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    Clinical Trial Results:
    Risperidone in the Treatment of Children and Adolescents With Autistic Disorder: A Double-Blind, Placebo-Controlled Study of Efficacy and Safety, Followed by an Open-Label Extension Study of Safety

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2015-001220-31
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    09 Mar 2010

    Results information
    Results version number
    v2(current)
    This version publication date
    15 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    RISAUT4002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00576732
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Johnson & Johnson Pharmaceutical Research and Development, L.L.C.
    Sponsor organisation address
    Archimedesweg 29, Leiden, Netherlands, 2333CM
    Public contact
    Clinical Registry Group-JB BV, Clinical Registry Group-JB BV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group-JB BV, Clinical Registry Group-JB BV, ClinicalTrialsEU@its.jnj.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Mar 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the effectiveness (change in level of irritability and related behaviors) and safety and tolerability of the administration of 2 different fixed dose levels of risperidone (an atypical antipsychotic drug) compared with placebo in children or adolescents who have autism, and to evaluate the safety and tolerability of the drug for additional 26 weeks after the initial 6-week study period.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Known instances of nonconformance were documented and are not considered to have had an impact on the overall conclusions of this study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Nov 2007
    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: 96
    Worldwide total number of subjects
    96
    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)
    74
    Adolescents (12-17 years)
    22
    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
    -

    Pre-assignment
    Screening details
    A total of 96 subjects were enrolled in the study.

    Period 1
    Period 1 title
    Overall study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects weighing 20 kg to <45 kg were started with 0.5 ml of placebo solution on Day 1 and were titrated up to 1.25 ml on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 ml of placebo solution on Day 1 and were titrated up to 1.75 ml on Day 4.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects weighing 20 kg to <45 kg were started with 0.5 ml of placebo solution on Day 1 and were titrated up to 1.25 ml on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 ml of placebo solution on Day 1 and were titrated up to 1.75 ml on Day 4.

    Arm title
    Risperidone Low Dose
    Arm description
    Subjects weighing 20 kg to <45 kg were started with 0.05 mg on Day 1 and were titrated up to 0.125 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.075 mg on Day 1 and were titrated up to 0.175 mg on Day 4.
    Arm type
    Experimental

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects weighing 20 kg to <45 kg were started with 0.05 mg on Day 1 and were titrated up to 0.125 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.075 mg on Day 1 and were titrated up to 0.175 mg on Day 4.

    Arm title
    Risperidone High Dose
    Arm description
    Subjects weighing 20 kg to <45 kg were started with 0.5 mg on Day 1 and were titrated up to 1.25 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 mg on Day 1 and were titrated up to 1.75 mg on Day 4.
    Arm type
    Experimental

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    ubjects weighing 20 kg to <45 kg were started with 0.5 mg on Day 1 and were titrated up to 1.25 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 mg on Day 1 and were titrated up to 1.75 mg on Day 4.

    Number of subjects in period 1
    Placebo Risperidone Low Dose Risperidone High Dose
    Started
    35
    30
    31
    Completed
    27
    25
    25
    Not completed
    8
    5
    6
         Consent withdrawn by subject
    1
    1
    3
         Adverse event, non-fatal
    -
    -
    1
         Other
    -
    2
    1
         Lost to follow-up
    -
    1
    1
         Protocol deviation
    1
    -
    -
         Lack of efficacy
    6
    1
    -
    Period 2
    Period 2 title
    Open Label
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    OL Risperidone
    Arm description
    Subjects who completed the double-blind phase, or discontinued after at least 3 weeks for reasons other than tolerability and, in the investigator's judgment needed risperidone treatment were eligible to enter the open-label phase. Risperidone was given as oral solution (1 mg/mL) for the first 3 days and as tablets from Day 4 on. On Day 1, subjects with a baseline weight of 20 kg to <45 kg were started on risperidone 0.125 mg/day, and subjects with a baseline weight of 45 kg or more were started on risperidone 0.175 mg/day. On Day 4, the dose was increased to 0.25 mg for all subjects. After Day 14, dose increments of 0.25 mg or 0.5 mg (upon the judgment of the investigator) were allowed every 2 weeks. The maximum allowed dose was 1.25 mg for subjects with baseline weight of 20 kg to <45 kg and 1.75 mg for subjects with a baseline weight of 45 kg or more.
    Arm type
    Experimental

    Investigational medicinal product name
    OL Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who completed the double-blind phase, or discontinued after at least 3 weeks for reasons other than tolerability and, in the investigator's judgment needed risperidone treatment were eligible to enter the open-label phase. Risperidone was given as oral solution (1 mg/mL) for the first 3 days and as tablets from Day 4 on. On Day 1, subjects with a baseline weight of 20 kg to <45 kg were started on risperidone 0.125 mg/day, and subjects with a baseline weight of 45 kg or more were started on risperidone 0.175 mg/day. On Day 4, the dose was increased to 0.25 mg for all subjects. After Day 14, dose increments of 0.25 mg or 0.5 mg (upon the judgment of the investigator) were allowed every 2 weeks. The maximum allowed dose was 1.25 mg for subjects with baseline weight of 20 kg to <45 kg and 1.75 mg for subjects with a baseline weight of 45 kg or more.

    Number of subjects in period 2
    OL Risperidone
    Started
    79
    Completed
    56
    Not completed
    23
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    5
         Other
    2
         Lost to follow-up
    4
         Protocol deviation
    3
         Lack of efficacy
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.5 ml of placebo solution on Day 1 and were titrated up to 1.25 ml on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 ml of placebo solution on Day 1 and were titrated up to 1.75 ml on Day 4.

    Reporting group title
    Risperidone Low Dose
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.05 mg on Day 1 and were titrated up to 0.125 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.075 mg on Day 1 and were titrated up to 0.175 mg on Day 4.

    Reporting group title
    Risperidone High Dose
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.5 mg on Day 1 and were titrated up to 1.25 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 mg on Day 1 and were titrated up to 1.75 mg on Day 4.

    Reporting group values
    Placebo Risperidone Low Dose Risperidone High Dose Total
    Number of subjects
    35 30 31 96
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    30 20 24 74
        Adolescents (12-17 years)
    5 10 7 22
        Adults (18-64 years)
    0 0 0 0
        From 65 to 84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    8.6 ± 2.57 10.2 ± 3.42 9.3 ± 3.11 -
    Title for Gender
    Units: subjects
        Female
    4 5 3 12
        Male
    31 25 28 84

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.5 ml of placebo solution on Day 1 and were titrated up to 1.25 ml on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 ml of placebo solution on Day 1 and were titrated up to 1.75 ml on Day 4.

    Reporting group title
    Risperidone Low Dose
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.05 mg on Day 1 and were titrated up to 0.125 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.075 mg on Day 1 and were titrated up to 0.175 mg on Day 4.

    Reporting group title
    Risperidone High Dose
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.5 mg on Day 1 and were titrated up to 1.25 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 mg on Day 1 and were titrated up to 1.75 mg on Day 4.
    Reporting group title
    OL Risperidone
    Reporting group description
    Subjects who completed the double-blind phase, or discontinued after at least 3 weeks for reasons other than tolerability and, in the investigator's judgment needed risperidone treatment were eligible to enter the open-label phase. Risperidone was given as oral solution (1 mg/mL) for the first 3 days and as tablets from Day 4 on. On Day 1, subjects with a baseline weight of 20 kg to <45 kg were started on risperidone 0.125 mg/day, and subjects with a baseline weight of 45 kg or more were started on risperidone 0.175 mg/day. On Day 4, the dose was increased to 0.25 mg for all subjects. After Day 14, dose increments of 0.25 mg or 0.5 mg (upon the judgment of the investigator) were allowed every 2 weeks. The maximum allowed dose was 1.25 mg for subjects with baseline weight of 20 kg to <45 kg and 1.75 mg for subjects with a baseline weight of 45 kg or more.

    Subject analysis set title
    Placebo/RIS
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Open-label Period. Subjects in the double-blind placebo group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).

    Subject analysis set title
    Ris Low Dose/RIS
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Open-label Period. Subjects in the double-blind risperidone low dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).

    Subject analysis set title
    Ris High Dose/RIS
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Open-label Period. Subjects in the double-blind risperidone high dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).

    Primary: Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale

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    End point title
    Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale
    End point description
    Measure of irritability symptoms of autism. Score range 0 to 45 (lower score = lesser severity). All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).
    End point type
    Primary
    End point timeframe
    Baseline and 6 weeks
    End point values
    Placebo Risperidone Low Dose Risperidone High Dose
    Number of subjects analysed
    34
    29
    29
    Units: participants
        arithmetic mean (standard deviation)
    -3.5 ± 10.67
    -7.4 ± 8.12
    -12.4 ± 6.52
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Risperidone High Dose
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.001 [2]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.19
         upper limit
    -3.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.18
    Notes
    [1] - A step-down testing procedure was employed with the risperidone high dose versus placebo comparison tested first. If this comparison was significant the risperidone low dose versus placebo comparison would be performed. A clinically relevant difference in the change from baseline on the ABC Irritability subscale was assumed to be 6 with a standard deviation of 8. To achieve 80% power with Type I error rate of 5%, 93 subjects were required.
    [2] - Type I error is preserved by the step down procedure, no multiple comparison adjustment is needed. A priori threshold for statistical significance was 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Risperidone Low Dose
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.164 [3]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.36
         upper limit
    1.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.17
    Notes
    [3] - Type I error is preserved by the step down procedure, no multiple comparison adjustment is needed. A priori threshold for statistical significance was 0.05.

    Secondary: Number of Participants Who Had at Least 25% Improvement in ABC-I

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    End point title
    Number of Participants Who Had at Least 25% Improvement in ABC-I
    End point description
    ABC-I is a measure of irritability symptoms of autism with score range 0 to 45 (lower score = lesser severity). All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    Placebo Risperidone Low Dose Risperidone High Dose
    Number of subjects analysed
    34
    29
    29
    Units: participants
    14
    15
    24
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Risperidone High Dose
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [4]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Risperidone Low Dose
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.817 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.

    Secondary: Change in Clinical Global Impression Severity (CGI-S)

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    End point title
    Change in Clinical Global Impression Severity (CGI-S)
    End point description
    Investigator evaluation of severity of illness and functional impairment on a 7-point scale (1="not ill", 2="very mild", 3="mild", 4="moderate", 5="marked", 6="severe", 7="extremely severe"). All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks
    End point values
    Placebo Risperidone Low Dose Risperidone High Dose
    Number of subjects analysed
    34
    29
    29
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.3 ± 0.79
    -0.4 ± 0.73
    -1 ± 0.78
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Risperidone High Dose
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    < 0.001 [7]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.02
         upper limit
    -0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [6] - Mean difference is change in Risperidone high dose arm minus change in placebo arm. P-value is not adjusted for multiple comparisons.
    [7] - ANCOVA model included factors for treatment group, center (after pooling of small centers), baseline weight stratification, and baseline CGI-S value.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Risperidone Low Dose
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.769 [8]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.39
         upper limit
    0.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [8] - ANCOVA model included factors for treatment group, center (after pooling of small centers), baseline weight stratification, and baseline CGI-S value.

    Secondary: Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved

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    End point title
    Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved
    End point description
    Investigator impression of change over time from double-blind baseline on a 7-point scale (1="very much improved", 2="much improved", 3="minimally improved", 4="no change", 5="minimally worse", 6="much worse", 7="very much worse"). All randomized subjects with at least one dose of study medication and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    Placebo Risperidone Low Dose Risperidone High Dose
    Number of subjects analysed
    34
    30
    30
    Units: participants
    5
    5
    19
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Risperidone Low Dose
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.985 [9]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [9] - Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Risperidone High Dose v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [10]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [10] - Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.

    Secondary: Change in Fasting Glucose (mg/dL) at 6 Weeks

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    End point title
    Change in Fasting Glucose (mg/dL) at 6 Weeks
    End point description
    All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline fasting laboratory samples. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks
    End point values
    Placebo Risperidone Low Dose Risperidone High Dose
    Number of subjects analysed
    22
    23
    23
    Units: mg/dL
        arithmetic mean (standard deviation)
    -0.4 ± 8.2
    -0.1 ± 8.81
    -0.3 ± 9.74
    No statistical analyses for this end point

    Secondary: Change in Insulin Resistance (IR) at 6 Weeks

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    End point title
    Change in Insulin Resistance (IR) at 6 Weeks
    End point description
    Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1)formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus. All randomized subjects with >=1 dose of study medication and fasting glucose and insulin at baseline and at >=1 postbaseline time point. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period. Means are adjusted for baseline weight (<45 kg, >=45 kg) and baseline IR.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks
    End point values
    Placebo Risperidone Low Dose Risperidone High Dose
    Number of subjects analysed
    22 [11]
    21 [12]
    22 [13]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    0.36 (-0.34 to 1.07)
    -0.1 (-0.76 to 0.55)
    0.45 (-0.18 to 1.08)
    Notes
    [11] - Here 'N' signifies subjects analyzed for this endpoint.
    [12] - Here 'N' signifies subjects analyzed for this endpoint.
    [13] - Here 'N' signifies subjects analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Change in Fasting Glucose (mg/dL) at 6 Months

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    End point title
    Change in Fasting Glucose (mg/dL) at 6 Months
    End point description
    All subjects with at least one dose of study medication in the open label phase and both double-blind baseline and at least one open-label period fasting laboratory samples. For subjects who discontinued, Month 6 data is imputed using the subject's last nonmissing, postbaseline value in the open-label period.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo/RIS Ris Low Dose/RIS Ris High Dose/RIS
    Number of subjects analysed
    19
    16
    16
    Units: milligram per deciliters (mg/dL)
        arithmetic mean (standard deviation)
    4 ± 12.27
    3.5 ± 12.27
    2.3 ± 8.7
    No statistical analyses for this end point

    Secondary: Change in Insulin Resistance (IR) at 6 Months

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    End point title
    Change in Insulin Resistance (IR) at 6 Months
    End point description
    Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1) formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus. All subjects with at least one dose of study medication in the open label phase and both double-blind baseline and at least one open-label period fasting laboratory samples. For subjects who discontinued, Month 6 data is imputed using the subject's last nonmissing, postbaseline value in the open-label period.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo/RIS Ris Low Dose/RIS Ris High Dose/RIS
    Number of subjects analysed
    19
    16
    16
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.09 ± 2.67
    0.36 ± 0.89
    0.75 ± 0.91
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-blind period: 6 weeks. Open-label period: 6 months
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.5 ml of placebo solution on Day 1 and were titrated up to 1.25 ml on Day 4. Subjects weighing >=45 kg at baseline were started with 0.75 ml of placebo solution on Day 1 and were titrated up to 1.75 ml on Day 4.

    Reporting group title
    Risperidone Low Dose
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.05 mg on Day 1 and were titrated up to 0.125 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.075 mg on Day 1 and were titrated up to 0.175 mg on Day 4.

    Reporting group title
    Risperidone High Dose
    Reporting group description
    Subjects weighing 20 kg to <45 kg were started with 0.05 mg on Day 1 and were titrated up to 0.125 mg on Day 4. Subjects weighing >=45 kg at baseline were started with 0.075 mg on Day 1 and were titrated up to 0.175 mg on Day 4.

    Reporting group title
    Open-label Risperidone
    Reporting group description
    Subjects who completed the double-blind phase, or discontinued after at least 3 weeks for reasons other than tolerability and, in the investigator's judgment needed risperidone treatment were eligible to enter the open-label phase. Risperidone was given as oral solution (1 mg/mL) for the first 3 days and as tablets from Day 4 on. On Day 1, subjects with a baseline weight of 20 kg to <45 kg were started on risperidone 0.125 mg/day, and subjects with a baseline weight of 45 kg or more were started on risperidone 0.175 mg/day. On Day 4, the dose was increased to 0.25 mg for all subjects. After Day 14, dose increments of 0.25 mg or 0.5 mg (upon the judgment of the investigator) were allowed every 2 weeks. The maximum allowed dose was 1.25 mg for subjects with baseline weight of 20 kg to <45 kg and 1.75 mg for subjects with a baseline weight of 45 kg or more.

    Serious adverse events
    Placebo Risperidone Low Dose Risperidone High Dose Open-label Risperidone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 79 (1.27%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    Placebo Risperidone Low Dose Risperidone High Dose Open-label Risperidone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 35 (57.14%)
    12 / 30 (40.00%)
    27 / 31 (87.10%)
    39 / 79 (49.37%)
    Investigations
    Weight increased
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 30 (10.00%)
    4 / 31 (12.90%)
    7 / 79 (8.86%)
         occurrences all number
    7
    4
    5
    7
    Nervous system disorders
    Sedation
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 30 (3.33%)
    8 / 31 (25.81%)
    6 / 79 (7.59%)
         occurrences all number
    0
    1
    10
    6
    Somnolence
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 30 (0.00%)
    7 / 31 (22.58%)
    4 / 79 (5.06%)
         occurrences all number
    1
    0
    7
    4
    Akathisia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 79 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Headache
         subjects affected / exposed
    4 / 35 (11.43%)
    2 / 30 (6.67%)
    2 / 31 (6.45%)
    4 / 79 (5.06%)
         occurrences all number
    4
    2
    2
    4
    Hypersomnia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 79 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    1 / 79 (1.27%)
         occurrences all number
    2
    1
    1
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    6 / 79 (7.59%)
         occurrences all number
    0
    0
    4
    7
    Thirst
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Fatigue
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    4 / 79 (5.06%)
         occurrences all number
    0
    0
    2
    6
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    5
    0
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 30 (3.33%)
    2 / 31 (6.45%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    0
    2
    Constipation
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    3 / 79 (3.80%)
         occurrences all number
    2
    0
    4
    3
    Nausea
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 30 (3.33%)
    2 / 31 (6.45%)
    0 / 79 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Vomiting
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 30 (6.67%)
    2 / 31 (6.45%)
    7 / 79 (8.86%)
         occurrences all number
    4
    5
    4
    7
    Diarrhoea
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    2
    2
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cough
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    4 / 79 (5.06%)
         occurrences all number
    0
    0
    0
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    0
    3
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    3
    0
    0
    2
    Agitation
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    3 / 79 (3.80%)
         occurrences all number
    4
    0
    3
    4
    Depression
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Insomnia
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    3
    0
    0
    3
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 30 (6.67%)
    2 / 31 (6.45%)
    4 / 79 (5.06%)
         occurrences all number
    0
    3
    10
    11
    Infections and infestations
    Ear infection
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    1 / 79 (1.27%)
         occurrences all number
    0
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 30 (6.67%)
    4 / 31 (12.90%)
    5 / 79 (6.33%)
         occurrences all number
    4
    3
    6
    5
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 30 (3.33%)
    3 / 31 (9.68%)
    6 / 79 (7.59%)
         occurrences all number
    3
    3
    8
    9
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    2 / 35 (5.71%)
    5 / 30 (16.67%)
    11 / 31 (35.48%)
    9 / 79 (11.39%)
         occurrences all number
    2
    5
    11
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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