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    Clinical Trial Results:
    A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Flexible Dosing of Brexpiprazole (OPC-34712) in the Treatment of Subjects with Agitation Associated with Dementia of the Alzheimer’s Type

    Summary
    EudraCT number
    2013-000503-17
    Trial protocol
    GB   FI   SI   BG  
    Global end of trial date
    30 Mar 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Nov 2020
    First version publication date
    14 Jun 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    331-12-284
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01922258
    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
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 609 524-6788, clinicaltransparency@otsuka-us.com
    Scientific contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 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
    30 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of flexible dosing of brexpiprazole (dose range of 0.5 to 2 mg/day) with placebo in subjects with agitation associated with dementia of the Alzheimer’s type, as assessed by the Cohen-Mansfield Agitation Inventory (CMAI) after 12 weeks of treatment.
    Protection of trial subjects
    This study was conducted in accordance with International Conference 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 a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Oct 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
    Bulgaria: 48
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Russian Federation: 52
    Country: Number of subjects enrolled
    Slovenia: 6
    Country: Number of subjects enrolled
    Ukraine: 78
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 61
    Worldwide total number of subjects
    270
    EEA total number of subjects
    66
    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)
    43
    From 65 to 84 years
    195
    85 years and over
    32

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 62 sites in 9 countries: Bulgaria, Canada, Finland, France, Russia, Slovenia, Ukraine, the United Kingdom (UK), and the United States (US) and 270 participants were randomized. The date of the first ICF signed by a participant in this trial was 28 October 2013 and the date of the last trial observation was 30 March 2017.

    Pre-assignment
    Screening details
    The screening period ranged from 2 to 42 days (with an option to extend with approval of the medical monitor). The screening period was to determine the participant’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, Monitor, Assessor, Data analyst
    Blinding implementation details
    During the trial, investigational medicinal product was administered in a double-blind manner so that neither the investigator nor the subject had knowledge of the treatment assignment. Treatment assignments were based on a computer-generated randomization code provided by the Biometrics Department. 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 (flexible dose range 0.5 to 2 mg/day)
    Arm description
    Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 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
    Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Arm title
    Placebo (flexible dose range 0.5 to 2 mg/day)
    Arm description
    Titrate up from 0.25 mg/day placebo to 1 mg/day placebo. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.
    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
    Titrate up from 0.25 mg/day placebo to 1 mg/day placebo. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Number of subjects in period 1
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day) Placebo (flexible dose range 0.5 to 2 mg/day)
    Started
    133
    137
    Completed
    117
    121
    Not completed
    16
    16
         Withdrawal By Participant
    5
    5
         Adverse event, non-fatal
    9
    2
         Met Withdrawal Criteria
    -
    4
         Lost to follow-up
    1
    1
         Withdrawn By The Investigator
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day)
    Reporting group description
    Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Reporting group title
    Placebo (flexible dose range 0.5 to 2 mg/day)
    Reporting group description
    Titrate up from 0.25 mg/day placebo to 1 mg/day placebo. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Reporting group values
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day) Placebo (flexible dose range 0.5 to 2 mg/day) Total
    Number of subjects
    133 137 270
    Age categorical
    Units: Subjects
        <65 years
    24 19 43
        >=65 <75 years
    46 49 95
        >=75 years
    63 69 132
    Gender categorical
    Units: Subjects
        Female
    82 88 170
        Male
    51 49 100
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 3 3
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    4 5 9
        White
    128 129 257
        More than one race
    0 0 0
        Unknown or Not Reported
    1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day)
    Reporting group description
    Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Reporting group title
    Placebo (flexible dose range 0.5 to 2 mg/day)
    Reporting group description
    Titrate up from 0.25 mg/day placebo to 1 mg/day placebo. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Primary: Change from baseline to week 12/early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) total score

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    End point title
    Change from baseline to week 12/early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) total score
    End point description
    The CMAI is widely used in clinical research for evaluation of agitation associated with Alzheimer’s dementia, with reliability and validity in both institutionalized and noninstitutionalized participants. It consists of 29 items, all rated on a 1 to 7 scale (1=Never and 7=Several times in an hour), with 1 being the “best” rating and 7 being the “worst” rating. The total score is the sum of ratings for all 29 items. The possible total scores range from 29 to 203. The total score will be unevaluable if less than 24 of the 29 items are recorded. If 24 to 28 of the 29 items are recorded, the total score will be the mean of the recorded items multiplied by 29 and rounded to the first decimal place. The mean change from baseline (Day 0) to week 12 in the CMAI total score is reported. Statistical comparison of interest was brexpiprazole flexible dose versus placebo, analyzed using a mixed-effect model repeated measure approach. A decrease in score indicates improvement in symptoms.
    End point type
    Primary
    End point timeframe
    From screening to week 12/early termination
    End point values
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day) Placebo (flexible dose range 0.5 to 2 mg/day)
    Number of subjects analysed
    131
    135
    Units: units on a scale
        least squares mean (standard error)
    -18.9 ± 1.17
    -16.5 ± 1.13
    Statistical analysis title
    Brexpiprazole versus Placebo
    Statistical analysis description
    Change from baseline in the CMAI Total Score after 12 weeks of brexpiprazole treatment (0.5 - 2 mg/day) compared to 12 weeks of placebo.
    Comparison groups
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day) v Placebo (flexible dose range 0.5 to 2 mg/day)
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1454
    Method
    Mixed-effect model repeated measure
    Parameter type
    Treatment Difference
    Point estimate
    -2.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.49
         upper limit
    0.82

    Secondary: Change in the Clinical Global Impression Severity of Illness (CGI-S) score, as related to symptoms of agitation

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    End point title
    Change in the Clinical Global Impression Severity of Illness (CGI-S) score, as related to symptoms of agitation
    End point description
    The severity of agitation for each participant was rated using the CGI-S. The investigator (or designee) answered the following question: “Considering your total clinical experience with this particular population, how mentally ill (as related to agitation) was the participant at the observation period?” Response choices 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 participants. The score 0 (= not assessed) was set to missing. The CGI-S was therefore a 7-point scale (1-7). The primary analysis used a mixed-effect model repeated measure approach.
    End point type
    Secondary
    End point timeframe
    From screening to week 12/early termination
    End point values
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day) Placebo (flexible dose range 0.5 to 2 mg/day)
    Number of subjects analysed
    131
    135
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.54 ± 0.77
    4.51 ± 0.74
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through the trial: From screening to Week 12 and 30 (+2) days follow-up period.
    Adverse event reporting additional description
    Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day)
    Reporting group description
    Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Reporting group title
    Placebo (flexible dose range 0.5 to 2 mg/day)
    Reporting group description
    Titrate up from 0.25 mg/day placebo to 1 mg/day placebo. After achieving 1 mg/day target, dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.

    Serious adverse events
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day) Placebo (flexible dose range 0.5 to 2 mg/day)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 132 (5.30%)
    6 / 137 (4.38%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
    alternative dictionary used: MedDRA 19.0
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brexpiprazole (flexible dose range 0.5 to 2 mg/day) Placebo (flexible dose range 0.5 to 2 mg/day)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 132 (18.18%)
    29 / 137 (21.17%)
    Nervous system disorders
    Somnolence
    alternative dictionary used: MedDRA 19.0
         subjects affected / exposed
    8 / 132 (6.06%)
    5 / 137 (3.65%)
         occurrences all number
    10
    5
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 132 (7.58%)
    17 / 137 (12.41%)
         occurrences all number
    10
    21
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 132 (4.55%)
    7 / 137 (5.11%)
         occurrences all number
    7
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2013
    The amendment changes were made on the basis of adjustments to facilitate appropriate trial implementation and communication. 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 complete the 331-12-284 (2013-000503-17) trial to enter the 331-13-211 (2014-000424-23) observational trial.
    07 Jul 2014
    The changes were made to address the potential issue of missing data due to subjects terminating early. Noninstitutionalized subjects were allowed with revisions to criteria and assessments for subjects in this setting. The RUD scale and Mortality Assessment at Week 16 for subjects who discontinue the trial early were added.
    10 Sep 2015
    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. The power was increased from 80% to 85%, which resulted in an increase in the sample size from 230 to 260 subjects. Actigraphy was removed and eDiary was replaced with paper diaries. Revisions were made to the Schedule of Assessments to decrease subject burden. Administrative clarifications were made to enhance readability and consistency.

    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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