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    Clinical Trial Results:
    A Randomized, Placebo-controlled Trial to Evaluate the Long-term (ie, Maintenance) Efficacy of Oral Aripiprazole in the Treatment of Pediatric Subjects with Tourette’s Disorder

    Summary
    EudraCT number
    		 2018-002270-48
    Trial protocol
    		 HU  
    Global end of trial date
    30 Jun 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Mar 2021
    First version publication date
    08 Jan 2021
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updates in alignment with revised record following QA review from clinicaltrials.gov.

    Trial information

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    Trial identification
    Sponsor protocol code
    31-14-204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03661983
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, 20850
    Public contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 844-687-8522, OtsukaRMReconciliation@rmpdc.org
    Scientific contact
    Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., +1 844-687-8522, OtsukaRMReconciliation@rmpdc.org
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to evaluate the long-term efficacy of aripiprazole once-daily treatment with oral tablets in pediatric subjects with TD.
    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 the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2018
    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
    Canada: 9
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    36
    EEA total number of subjects
    4
    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)
    22
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 13 investigative sites in Canada, the United States and Hungary from Oct 13, 2018 to Jun 30, 2020.

    Pre-assignment
    Screening details
    		 Pediatric participants with a diagnosis of Tourette's Disorder were enrolled in this to receive oral aripiprazole in an Open-label Stabilization Phase and a Double-blind Randomized Withdrawal Phase and then followed for safety up to 30 days post-last dose.

    Period 1
    Period 1 title
    Open Label Stabilization Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open Label Stabilization Phase: Aripiprazole
    Arm description
    		 Participants began treatment with aripiprazole at a 2.0 mg/day dose, with the dose titrated to 5.0 mg/day after 2 days. Subsequent dose adjustments were based on the participant's weight to achieve optimum control of tics up to the maximum recommended doses based on the United States Labeling, up to Week 8 and then continued on the most stabilized dose up to minimum Week 14 or maximum Week 20. Participants who met stabilization criteria were randomized to Double-blind Randomization Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received aripiprazole matching-placebo tablets, orally as per the regimen specified in the arm description.

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    OPC-14597
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received aripiprazole tablets, orally as per the regimen specified in the arm description.

    Number of subjects in period 1
    		Open Label Stabilization Phase: Aripiprazole
    Started
    36
    Completed
    25
    Not completed
    11
         Adverse event, non-fatal
    5
         Withdrawal by Parent/Guardian
    2
         Study Terminated by Sponsor
    3
         Lack of efficacy
    1
    Period 2
    Period 2 title
    Double-blind Randomized Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double Blind Phase: Aripiprazole Full Dose
    Arm description
    		 Participants who met stabilization criteria and randomized to receive full dose of aripiprazole i.e. 5 mg or 10 mg for <50 kg participants,and 10 mg or 20 mg for >50 kg participants (2 tablets a day), based on stabilized dose in open-label stabilization phase, up to 12 weeks in Double-Blind Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    OPC-14597
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received aripiprazole tablets, orally as per the regimen specified in the arm description.

    Arm title
    		 Double Blind Phase: Aripiprazole Half Dose
    Arm description
    		 Participants who met stabilization criteria and randomized to receive half dose of aripiprazole i.e. 2 mg or 5 mg for <50 kg participants, and 5 mg or 10 mg for >50 kg participants (2 tablets a day), based on stabilized dose in open-label stabilization phase,up to 12 weeks in Double-Blind Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    OPC-14597
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received aripiprazole tablets, orally as per the regimen specified in the arm description.

    Arm title
    		 Double Blind Phase: Placebo
    Arm description
    		 Participants who met randomization criteria and randomized to receive aripiprazole matching-placebo tablets, 2 daily, orally, up to 12 weeks in Double-Blind Phase.
    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
    Participants received aripiprazole matching-placebo tablets, orally as per the regimen specified in the arm description.

    Number of subjects in period 2
    		Double Blind Phase: Aripiprazole Full Dose Double Blind Phase: Aripiprazole Half Dose Double Blind Phase: Placebo
    Started
    9
    8
    8
    Completed
    7
    7
    0
    Not completed
    2
    1
    8
         Disease Relapse
    -
    -
    6
         Adverse event, non-fatal
    1
    -
    -
         Withdrawal by Parent/Guardian
    -
    -
    1
         Study Terminated by Sponsor
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open Label Stabilization Phase: Aripiprazole
    Reporting group description
    		 Participants began treatment with aripiprazole at a 2.0 mg/day dose, with the dose titrated to 5.0 mg/day after 2 days. Subsequent dose adjustments were based on the participant's weight to achieve optimum control of tics up to the maximum recommended doses based on the United States Labeling, up to Week 8 and then continued on the most stabilized dose up to minimum Week 14 or maximum Week 20. Participants who met stabilization criteria were randomized to Double-blind Randomization Phase.

    Reporting group values
    		 Open Label Stabilization Phase: Aripiprazole Total
    Number of subjects
    		 36 36
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 22 22
        Adolescents (12-17 years)
    		 14 14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.9 ( 3.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 30 30
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 7 7
        Not Hispanic or Latino
    		 29 29
        Unknown or Not Reported
    		 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 32 32
        More than one race
    		 0 0
        Unknown or Not Reported
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    Open Label Stabilization Phase: Aripiprazole
    Reporting group description
    		 Participants began treatment with aripiprazole at a 2.0 mg/day dose, with the dose titrated to 5.0 mg/day after 2 days. Subsequent dose adjustments were based on the participant's weight to achieve optimum control of tics up to the maximum recommended doses based on the United States Labeling, up to Week 8 and then continued on the most stabilized dose up to minimum Week 14 or maximum Week 20. Participants who met stabilization criteria were randomized to Double-blind Randomization Phase.
    Reporting group title
    Double Blind Phase: Aripiprazole Full Dose
    Reporting group description
    		 Participants who met stabilization criteria and randomized to receive full dose of aripiprazole i.e. 5 mg or 10 mg for <50 kg participants,and 10 mg or 20 mg for >50 kg participants (2 tablets a day), based on stabilized dose in open-label stabilization phase, up to 12 weeks in Double-Blind Phase.

    Reporting group title
    Double Blind Phase: Aripiprazole Half Dose
    Reporting group description
    		 Participants who met stabilization criteria and randomized to receive half dose of aripiprazole i.e. 2 mg or 5 mg for <50 kg participants, and 5 mg or 10 mg for >50 kg participants (2 tablets a day), based on stabilized dose in open-label stabilization phase,up to 12 weeks in Double-Blind Phase.

    Reporting group title
    Double Blind Phase: Placebo
    Reporting group description
    		 Participants who met randomization criteria and randomized to receive aripiprazole matching-placebo tablets, 2 daily, orally, up to 12 weeks in Double-Blind Phase.

    Primary: Percentage of Participants With Relapse During the Double-blind Randomized Withdrawal Phase

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    End point title
    		 Percentage of Participants With Relapse During the Double-blind Randomized Withdrawal Phase [1]
    End point description
    Relapse was defined as a loss of ≥ 50% of the improvement experienced during the open-label stabilization phase (i.e., improvement at the last assessment of Yale Global Tic Severity Scale [YGTSS] before randomization) on the Yale Global Tic Severity Scale Total Tic Score (YGTSS TTS). YGTSS provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. Intent to Treat (ITT) Sample included all participants who were randomized and received at least 1 dose of randomized Investigational medicinal product (IMP) were included in this dataset and were analyzed according to the treatment group they were randomized to.
    End point type
    Primary
    End point timeframe
    From Randomization up to 12 weeks in Double-blind Randomized Withdrawal Phase
    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: No statistical analyses have been identified for this primary end point.
    End point values
    		 Double Blind Phase: Aripiprazole Full Dose Double Blind Phase: Aripiprazole Half Dose Double Blind Phase: Placebo
    Number of subjects analysed
    9
    8
    8
    Units: percentage of participants
        number (not applicable)
    0
    0
    75.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to 30 days after last dose of study drug (Up to approximately 36 weeks)
    Adverse event reporting additional description
    Open-label Safety Sample included all participants that had administered at least 1 dose of IMP during the open-label stabilization phase.Randomized Safety Sample included all participants who received at least 1 dose of randomized IMP during double-blind randomized withdrawal phase were included and analyzed according to the treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Open Label Stabilization Phase: Aripiprazole
    Reporting group description
    		 Participants began treatment with aripiprazole at a 2.0 mg/day dose, with the dose titrated to 5.0 mg/day after 2 days. Subsequent dose adjustments were based on the participant's weight to achieve optimum control of tics up to the maximum recommended doses based on the United States Labeling, up to Week 8 and then continued on the most stabilized dose up to minimum Week 14 or maximum Week 20. Participants who met stabilization criteria were randomized to Double-blind Randomization Phase.

    Reporting group title
    Double Blind Phase: Aripiperazole Full Dose
    Reporting group description
    		 Participants who met stabilization criteria and randomized to receive full dose of aripiprazole i.e. 5 mg or 10 mg for <50 kg participants,and 10 mg or 20 mg for >50 kg participants (2 tablets a day), based on stabilized dose in open-label stabilization phase, up to Week 32.

    Reporting group title
    Double Blind Phase: Aripiperazole Half Dose
    Reporting group description
    		 Participants who met stabilization criteria and randomized to receive half dose of aripiprazole i.e. 2 mg or 5 mg for <50 kg participants, and 5 mg or 10 mg for >50 kg participants (2 tablets a day), based on stabilized dose in open-label stabilization phase, up to Week 32.

    Reporting group title
    Double Blind Phase: Placebo
    Reporting group description
    		 Participants who met randomization criteria and randomized to receive aripiprazole matching-placebo tablets, 2 daily, orally, up to Week 32.

    Serious adverse events
    		 Open Label Stabilization Phase: Aripiprazole Double Blind Phase: Aripiperazole Full Dose Double Blind Phase: Aripiperazole Half Dose Double Blind Phase: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Psychiatric disorders
    Suicidal Ideation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         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
    		 Open Label Stabilization Phase: Aripiprazole Double Blind Phase: Aripiperazole Full Dose Double Blind Phase: Aripiperazole Half Dose Double Blind Phase: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 36 (47.22%)
    3 / 9 (33.33%)
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    Investigations
    Weight increased
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    5 / 36 (13.89%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    5
    0
    1
    0
    Headache
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Sedation
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    4
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 36 (19.44%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    7
    0
    0
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Enuresis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Irritability
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Restlessness
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Anxiety
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infections and infestations
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Apr 2018
    The following updates were made as per Amendment 01: Added a Week 10 visit to the double-blind phase. Allowed for remote visits (i.e., telemedicine) for selected trial visits. Decreased the number of Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS) assessments and vital signs measurements. Added waist circumference. Specified that the C-SSRS is the children’s version. Added the option of micro-sampling for clinical laboratory tests. Added an interim analysis (IA). Revised language regarding sample size calculation and primary endpoint analysis. Clarified inclusion/exclusion criteria. Deleted Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) contact information in the appendices. Deleted sample assessment scales in the appendices. Updated the protocol to conform to the Otsuka template and style guide. Corrected minor typographical errors.
    20 Jun 2018
    The following updates were made as per Amendment 01: Added the EudraCT number. Increased the number of proposed sites. Specified that randomization will be stratified by region and body weight. Clarified exclusion criterion #17. Removed the option for the screening visit to be conducted remotely. Removed the option for remote visits during the open-label stabilization phase after the Week 12 visit. Clarified dose titration and specify when and how dose adjustments are permitted. Added language regarding relapse. Specified conditions for the measurement of blood pressure. Removed triplicate electrocardiograms (ECGs) so that only one ECG is done. Added details regarding Columbia-Suicide Severity Rating Scale (C-SSRS) results. Added missing clinical laboratory assessments. Corrected minor typographical errors and add clarifications to text.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Jun 2020
    This trial was terminated early due to the withdrawal of post-marketing commitment (PMC) to FDA. The planned interim analysis was not conducted either.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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