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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind Trial of Brexpiprazole versus Placebo for the Acute Treatment Manic Episodes, With or Without Mixed Features, Associated With Bipolar I Disorder

    Summary
    EudraCT number
    		 2017-002190-20
    Trial protocol
    		 HR  
    Global end of trial date
    22 Jan 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Feb 2020
    First version publication date
    29 Dec 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update for alignment with revised clinicaltrials.gov results posting

    Trial information

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    Trial identification
    Sponsor protocol code
    331-201-00081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03257865
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, MD, 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
    10 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of brexpiprazole for the acute treatment of manic episodes, with or without mixed features, in participants with a diagnosis of bipolar I disorder.
    Protection of trial subjects
    This trial was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the trial was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ukraine: 93
    Country: Number of subjects enrolled
    United States: 239
    Country: Number of subjects enrolled
    Croatia: 1
    Worldwide total number of subjects
    333
    EEA total number of subjects
    1
    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)
    333
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The trial population consisted of adult participants (18 to 65 years) diagnosed with bipolar I disorder displaying an acute manic episode with or without mixed features requiring hospitalization. One participant randomized to brexpiprazole was not treated and excluded from the safety analysis set.

    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
    		 Investigator, Subject
    Blinding implementation details
    Treatment assignments were based on a computer-generated randomization code. Sponsor personnel, including those involved in monitoring, data management, and data analysis, did not have access to the treatment code during the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brexpiprazole
    Arm description
    		 Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 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
    Starting dose of 2 mg/day; titrated to a maximum of 4 mg/day. Adjustments could be made to dosing. Treatment duration was 3 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.
    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
    Tablet taken daily for 3 weeks.

    Number of subjects in period 1
    		Brexpiprazole Placebo
    Started
    163
    170
    Received at least 1 dose of study drug
    162
    170
    Completed
    128
    135
    Not completed
    35
    35
         Consent withdrawn by subject
    23
    17
         Physician decision
    3
    1
         Adverse event, non-fatal
    4
    8
         Other
    -
    1
         Non-Compliance With Study Drug
    -
    2
         Lost to follow-up
    4
    4
         Lack of efficacy
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 mg/day.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.

    Reporting group values
    		 Brexpiprazole Placebo Total
    Number of subjects
    		 163 170 333
    Age categorical
    Units:
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 44.6 ± 10.7 44.3 ± 12.0 -
    Gender categorical
    Units: Subjects
        Female
    		 85 82 167
        Male
    		 78 88 166
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 90 102 192
        Black or African American
    		 70 67 137
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other Race
    		 2 1 3
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 22 17 39
        Not Hispanic or Latino
    		 140 153 293
        Other Ethnicity
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 mg/day.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.

    Primary: Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3

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    End point title
    		 Change From Baseline In Young-Mania Rating Scale (YMRS) Score At Week 3
    End point description
    The YMRS was utilized to assess a participant's level of manic symptoms. It consists of 11 items: 1) elevated mood, 2) increased motor activity-energy, 3) sexual interest, 4) sleep, 5) irritability, 6) speech (rate and amount), 7) language-thought disorder, 8) content, 9) disruptive-aggressive behavior, 10) appearance, and 11) insight. Seven items are rated on a 0- to 4-scale, while four items (Items 5, 6, 8, and 9) are rated on a 0- to 8-scale with 0, 2, 4, 6, and 8 being the possible scores (twice the weight of the other items). For all items, 0 is the “best” rating and the highest score (4 or 8) is the ‘worst’ rating. The YMRS total score is the sum of ratings for all 11 items; therefore, possible total scores range from 0 to 60, with higher scores signifying more severe manic symptoms. Comparison between treatment groups was carried out using mixed-effect model repeated measure (MMRM).
    End point type
    Primary
    End point timeframe
    Baseline, Week 3
    End point values
    		 Brexpiprazole Placebo
    Number of subjects analysed
    128 [1]
    133 [2]
    Units: units on a scale
        least squares mean (standard error)
    -12.3 ± 0.73
    -10.7 ± 0.71
    Notes
    [1] - Participants who had analyzable data at the specified timepoint.
    [2] - Participants who had analyzable data at the specified timepoint.
    Statistical analysis title
    		 Treatment Difference in YMRS
    Comparison groups
    Brexpiprazole v Placebo
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1011
    Method
    		 mixed-effect model repeated measure
    Parameter type
    		 Treatment difference
    Point estimate
    -1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.56
         upper limit
    		 0.32

    Secondary: Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3

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    End point title
    		 Change From Baseline In Clinical Global Impression-Bipolar (CGI-BP) Severity Score In Mania At Week 3
    End point description
    The CGI-BP scale refers to the global impression of the participant with respect to bipolar disorder. The scale rates the participant’s severity of illness (CGI-BP severity of illness: mania, depression, and overall bipolar illness) based on a 7-point scale: 1 = normal, not at all ill, 2 = minimally ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, 7 = very severely ill.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3
    End point values
    		 Brexpiprazole Placebo
    Number of subjects analysed
    128 [3]
    133 [4]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.31 ± 1.22
    -1.06 ± 1.09
    Notes
    [3] - Participants who had analyzable data at the specified timepoint.
    [4] - Participants who had analyzable data at the specified timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 (after dosing) through 6 weeks (3 weeks treatment, 3 weeks safety follow-up).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Brexpiprazole
    Reporting group description
    		 Brexpiprazole was administered orally with flexible dosing from 2 to 4 milligram (mg)/day; titrated to a maximum of 4 mg/day.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered orally in the same way as brexpiprazole to maintain the blind.

    Serious adverse events
    		 Brexpiprazole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 162 (0.00%)
    3 / 170 (1.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Brexpiprazole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 162 (19.75%)
    28 / 170 (16.47%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    13 / 162 (8.02%)
    4 / 170 (2.35%)
         occurrences all number
    14
    4
    Dizziness
         subjects affected / exposed
    5 / 162 (3.09%)
    1 / 170 (0.59%)
         occurrences all number
    5
    1
    Headache
         subjects affected / exposed
    10 / 162 (6.17%)
    18 / 170 (10.59%)
         occurrences all number
    12
    19
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 162 (3.70%)
    5 / 170 (2.94%)
         occurrences all number
    6
    5
    Nausea
         subjects affected / exposed
    2 / 162 (1.23%)
    7 / 170 (4.12%)
         occurrences all number
    2
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 162 (3.09%)
    2 / 170 (1.18%)
         occurrences all number
    6
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2017
    • Remove an incorrect exclusion criteria of ≥ 30% decrease in YMRS between screening and baseline • Add clarifying details on administration of the Clinical Global Impressions – Bipolar Scale assessment • Add information on retesting participants with elevated lithium, valproate, or carbamazepine at screening • Add information on use of anticholinergics • Update the efficacy scales in the appendices to match the licensed versions currently available

    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
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