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    Clinical Trial Results:
    A 2-month, Observational, Rollover Trial to Evaluate the Safety of Subjects with Agitation Associated with Dementia of the Alzheimer’s Type who were Previously Treated with Brexpiprazole (OPC-34712) or Placebo in a Phase 3, Double-blind Trial

    Summary
    EudraCT number
    2014-000424-23
    Trial protocol
    ES   DE   SI   FR   GB   HR   BG  
    Global end of trial date
    30 May 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Apr 2021
    First version publication date
    02 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    331-13-211
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02192554
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, MD 20850
    Public contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    Scientific contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    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
    30 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of subjects with agitation associated with dementia of the Alzheimer's type who were previously treated with brexpiprazole (0.5, 1, or 2 mg/day) or placebo during Trial 331-12-283 or Trial 331-12-284.
    Protection of trial subjects
    This trial was conducted in compliance with Good Clinical Practice 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 had been obtained from them. The informed consent form, protocol, and amendments for this trial were submitted to and approved by the institutional review board or ethics committee at each respective trial center. During the phase 3 trials, subjects were treated for a period of 12 weeks with a 30-day safety follow-up period. Trial 331-13-211 was designed to extend the duration of the safety follow-up period for the aforementioned Phase 3 trials from 30 days to 3 months (ie, 30 days from the previous phase 3 trials [331-12-283 or 331-12-284] plus 2 months from Trial 331-13-211).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jul 2014
    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
    Slovenia: 4
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Croatia: 16
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Russian Federation: 108
    Country: Number of subjects enrolled
    Serbia: 37
    Country: Number of subjects enrolled
    Ukraine: 92
    Country: Number of subjects enrolled
    United States: 111
    Country: Number of subjects enrolled
    Bulgaria: 42
    Worldwide total number of subjects
    450
    EEA total number of subjects
    95
    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)
    66
    From 65 to 84 years
    339
    85 years and over
    45

    Subject disposition

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    Recruitment
    Recruitment details
    This trial was conducted at 87 sites in 12 countries: Bulgaria, Canada, Croatia, France, Germany, Great Britain, Russia, Serbia, Slovenia, Spain, Ukraine, and United States. Subjects with agitation associated with dementia of the Alzheimer's type were involved in this study.

    Pre-assignment
    Screening details
    This was an observational trial without study drug to characterize the long-term safety of subjects after the investigational trials (Trials 331-12-283 & Trial 331-12-284). Subjects were allowed to take any medications to treat agitation or other symptoms of illness without limitation. Informed consent signed, eligibility criteria checked.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Prior Brexpiprazole
    Arm description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type who previously received brexpiprazole (0.5, 1, or 2 mg/day) during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). This study comprised of 2 months of continued observation following a subject's completion of participation in the previous phase 3 brexpiprazole trials and included 3 visits: at baseline, Month 1 (± 5 days), and Month 2 (±5 days)/ Early termination (ET). No Investigational medicinal product (IMP) was provided during this 2-month observational rollover trial.
    Arm type
    Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    OPC-34712
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brexpiprazole (0.5, 1, or 2 mg/day) was administered during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284).

    Arm title
    Prior Placebo
    Arm description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type, who previously received brexpiprazole matching placebo during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). In this rollover study no placebo was administered.
    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
    Brexpiprazole matching placebo was administered during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284).

    Number of subjects in period 1
    Prior Brexpiprazole Prior Placebo
    Started
    262
    188
    Completed
    259
    188
    Not completed
    3
    0
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prior Brexpiprazole
    Reporting group description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type who previously received brexpiprazole (0.5, 1, or 2 mg/day) during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). This study comprised of 2 months of continued observation following a subject's completion of participation in the previous phase 3 brexpiprazole trials and included 3 visits: at baseline, Month 1 (± 5 days), and Month 2 (±5 days)/ Early termination (ET). No Investigational medicinal product (IMP) was provided during this 2-month observational rollover trial.

    Reporting group title
    Prior Placebo
    Reporting group description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type, who previously received brexpiprazole matching placebo during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). In this rollover study no placebo was administered.

    Reporting group values
    Prior Brexpiprazole Prior Placebo Total
    Number of subjects
    262 188 450
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    40 26 66
        From 65-84 years
    193 146 339
        85 years and over
    29 16 45
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    74.1 ± 8.3 74.0 ± 7.8 -
    Gender categorical
    Units: Subjects
        Female
    155 102 257
        Male
    107 86 193

    End points

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    End points reporting groups
    Reporting group title
    Prior Brexpiprazole
    Reporting group description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type who previously received brexpiprazole (0.5, 1, or 2 mg/day) during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). This study comprised of 2 months of continued observation following a subject's completion of participation in the previous phase 3 brexpiprazole trials and included 3 visits: at baseline, Month 1 (± 5 days), and Month 2 (±5 days)/ Early termination (ET). No Investigational medicinal product (IMP) was provided during this 2-month observational rollover trial.

    Reporting group title
    Prior Placebo
    Reporting group description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type, who previously received brexpiprazole matching placebo during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). In this rollover study no placebo was administered.

    Primary: Number of participants with Adverse Events (AEs)

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    End point title
    Number of participants with Adverse Events (AEs) [1]
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A SAE included any event that resulted in death, life-threatening event, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, in-patient hospitalization or prolonged hospitalization, congenital anomaly/birth defect, and other medically significant events that, based upon appropriate medical judgment, jeopardized the subject and required medical or surgical intervention. Safety endpoints related to AEs that were evaluated during this trial were: frequency and severity of AEs, SAEs, and discontinuations from the trial due to AEs, frequency and severity of AEs related to the worsening of agitation and cognition associated with Alzheimer's disease. Subjects had no limitations to take any medication to treat agitation or other symptoms during this study.
    End point type
    Primary
    End point timeframe
    From baseline to Month 2/ET
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety results were summarized and presented and no formal statistical analysis was performed.
    End point values
    Prior Brexpiprazole Prior Placebo
    Number of subjects analysed
    262
    188
    Units: Participants
    number (not applicable)
        Participants with adverse events
    57
    37
        Participants with serious adverse events
    1
    1
        Participants with nonserious adverse events
    57
    36
        Participants with severe adverse events
    1
    0
        Death
    1
    0
    No statistical analyses for this end point

    Primary: Mean Change in Mini-Mental State Examination (MMSE) Score

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    End point title
    Mean Change in Mini-Mental State Examination (MMSE) Score [2]
    End point description
    The MMSE was a brief practical test used for assessing cognitive dysfunction. The test consisted of 5 sections (orientation,registration, attention and calculation, recall, and language) and had a total possible score of 30. Higher scores indicate better cognitive functioning. MMSE safety scale was used as one of the safety variable. The MMSE was performed at the Month 2/ET visit.
    End point type
    Primary
    End point timeframe
    From baseline to Month 2/ET
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was a non-comparative, observational study. The mean change in the MMSE score from baseline to Month 2/ET was summarized by descriptive statistics, eg, mean and standard deviation.
    End point values
    Prior Brexpiprazole Prior Placebo
    Number of subjects analysed
    260
    187
    Units: Unit on scale
    arithmetic mean (standard deviation)
        Month 2
    -0.34 ± 2.12
    -0.46 ± 2.17
        Last visit
    -0.34 ± 2.12
    -0.46 ± 2.17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to Month 2/ET
    Adverse event reporting additional description
    An AE was defined as any untoward medical occurrence associated with the use of a drug in human. An serious adverse event (SAE) included events that resulted in death, life threatening event, persistent incapacity of the ability to conduct normal life functions, in-patient hospitalization, congenital anomaly, and other medically events.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Prior Brexpiprazole
    Reporting group description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type who previously received brexpiprazole (0.5, 1, or 2 mg/day)during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). This study comprised of 2 months of continued observation following a participant's completion of participation in the previous phase 3 brexpiprazole trials and included 3 visits: at baseline, Month 1 (± 5 days), and Month 2 (± 5 days)/ Early termination (ET). No Investigational medicinal product (IMP) was provided during this 2-month observational rollover trial.months of continued observation following a subject's completion of participation in the previous phase 3 brexpiprazole trials and included 3 visits: at baseline, Month 1 (± 5 days), and Month 2 (± 5 days)/ Early termination (ET). No Investigational medicinal product (IMP) was provided during this 2-month observational rollover trial.

    Reporting group title
    Prior Placebo
    Reporting group description
    This arm comprised of subjects with agitation associated with dementia of the Alzheimer's type, who previously received brexpiprazole matching placebo during a phase 3 brexpiprazole trial (Trial 331-12-283 and Trial 331-12-284). In this rollover study no placebo was administered.

    Serious adverse events
    Prior Brexpiprazole Prior Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 188 (0.53%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Prior Brexpiprazole Prior Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 262 (5.34%)
    9 / 188 (4.79%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 262 (5.34%)
    9 / 188 (4.79%)
         occurrences all number
    14
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2014
    This first amendment served to reflect clarifications and additions to study procedures intended to enhance participant safety and accuracy of data. In addition, administrative clarifications were made, including changes to text to enhance readability and consistency and to correct typographical, punctuation, and formatting errors. These changes were minor and did not change the design or content of the protocol.

    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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