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    Clinical Trial Results:
    Safety and Efficacy of Aripiprazole in the Long-Term Maintenance Treatment of Pediatric Subjects with Irritability Associated with Autistic Disorder

    Summary
    EudraCT number
    		 2017-000174-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    20 Jun 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Feb 2018
    First version publication date
    25 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CN138603
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01227668
    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
    Angela Smith, Otsuka Pharmaceutical Development & Commercialization, Inc, +1 8609202209, angela.smith@otsuka-us.com
    Scientific contact
    Angela Smith, Otsuka Pharmaceutical Development & Commercialization, Inc, +1 8609202209, angela.smith@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
    04 Jan 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jun 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of aripiprazole compared with placebo to prevent relapses in pediatric subjects who maintained a response for 12 weeks of aripiprazole treatment for their symptoms of irritability associated with autistic disorder as measured by the time from randomization to relapse.
    Protection of trial subjects
    In accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline, in accordance with the ethical principles underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) and the applicable local laws and regulatory requirements of the countries in which the trial was conducted, copies of the protocol, amendments, and informed consent form (ICF) were reviewed and approved by the governing institutional review board (IRB) or independent ethics committee (IEC) for each investigational site or country, as appropriate, prior to trial start or prior to implementation of the amendment at that site or country.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Mar 2011
    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
    United States: 157
    Worldwide total number of subjects
    157
    EEA total number of subjects
    0
    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)
    114
    Adolescents (12-17 years)
    43
    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
    		 A total of 215 subjects were enrolled in the study, and 157 (73%) completed the screening phase and entered Phase 1. Eighty-five subjects (54%) completed Phase 1 and were randomized in Phase 2 (41 and 44 in the aripiprazole and placebo groups, respectively).

    Pre-assignment
    Screening details
    		 The study included 2 phases: Phase 1 (stabilization phase) - 13 - 26 weeks of single-blind aripiprazole treatment and Phase 2 (randomization phase) - 16 weeks of double-blind treatment with aripiprazole or placebo.

    Period 1
    Period 1 title
    Phase 1 (Stabilization phase)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Arm title
    		 Aripiprazole
    Arm description
    		 Phase 1 (stabilization phase) - Participants received 13 - 26 weeks of single-blind aripiprazole treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    aripiprazole 2, 5, 10, and 15 mg tablets, once daily at the same time each day

    Number of subjects in period 1
    		Aripiprazole
    Started
    157
    Completed
    85
    Not completed
    72
         Consent withdrawn by subject
    7
         Administrative reason by Sponsor
    11
         Poor/Non compliance
    2
         Adverse event, non-fatal
    12
         Lost to follow-up
    8
         Subject no longer meets study criteria
    7
         Lack of efficacy
    25
    Period 2
    Period 2 title
    Phase 2 (Randomization phase)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Phase 2: Randomization phase - Participants received 16 weeks of double-blind treatment with placebo
    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
    Matching placebo once daily at the same time each day

    Arm title
    		 Aripiprazole
    Arm description
    		 Phase 2: Randomization phase - Participants received 16 weeks of double-blind treatment with aripiprazole
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aripiprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    aripiprazole 2, 5, 10, and 15 mg tablets, once daily at the same time each day

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics were presented based on Phase 2 as Baseline period.
    Number of subjects in period 2 [2]
    		Placebo Aripiprazole
    Started
    44
    41
    Completed
    19
    22
    Not completed
    25
    19
         Consent withdrawn by subject
    -
    5
         Poor/Non compliance
    1
    -
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    -
    1
         Lack of efficacy
    23
    13
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 215 subjects were enrolled in the study, and 157 (73%) completed the screening phase and entered Phase 1. Eighty-five subjects (54%) completed Phase 1 and were randomized in Phase 2 (41 and 44 in the aripiprazole and placebo groups, respectively).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Phase 2: Randomization phase - Participants received 16 weeks of double-blind treatment with placebo

    Reporting group title
    Aripiprazole
    Reporting group description
    		 Phase 2: Randomization phase - Participants received 16 weeks of double-blind treatment with aripiprazole

    Reporting group values
    		 Placebo Aripiprazole Total
    Number of subjects
    		 44 41 85
    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)
    		 10.8 ( 2.77 ) 10.1 ( 2.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 11 17
        Male
    		 38 30 68

    End points

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    End points reporting groups
    Reporting group title
    Aripiprazole
    Reporting group description
    		 Phase 1 (stabilization phase) - Participants received 13 - 26 weeks of single-blind aripiprazole treatment
    Reporting group title
    Placebo
    Reporting group description
    		 Phase 2: Randomization phase - Participants received 16 weeks of double-blind treatment with placebo

    Reporting group title
    Aripiprazole
    Reporting group description
    		 Phase 2: Randomization phase - Participants received 16 weeks of double-blind treatment with aripiprazole

    Subject analysis set title
    The Phase 1 Safety Sample
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Phase 1 Safety Sample comprised all subjects who took at least 1 dose of single-blind aripiprazole in Phase 1 (Stabilization Phase)

    Subject analysis set title
    Phase 1 Efficacy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Phase 1 Efficacy Sample comprised all subjects who were in the Phase 1 Safety Sample and had at least 1 efficacy evaluation after the start of Phase 1 study drug.

    Subject analysis set title
    Randomized Sample
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Randomized Sample comprises all patients who are randomized in Phase 2 (Randomization Phase).

    Subject analysis set title
    Phase 2 Safety Sample
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Phase 2 Safety Sample comprised all subjects in the Randomized Sample who took at least 1 dose of double-blind medication in Phase 2,

    Subject analysis set title
    Phase 2 Efficacy Sample
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Phase 2 Efficacy Sample comprised all subjects who were in the Phase 2 Safety Sample and had at least 1 efficacy evaluation after the start of Phase 2 study drug.

    Primary: Percentage of Patients Relapsing by Week 16

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    End point title
    		 Percentage of Patients Relapsing by Week 16
    End point description
    Time of relapse=date when patient meets relapse criteria. There are 4 definitions for relapse: 1. Patient meets the following criteria for 2 consecutive visits: (a) Aberrant Behavior Checklist Irritability score ≥25% than score at end of Phase 1 AND (b) Clinical Global Impression Improvement scale rating of 'Much Worse' or 'Very Much Worse' relative to rating at end of Phase 1. If relapse criteria met at 1 visit, 2nd visit should occur in about 1 week to reevaluate whether relapse criteria are still met. 2. Patient discontinues for "Lost to Follow-up" after a visit in which he or she met Definition 1 criteria (a&b). 3. Patient begins a prohibited drug (whether a study investigator or outside source prescribed) to treat worsening symptoms of irritability of autistic disorder after a visit where patient met Definition 1 criteria (a&b). 4. Patient discontinues due to hospitalization for worsening symptoms of irritability or due to lack of efficacy based on investigator's assessment.
    End point type
    Primary
    End point timeframe
    From end of Phase 1 (Date of randomization) to Week 16 of Phase 2 (end of treatment)
    End point values
    		 Placebo Aripiprazole
    Number of subjects analysed
    44
    41
    Units: Number of events
        Number of Events
    22
    13
    Statistical analysis title
    		 Summary of Time from Randomization to Relapse
    Comparison groups
    Aripiprazole v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.097
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.12

    Secondary: Adjusted Mean Change From Baseline to Week 16 on the Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score (Last Observation Carried Forward [LOCF])

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    End point title
    		 Adjusted Mean Change From Baseline to Week 16 on the Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score (Last Observation Carried Forward [LOCF])
    End point description
    ABC is an informant-based checklist used to assess and classify problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0=not at all a problem to 3=the problem is severe in degree), and resolve into 5 subscales: 1) irritability, agitation; 2) lethargy, social withdrawal; 3) stereotypic behavior; 4) hyperactivity, noncompliance; and 5) inappropriate speech. The ABC can be completed by parents, special educators, psychologists, direct caregivers, nurses, and others knowing the participant. Psychometric assessment of the ABC indicates that its subscales have high internal consistency, adequate reliability, and established validity. The ABC-I Subscale Score ranges from 0 to 45, with a negative change in score signifying improvement. LOCF data set includes data recorded at a given visit or, if no observation was recorded at that visit, data carried forward from the prior visit. (chg=change; BL=baseline; APR=aripiprazole; vs=versus).
    End point type
    Secondary
    End point timeframe
    From Baseline (end of Phase 1) to Week 16 of Phase 2 (end of treatment)
    End point values
    		 Placebo Aripiprazole
    Number of subjects analysed
    43
    39
    Units: Number of Partcipants
    arithmetic mean (standard error)
        ABC Irritability (ABC-I) Subscale Scores
    9.6 ( 1.56 )
    5.2 ( 1.61 )
    Statistical analysis title
    		 ABC Irritability (ABC-I) Subscale Scores
    Comparison groups
    Placebo v Aripiprazole
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.051
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 0

    Secondary: Change From Baseline in Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 16 (Last Observation Carried Forward [LOCF])

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    End point title
    		 Change From Baseline in Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 16 (Last Observation Carried Forward [LOCF])
    End point description
    CG-I rating scale permits global evaluation of patient's improvement over time. At baseline (BL), CGI Severity of Illness assessment is performed, in which the clinician rates severity of patient's condition on a 7-point scale ranging from 1=no symptoms to 7=very severe symptoms. Higher total score=worse symptoms. At subsequent visits, clinician assesses patient's improvement relative to symptoms at baseline on CGI-I 7-point scale ranging from 1=very much improved to 7=very much worse. Since the drug targets irritability symptoms, the CGI focuses on severity of irritability secondary to autistic disorder. Lower score=more improved symptoms. LOCF data set includes data recorded at a given visit or, if nothing recorded, data areccarried forward from the prior visit. For secondary endpoints (endpt), hierarchical testing was used to keep overall experiment-wise type I error rate to <=0.05. (diff=difference; IS=irritability scale; PA=primary analysis; signif=significance/significantly).
    End point type
    Secondary
    End point timeframe
    From Baseline (end of Phase 1) to Week 16 of Phase 2 (end of treatment)
    End point values
    		 Placebo Aripiprazole
    Number of subjects analysed
    43
    39
    Units: Number of Participants
    arithmetic mean (standard error)
        Mean change in CGI-I Score
    4.8 ( 0.26 )
    4.2 ( 0.26 )
    Statistical analysis title
    		 Mean change in CGI-I Score
    Comparison groups
    Placebo v Aripiprazole
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from screening (7 - 42 days) up to the end of study treatment or early termination (ET)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Phase 1 Aripiprazole
    Reporting group description
    		 Phase 1 (stabilization phase) - 13 - 26 weeks of single-blind aripiprazole treatment

    Reporting group title
    Phase 2 Aripiprazole
    Reporting group description
    		 Phase 2: Randomization phase (16 weeks of double-blind treatment with aripiprazole)

    Reporting group title
    Phase 2 Placebo
    Reporting group description
    		 Phase 2: Randomization phase (16 weeks of double-blind treatment with placebo)

    Serious adverse events
    		 Phase 1 Aripiprazole Phase 2 Aripiprazole Phase 2 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1 Aripiprazole Phase 2 Aripiprazole Phase 2 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    124 / 155 (80.00%)
    22 / 39 (56.41%)
    14 / 43 (32.56%)
    Investigations
    Weight increased
         subjects affected / exposed
    39 / 155 (25.16%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    47
    0
    0
    Nervous system disorders
    Movement disorder
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 39 (5.13%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    Headache
         subjects affected / exposed
    8 / 155 (5.16%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    14
    0
    0
    Lethargy
         subjects affected / exposed
    8 / 155 (5.16%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    8
    0
    0
    Somnolence
         subjects affected / exposed
    23 / 155 (14.84%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    27
    0
    0
    Tremor
         subjects affected / exposed
    9 / 155 (5.81%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    11
    0
    0
    Insomnia
         subjects affected / exposed
    13 / 155 (8.39%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    14
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 155 (8.39%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    20
    0
    0
    Pyrexia
         subjects affected / exposed
    8 / 155 (5.16%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    8
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 39 (5.13%)
    0 / 43 (0.00%)
         occurrences all number
    0
    2
    0
    Vomiting
         subjects affected / exposed
    22 / 155 (14.19%)
    2 / 39 (5.13%)
    2 / 43 (4.65%)
         occurrences all number
    30
    2
    3
    Diarrhoea
         subjects affected / exposed
    11 / 155 (7.10%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    12
    0
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    9 / 155 (5.81%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    9
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 155 (10.32%)
    4 / 39 (10.26%)
    1 / 43 (2.33%)
         occurrences all number
    18
    5
    1
    Nasopharyngitis
         subjects affected / exposed
    9 / 155 (5.81%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    9
    0
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    20 / 155 (12.90%)
    0 / 39 (0.00%)
    0 / 43 (0.00%)
         occurrences all number
    25
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2011
    This amendment was written to remove the interim analysis from the study. This was done on the advice of the United States Food and Drug Administration. • Clarification was made to allow for the Autism Diagnostic Interview- Revised (ADI-R) to be completed via telephone. • Included modifications made by Administrative Letter 01 dated 20 Dec 2010. Deleted references to aftercare from the protocol and correct typographical errors. • Correct Typographical errors and formatting errors. • This revision applies to all study sites and subjects.

    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
    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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