial center.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jul 2013
    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
    Croatia: 37
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Russian Federation: 126
    Country: Number of subjects enrolled
    Serbia: 53
    Country: Number of subjects enrolled
    Ukraine: 64
    Country: Number of subjects enrolled
    United States: 121
    Country: Number of subjects enrolled
    Spain: 19
    Worldwide total number of subjects
    433
    EEA total number of subjects
    69
    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)
    72
    From 65 to 84 years
    321
    85 years and over
    40

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 433 subjects at 81 sites in 7 countries: Croatia, Germany, Serbia, Spain, Russia, Ukraine, and the United States (US)

    Pre-assignment
    Screening details
    		 Subjects attended screening period ranging from 2 to 42 days. The purpose of the screening period was to determine the subject's eligibility and to washout prohibited concomitant pharmacotherapy prior to randomization.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brexpiprazole(Brex) 0.5mg/Day
    Arm description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 0.5 mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All randomized subjects received orally brexpiprazole 0.5 mg/day tablet.

    Arm title
    		 Brexpiprazole(Brex) 1mg/Day
    Arm description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All randomized subjects received orally brexpiprazole 1 mg/day tablet.

    Arm title
    		 Brexpiprazole(Brex) 2mg/Day
    Arm description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All randomized subjects received orally brexpiprazole 2 mg/day tablet.

    Arm title
    		 Placebo
    Arm description
    		 All randomized subjects received orally brexpiprazole matching Placebo tablet once daily in form of tablets.
    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
    All randomized subjects received orally brexpiprazole matching Placebo tablet.

    Number of subjects in period 1
    		Brexpiprazole(Brex) 0.5mg/Day Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Started
    20
    137
    140
    136
    Completed
    13
    121
    122
    121
    Not completed
    7
    16
    18
    15
         Consent withdrawn by subject
    2
    4
    8
    5
         Adverse Event
    4
    10
    6
    8
         Subject met withdrawal criteria
    1
    1
    2
    1
         Subject withdrawn by Investigator
    -
    1
    1
    1
         Protocol deviation
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole(Brex) 0.5mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 0.5 mg/day.

    Reporting group title
    Brexpiprazole(Brex) 1mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day.

    Reporting group title
    Brexpiprazole(Brex) 2mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day.

    Reporting group title
    Placebo
    Reporting group description
    		 All randomized subjects received orally brexpiprazole matching Placebo tablet once daily in form of tablets.

    Reporting group values
    		 Brexpiprazole(Brex) 0.5mg/Day Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo Total
    Number of subjects
    		 20 137 140 136 433
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.9 ± 9.1 73.8 ± 8.8 73.7 ± 8.1 74.1 ± 8.0 -
    Gender categorical
    Units: Subjects
        Female
    		 12 78 79 70 239
        Male
    		 8 59 61 66 194

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole(Brex) 0.5mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 0.5 mg/day.

    Reporting group title
    Brexpiprazole(Brex) 1mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day.

    Reporting group title
    Brexpiprazole(Brex) 2mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day.

    Reporting group title
    Placebo
    Reporting group description
    		 All randomized subjects received orally brexpiprazole matching Placebo tablet once daily in form of tablets.

    Primary: Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks of Brexpiprazole Treatment.

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    End point title
    		 Change From Baseline in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks of Brexpiprazole Treatment. [1]
    End point description
    The CMAI assess the frequency of agitated behaviors in elderly persons. It consisted of 29 agitated behaviors that are further categorized into distinct agitation syndromes or CMAI factors of agitation. These distinct agitation syndromes include aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior.
    End point type
    Primary
    End point timeframe
    From baseline to Week 12/Early Termination (ET)
    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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    138
    131
    Units: Participants
        least squares mean (standard error)
    -17.6 ± 1.33
    -21.6 ± 1.32
    -17.8 ± 1.34
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9015
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 3.86
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0404
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -3.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.38
         upper limit
    		 -0.17

    Secondary: Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation After 12 Weeks of Brexpiprazole Treatment.

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    End point title
    		 Change From Baseline in the Clinical Global Impression-Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation After 12 Weeks of Brexpiprazole Treatment. [2]
    End point description
    The CGI-S was used to rate the severity of agitation. Scores were: 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.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [2] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    138
    131
    Units: Participants
        arithmetic mean (standard deviation)
    -1.04 ± 1.12
    -1.29 ± 1.05
    -1.08 ± 0.89
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.444
    Method
    		 Mixed-effect model repeated measure]
    Parameter type
    		 LS mean difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.32
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Comparison groups
    Placebo v Brexpiprazole(Brex) 2mg/Day
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1566
    Method
    		 Mixed-effect model repeated measure]
    Parameter type
    		 LS mean difference]
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.06

    Secondary: Change From Baseline in the CMAI Subscale Scores (Aggressive Behavior) After 12 Weeks of Brexpiprazole Treatment.

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    End point title
    		 Change From Baseline in the CMAI Subscale Scores (Aggressive Behavior) After 12 Weeks of Brexpiprazole Treatment. [3]
    End point description
    The CMAI was developed to assess the frequency of agitated behaviors in elderly persons and consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes or CMAI factors of agitation. These distinct agitation syndromes include aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior. This endpoint provides an overview for aggressive behavior.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [3] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    138
    131
    Units: Participants
        arithmetic mean (standard deviation)
    -5.69 ± 8.43
    -7.42 ± 7.63
    -6.53 ± 7.62
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.9814
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 1.34
    Notes
    [4] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.1477
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.29
         upper limit
    		 0.35
    Notes
    [5] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.

    Secondary: Change From Baseline in the CMAI Subscale Scores (Physically Nonaggressive Behavior) After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in the CMAI Subscale Scores (Physically Nonaggressive Behavior) After 12 Weeks of Brexpiprazole Treatment [6]
    End point description
    The CMAI was developed to assess the frequency of agitated behaviors in elderly persons and consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes or CMAI factors of agitation. These distinct agitation syndromes include aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior. This endpoint provides an overview for physically non aggressive behavior.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [6] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    138
    131
    Units: Participants
        arithmetic mean (standard deviation)
    -5.40 ± 6.69
    -6.75 ± 6.12
    -5.42 ± 5.39
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.5506
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 1.81
    Notes
    [7] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Placebo v Brexpiprazole(Brex) 2mg/Day
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.0945
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.57
         upper limit
    		 0.2
    Notes
    [8] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.

    Secondary: Change From Baseline in the CMAI Subscale Scores (Verbally Agitated Behavior) After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in the CMAI Subscale Scores (Verbally Agitated Behavior) After 12 Weeks of Brexpiprazole Treatment [9]
    End point description
    The CMAI was developed to assess the frequency of agitated behaviors in elderly persons and consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes or CMAI factors of agitation. These distinct agitation syndromes include aggressive behavior, physically nonaggressive behavior, and verbally agitated behavior. This endpoint provides an overview for verbally agitated behavior.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [9] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    138
    131
    Units: Participants
        arithmetic mean (standard deviation)
    -3.02 ± 4.84
    -4.35 ± 4.59
    -3.35 ± 4.34
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.598
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.75
    Notes
    [10] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0153
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.29
         upper limit
    		 -0.24
    Notes
    [11] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.

    Secondary: Change From Baseline in the Neuropsychiatric Inventory-Nursing Home Rating Scale (NPI-NH) 12- Item Total Score After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in the Neuropsychiatric Inventory-Nursing Home Rating Scale (NPI-NH) 12- Item Total Score After 12 Weeks of Brexpiprazole Treatment [12]
    End point description
    The NPI-NH questionnaire was used to interview the identified caregiver about the institutionalized subject's possible neuropsychiatric symptoms (ie, delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability, aberrant motor behavior, nighttime behaviors, and appetite/eating behaviors). For each of the 12 separate behavioral domains, the NPI-NH evaluates the frequency (scale = 1 to 4), severity (scale = 1 to 3), and occupational disruption (scale = 0 to 5). A total NPI-NH score was calculated by adding the first 10 domain total scores (frequency x severity scores) together.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [12] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    138
    130
    Units: Participants
        arithmetic mean (standard deviation)
    -15.9 ± 15.77
    -17.4 ± 14.78
    -15.9 ± 14.22
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.8802
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.48
         upper limit
    		 2.98
    Notes
    [13] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.281
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.99
         upper limit
    		 1.45
    Notes
    [14] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.

    Secondary: Change From Baseline in the NPI-NH Agitation/Aggression Score After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in the NPI-NH Agitation/Aggression Score After 12 Weeks of Brexpiprazole Treatment [15]
    End point description
    The NPI-NH questionnaire was used to interview the identified caregiver about the institutionalized subject's possible neuropsychiatric symptoms (ie, delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability, aberrant motor behavior, nighttime behaviors, and appetite/eating behaviors). For each of the 12 separate behavioral domains, the NPI-NH evaluates the frequency (scale = 1 to 4), severity (scale = 1 to 3), and occupational disruption (scale = 0 to 5). For each behavioral domain, 4 scores were calculated based on frequency, severity, total (frequency x severity), and occupational disruptiveness.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [15] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    138
    131
    Units: Participants
        arithmetic mean (standard deviation)
    -3.43 ± 3.33
    -3.97 ± 3.16
    -3.60 ± 2.95
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.7823
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.6
    Notes
    [16] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported.
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.1222
    Method
    		 Mixed-effect model repeated measure
    Parameter type
    		 LS mean difference
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 0.15
    Notes
    [17] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported

    Secondary: Change From Baseline in Clinical Global Impression-Improvement (CGI-I) Score, as Related to Agitation After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in Clinical Global Impression-Improvement (CGI-I) Score, as Related to Agitation After 12 Weeks of Brexpiprazole Treatment [18]
    End point description
    The CGI-I was used to rate the total improvement (as related to agitation) for each subject whether or not it was due entirely to drug treatment. Scores 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.
    End point type
    Secondary
    End point timeframe
    From Week 2 to Week 12/ET
    Notes
    [18] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    135
    138
    131
    Units: Participants
        arithmetic mean (standard deviation)
    2.88 ± 1.26
    2.58 ± 1.17
    2.81 ± 1.11
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.7499
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 LS mean difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.33
    Notes
    [19] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.1311
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 LS mean difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.06
    Notes
    [20] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported

    Other pre-specified: Change From Baseline in Assessments of Extrapyramidal Symptoms (EPS) Using Simpson Angus Scale (SAS) After 12 Weeks of Brexpiprazole Treatment.

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    End point title
    		 Change From Baseline in Assessments of Extrapyramidal Symptoms (EPS) Using Simpson Angus Scale (SAS) After 12 Weeks of Brexpiprazole Treatment. [21]
    End point description
    The EPS was evaluated as a variable of safety assessment of 2 fixed doses of brexpiprazole (1 mg/day and 2 mg/day) compared with placebo using SAS, which consisted of 10 symptoms of Parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms and a score of 4 representing a severe condition. The SAS total score was the sum of the scores for all 10 items.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [21] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    137
    139
    132
    Units: Participants
        arithmetic mean (standard deviation)
    -0.13 ± 0.96
    0.37 ± 2.82
    -0.13 ± 1.10
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.8453
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.44
    Notes
    [22] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.013
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 0.9
    Notes
    [23] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported

    Other pre-specified: Change From Baseline in Assessments of EPS Using the Abnormal Involuntary Movement Scale (AIMS) After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in Assessments of EPS Using the Abnormal Involuntary Movement Scale (AIMS) After 12 Weeks of Brexpiprazole Treatment [24]
    End point description
    The EPS was evaluated using AIMS, which consisted of 10 items describing symptoms of dyskinesia. Each item was rated on a 5-point scale, with a score of 0 representing absence of symptoms (for item 10, no awareness), and a score of 4 indicating a severe condition (for item 10, awareness, severe distress).
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12/Early Termination
    Notes
    [24] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    134
    137
    132
    Units: Participants
        arithmetic mean (standard deviation)
    -0.01 ± 0.51
    -0.05 ± 0.47
    -0.05 ± 0.49
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.7228
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.12
    Notes
    [25] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.8804
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.09
    Notes
    [26] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported

    Other pre-specified: Change From Baseline in Assessments of EPS Using the Barnes Akathisia Rating Scale (BARS) After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in Assessments of EPS Using the Barnes Akathisia Rating Scale (BARS) After 12 Weeks of Brexpiprazole Treatment [27]
    End point description
    The EPS was evaluated using BARS, consisted of items related to akathisia. The first 3 items were rated on a 4-point scale, with a score of 0 representing absence of symptoms and a score of 3 representing a severe condition. The global clinical evaluation was made on a 6-point scale, with 0 representing absence of symptoms and a score of 5 representing severe akathisia.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [27] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    137
    139
    132
    Units: Participants
        arithmetic mean (standard deviation)
    -0.05 ± 0.33
    -0.01 ± 0.28
    -0.04 ± 0.26
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.8891
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.05
    Notes
    [28] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.4465
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.08
    Notes
    [29] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported

    Other pre-specified: Change From Baseline in Assessment of Suicidality Using Sheehan Suicidality Tracking Scale (Sheehan-STS) After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in Assessment of Suicidality Using Sheehan Suicidality Tracking Scale (Sheehan-STS) After 12 Weeks of Brexpiprazole Treatment [30]
    End point description
    The EPS was evaluated using Sheehan-STS, which was a prospective scale that assesses treatment-emergent suicidal thoughts and behaviors. Each item of the Sheehan-STS was scored on a 5-point Likert scale (0 = not at all; 1 = a little; 2 = moderate; 3 = very; and 4 = extremely).
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [30] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    137
    139
    132
    Units: Participants
        arithmetic mean (standard deviation)
    0.00 ± 0.40
    0.00 ± 0.20
    0.10 ± 0.50
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Assessment of Cognitive Function Using the Mini-mental State Examination (MMSE) After 12 Weeks of Brexpiprazole Treatment

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    End point title
    		 Change From Baseline in Assessment of Cognitive Function Using the Mini-mental State Examination (MMSE) After 12 Weeks of Brexpiprazole Treatment [31]
    End point description
    The safety of 2 fixed doses of brexpiprazole (1 mg/day and 2 mg/day) compared with placebo was evaluated using MMSE, which was a brief practical test for assessing cognitive dysfunction. The test consisted of 5 sections (orientation, registration, attention and calculation, recall, and language) and has a total possible score of 30.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to Week 12/ET
    Notes
    [31] - 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: The analysis population consisted of modified ITT population. The modified ITT population consisted of all subjects in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least one post baseline evaluation for the CMAI total score.
    End point values
    		 Brexpiprazole(Brex) 1mg/Day Brexpiprazole(Brex) 2mg/Day Placebo
    Number of subjects analysed
    123
    133
    127
    Units: Participants
        arithmetic mean (standard deviation)
    0.15 ± 1.98
    0.15 ± 2.35
    -0.14 ± 2.03
    Statistical analysis title
    		 Stat. comparison between Brex1mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 1mg/Day v Placebo
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.7932
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.6
    Notes
    [32] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported
    Statistical analysis title
    		 Stat. comparison between Brex2mg/day and Placebo
    Statistical analysis description
    Safety set consisted of all subjects who were administered at least 1 dose of IMP.
    Comparison groups
    Brexpiprazole(Brex) 2mg/Day v Placebo
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.279
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.79
    Notes
    [33] - No alternative hypotheses was pre-specified and only nominal exploratory comparisons are reported

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected throughout the study (Baseline to Week 12/ET)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Brexpiprazole≤1mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day.

    Reporting group title
    Brexpiprazole 2mg/Day
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day.

    Reporting group title
    All Brexpiprazole
    Reporting group description
    		 All randomized subjects received orally brexpiprazole tablet 0.25 mg/day as a starting dose, which was up titrated to 1 to 2mg/day.

    Reporting group title
    Placebo
    Reporting group description
    		 All randomized subjects received orally matching Placebo tablet oncedaily.

    Serious adverse events
    		 Brexpiprazole≤1mg/Day Brexpiprazole 2mg/Day All Brexpiprazole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 157 (10.19%)
    13 / 140 (9.29%)
    29 / 297 (9.76%)
    7 / 136 (5.15%)
         number of deaths (all causes)
    4
    1
    5
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella Fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 140 (0.00%)
    0 / 297 (0.00%)
    1 / 136 (0.74%)
         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
    Vascular disorders
    Venous Thrombosis Limb
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 140 (0.71%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's Type
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 140 (0.71%)
    2 / 297 (0.67%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Lacunar Infarction
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychomotor Hyperactivity
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 140 (0.71%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 140 (0.00%)
    0 / 297 (0.00%)
    1 / 136 (0.74%)
         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
    Syncope
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 140 (0.00%)
    0 / 297 (0.00%)
    1 / 136 (0.74%)
         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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 140 (0.71%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Microcytic Anaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 140 (0.71%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 140 (0.00%)
    0 / 297 (0.00%)
    1 / 136 (0.74%)
         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
    Pancreatitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 140 (0.71%)
    2 / 297 (0.67%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 140 (0.71%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive Airways Disorder
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 140 (0.71%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal Behaviour
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 140 (0.71%)
    3 / 297 (1.01%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional Self-Injury
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 140 (0.00%)
    0 / 297 (0.00%)
    1 / 136 (0.74%)
         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
    Psychotic Disorder
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 140 (0.71%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial Sepsis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 140 (0.00%)
    1 / 297 (0.34%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 157 (0.00%)
    0 / 140 (0.00%)
    0 / 297 (0.00%)
    1 / 136 (0.74%)
         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
    Urinary Tract Infection
         subjects affected / exposed
    0 / 157 (0.00%)
    4 / 140 (2.86%)
    4 / 297 (1.35%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    4 / 4
    1 / 1
         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≤1mg/Day Brexpiprazole 2mg/Day All Brexpiprazole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 157 (12.74%)
    29 / 140 (20.71%)
    49 / 297 (16.50%)
    21 / 136 (15.44%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 157 (0.64%)
    8 / 140 (5.71%)
    9 / 297 (3.03%)
    4 / 136 (2.94%)
         occurrences all number
    1
    10
    11
    6
    Headache
         subjects affected / exposed
    12 / 157 (7.64%)
    13 / 140 (9.29%)
    25 / 297 (8.42%)
    11 / 136 (8.09%)
         occurrences all number
    13
    17
    30
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 157 (4.46%)
    8 / 140 (5.71%)
    15 / 297 (5.05%)
    6 / 136 (4.41%)
         occurrences all number
    10
    9
    19
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2013
    Amendment number 1: Based on FDA feedback, the randomization ratio was changed from 1:2:2:2 to 1:1:1:1 (brexpiprazole 0.5 mg/day, brexpiprazole 1 mg/day, brexpiprazole 2 mg/day, placebo, respectively). Actigraphy and eDiary assessments were added to the protocol along with description of the use of day passes in this trial.
    16 Dec 2013
    Protocol amendment number 2: The second amendment changes were made on the basis of adjustments to facilitate appropriate trial implementation and communication. It served to reflect clarifications and additions to study procedures intended to enhance subject safety and accuracy of data. Revised items included increasing the number of participating sites and recruitment period, clarification on consenting requirements, clarification of certain inclusion/exclusion criteria, and updates to the prohibited medication list. The amendment also added the option for subjects who completed the 331-12-283 trial to enter the 331-13-211 safety trial.
    07 Jul 2014
    Protocol amendment number 3: The changes were made to address the potential issue of missing data due to subjects terminating early, as well as on the basis of adjustments considered important to ensure the safety of the subjects enrolled and to facilitate appropriate study implementation and communication. The 0.5-mg arm was removed, which resulted in a reduction to the number of subjects randomized. Noninstitutionalized subjects were included with revisions to criteria and assessments for subjects in this setting. The RUD scale and Mortality Assessment at Week 16 for subjects who discontinued the trial early were added.
    10 Sep 2015
    Amendment number 4: The changes reflect clarifications and changes to trial procedures intended to enhance subject safety and accuracy of data as well as streamline the inclusion/exclusion criteria. The number of trial sites as well as participating countries was increased. Actigraphy was removed and eDiary was replaced with paper diaries. Revisions were made to the Schedule of Assessments to decrease subject burden.

    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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