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    Clinical Trial Results:
    Evaluation of Growth, Sexual Maturation, and Prolactin-Related Adverse Events in the Pediatric Population Exposed to Atypical Antipsychotic Drugs

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2009-012003-26
    Trial protocol
    		 NL   BE   GR  
    Global end of trial date
    08 Aug 2011

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

    Trial information

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    Trial identification
    Sponsor protocol code
    RIS-NAP-4022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01050582
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International, NV
    Sponsor organisation address
    Turnhoutseweg 30, 2340, Beerse, Belgium,
    Public contact
    Clinical Registry Group, Janssen-Cilag International, NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International, NV, 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
    08 Aug 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of risperidone as compared with other atypical antipsychotic medications on child growth and sexual maturation and to evaluate the risk of other prolactin-related adverse events associated with risperidone as compared with other atypical antipsychotic medications in a pediatric population
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 2009
    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
    Belgium: 3
    Country: Number of subjects enrolled
    Germany: 47
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    United States: 99
    Worldwide total number of subjects
    184
    EEA total number of subjects
    85
    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)
    75
    Adolescents (12-17 years)
    109
    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 244 subjects were assessed for eligibility of whom 230 signed informed consent. Of the 230, 43 were found not to meet inclusion or exclusion criteria, 2 withdrew consent, and 1 was not kept in the study due to a site decision. A total of 184 subjects were included in the analysis.

    Pre-assignment
    Screening details
    		 A total of 350 paediatric subjects, (aged 8-16 years) with diagnosis of schizophrenia, bipolar mania, autistic disorder, or conduct and other DBDs, having medical records for atleast 1 year prior to start of qualifying antipsychotic medication from 2 exposure groups of 175 subjects each: risperidone group and other atypical antipsychotic group.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Other Atypical Antipsychotics
    Arm description
    		 Subjects with at least 6 months of exposure to an atypical antipsychotic other than risperidone within 24 months prior to enrollment. Subjects were to have no exposure to risperidone within the past 24 months, and total lifetime exposure to risperidone must have been less than or equal to 30 days total over their lifetime.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Other atypical antipsychotic drugs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As per local prescribing practices

    Arm title
    		 Risperidone
    Arm description
    		 Subjects with at least 6 months of exposure to risperidone within 24 months prior to enrollment. Exposure to other atypical antipsychotics within 24 months was allowed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As per local prescribing practices

    Number of subjects in period 1
    		Other Atypical Antipsychotics Risperidone
    Started
    51
    133
    Completed
    51
    133

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Other Atypical Antipsychotics
    Reporting group description
    		 Subjects with at least 6 months of exposure to an atypical antipsychotic other than risperidone within 24 months prior to enrollment. Subjects were to have no exposure to risperidone within the past 24 months, and total lifetime exposure to risperidone must have been less than or equal to 30 days total over their lifetime.

    Reporting group title
    Risperidone
    Reporting group description
    		 Subjects with at least 6 months of exposure to risperidone within 24 months prior to enrollment. Exposure to other atypical antipsychotics within 24 months was allowed.

    Reporting group values
    		 Other Atypical Antipsychotics Risperidone Total
    Number of subjects
    		 51 133 184
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 20 55 75
        Adolescents (12-17 years)
    		 31 78 109
        Adults (18-64 years)
    		 0 0 0
        From 65 to 84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.2 ( 2.48 ) 12.1 ( 2.53 ) -
    Title for Gender
    Units: subjects
        Female
    		 18 16 34
        Male
    		 33 117 150

    End points

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    End points reporting groups
    Reporting group title
    Other Atypical Antipsychotics
    Reporting group description
    		 Subjects with at least 6 months of exposure to an atypical antipsychotic other than risperidone within 24 months prior to enrollment. Subjects were to have no exposure to risperidone within the past 24 months, and total lifetime exposure to risperidone must have been less than or equal to 30 days total over their lifetime.

    Reporting group title
    Risperidone
    Reporting group description
    		 Subjects with at least 6 months of exposure to risperidone within 24 months prior to enrollment. Exposure to other atypical antipsychotics within 24 months was allowed.

    Primary: Height (cm) Z-score at Study Visit

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    End point title
    		 Height (cm) Z-score at Study Visit
    End point description
    Height (cm) measured at the study visit was converted to a Z-score based on the US Center for Disease Control 2000 growth charts for US subjects and European growth charts for ex-US subjects. A z-score indicates how many standard deviations a subject is away from the expected height for the subject's age and gender.
    End point type
    Primary
    End point timeframe
    One single study visit, approximately one week after informed consent has been obtained
    End point values
    		 Other Atypical Antipsychotics Risperidone
    Number of subjects analysed
    50 [1]
    132 [2]
    Units: z-score
        arithmetic mean (standard deviation)
    0.09 ( 1.079 )
    0.4 ( 1.189 )
    Notes
    [1] - All subjects with a height assessment available at the study visit.
    [2] - All subjects with a height assessment available at the study visit.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Risperidone v Other Atypical Antipsychotics
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Slope
    Point estimate
    0.447
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.674
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.116

    Secondary: Age (Years) at Current Tanner Stage

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    End point title
    		 Age (Years) at Current Tanner Stage
    End point description
    Tanner stage is an evaluation of pubertal development with values ranging from 1 (pre-pubertal) to 5 (adult). A standardized, validated tool containing standardized pictures and written descriptions of the stages of pubic hair development, breast development for girls, and genital development for boys was used by physicians to make their assessment.
    End point type
    Secondary
    End point timeframe
    One single study visit, approximately one week after informed consent has been obtained
    End point values
    		 Other Atypical Antipsychotics Risperidone
    Number of subjects analysed
    49 [3]
    124 [4]
    Units: Years
    arithmetic mean (standard deviation)
        Tanner Stage 1
    10.34 ( 1.784 )
    10.22 ( 1.309 )
        Tanner Stage 2
    11.23 ( 1.729 )
    11.25 ( 1.68 )
        Tanner Stage 3
    12.15 ( 1.206 )
    13.07 ( 2.181 )
        Tanner Stage 4
    15 ( 1.458 )
    14.93 ( 1.265 )
        Tanner Stage 5
    14.98 ( 1.82 )
    15.1 ( 0.688 )
    Notes
    [3] - subjects with a physician assessed Tanner stage value.
    [4] - subjects with a physician assessed Tanner stage value.
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Risperidone v Other Atypical Antipsychotics
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.378
    Method
    		 Regression, Linear
    Parameter type
    		 Slope
    Point estimate
    -0.221
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.711
         upper limit
    		 0.269
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25

    Secondary: Number of Subjects With Retrospectively Reported Potentially Prolactin-Related Adverse Events

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    End point title
    		 Number of Subjects With Retrospectively Reported Potentially Prolactin-Related Adverse Events
    End point description
    Previous potentially prolactin-related adverse events, including hyperprolactinemia, were reviewed and abstracted from subjects' medical records. Potentially prolactin-related adverse events include breast symptoms, menstrual disorders, hyperprolactinemia, and prolactinoma.
    End point type
    Secondary
    End point timeframe
    Retrospectively during the time of exposure for up to 2 years prior to the study visit
    End point values
    		 Other Atypical Antipsychotics Risperidone
    Number of subjects analysed
    51
    133
    Units: Subjects
        number (not applicable)
    3
    7
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Risperidone v Other Atypical Antipsychotics
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.999
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.865
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.189
         upper limit
    		 3.963

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time of signing informed consent to the study visit
    Adverse event reporting additional description
    Adverse events include retrospectively reported prolactin-related events and prospectively reported events from the time of signing informed consent to the study visit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Other Atypical Antipsychotics
    Reporting group description
    		 Subjects with at least 6 months of exposure to an atypical antipsychotic other than risperidone within 24 months prior to enrollment. Subjects were to have no exposure to risperidone within the past 24 months, and total lifetime exposure to risperidone must have been less than or equal to 30 days total over their lifetime.

    Reporting group title
    Risperidone
    Reporting group description
    		 Subjects with at least 6 months of exposure to risperidone within 24 months prior to enrollment. Exposure to other atypical antipsychotics within 24 months was allowed.

    Serious adverse events
    		 Other Atypical Antipsychotics Risperidone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 133 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Other Atypical Antipsychotics Risperidone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 51 (9.80%)
    14 / 133 (10.53%)
    Investigations
    Weight Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 133 (1.50%)
         occurrences all number
    0
    1
    Blood Prolactin Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1
    Sedation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    0
    General disorders and administration site conditions
    Drug Ineffective
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 133 (0.75%)
         occurrences all number
    1
    1
    Oedema
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Breast Enlargement
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 133 (0.00%)
         occurrences all number
    0
    0
    Amenorrhoea
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 133 (0.00%)
         occurrences all number
    0
    0
    Galactorrhoea
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 133 (0.00%)
         occurrences all number
    0
    0
    Breast Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 133 (0.00%)
         occurrences all number
    1
    0
    Gynaecomastia
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 133 (3.01%)
         occurrences all number
    0
    1
    Scrotal Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    0
    Psychiatric disorders
    Middle Insomnia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1
    Endocrine disorders
    Early Menarche
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    0
    Infections and infestations
    Eye Infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 133 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 133 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 133 (0.75%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2009
    The overall reason for the amendment was to allow data collection from medical records as well as automated databases, and to exclude subjects with specific developmental disorders known to be associated with growth or sexual maturation delays. In addition,this amendment allowed for the previous brief use of risperidone and concomitant use of serotonin reuptake inhibitors (SSRIs), and changed the primary efficacy analysis endpoint to compare Z-scores for height, age at current Tanner stage (rather than age at entry into current Tanner stage) and prolactin-related AEs, between risperidone-exposed and OAA-exposed groups.
    27 Nov 2009
    The main reason for the amendment was to clarify AE reporting procedures to ensure that the investigator collected all AEs reported after signing of the Informed Consent Form (ICF), that the investigator collected Serious Adverse Drug Reactions (SADRs) related to any J&J compound, which occurred prior to signing of the ICF, and to clarify the sponsor's responsibilities to report SAEs appropriately to the regulatory authorities. In addition, this amendment provided clarification on the use of concomitant medications with potential growth and prolactin effects, and provided clarification regarding subject selection, including a new diagrammatic flow chart.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Aug 2011
    The study was terminated due to recruitment difficulties, which meant that the enrollment target could not be met.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Study was terminated early due to recruitment challenges in OAA(comparator) group such that the enrollment target was not achievable. In addition there were more subjects in risperidone treatment group (n=133) than in the OAA group (n=51).
    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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