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    Clinical Trial Results:
    A placebo-controlled discontinuation trial of off-label used risperidone in people with intellectual disability

    Summary
    EudraCT number
    		 2014-003718-10
    Trial protocol
    		 NL  
    Global end of trial date
    04 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2019
    First version publication date
    06 Mar 2019
    Other versions
    Summary report(s)
    		 Summary risperidone and ID

    Trial information

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    Trial identification
    Sponsor protocol code
    2014RISP-ID01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Netherlands Trial Register: NL5252
    Sponsors
    Sponsor organisation name
    University Medical Center Groningen
    Sponsor organisation address
    Hanzeplein 1, Groningen, Netherlands,
    Public contact
    Risperidone ID trial information, UMCG, 0031 592334100, l.ramerman@umcg.nl
    Scientific contact
    Risperidone ID trial information, UMCG, 0031 592334100, l.ramerman@umcg.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is: To study the effect of controlled discontinuation of long-term used risperidone, for the treatment of challenging behaviour, on behaviour and health. Our hypothesis is that long-term use of risperidone for challenging behaviour is not more effective than a placebo.
    Protection of trial subjects
    All trial subjects were allowed to deblind and stop participation in the study at any time. Furthermore, when withdrawal symptoms such as dyskinesia presented, additional medication was allowed (such as Lorazepam). In addition, the protocol provided information on medications to prescribe when behaviour worsened. When participants did not want to comply with blood withdrawal, the withdrawal would be stopped and participation continued without blood withdrawal.
    Background therapy
    		 Psychotropic drugs, that were not antipsychotic drugs, were allowed during the study, such as sertraline, oxazepam, lorazepam and Ritalin. In both study arms, different psychotropic drugs were already used by approximately 50% of the participants before the start of the trial. In addition, during the trial, non-pharmacological treatments/behavioural interventions were allowed. This included restrictive measures, changes in daily schedule and the approach of supervisors to challenging behaviours. All these pharmacological and non-pharmacological measures were applied in an equal amount in the intervention and control arm.
    Evidence for comparator
    		 In the trial, risperidone is compared to a placebo. There is no evidence for the effectiveness of long-term used risperidone when prescribed for reducing challenging behaviours. A previous trial of the short term effectiveness of risperidone in aggression did suggest that placebo is more effective than risperidone in reducing aggression. Furthermore, a previous discontinuation trial of long-term used antipsychotic drugs indicated that discontinuation is possible without a worsening in challenging behaviours.
    Actual start date of recruitment
    04 Jan 2016
    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
    Netherlands: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    13
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were recruited between the 4th of January 2016 and the 28th of February 2017 from 3 different organisations for intellectual disability care and 2 organisations for mental health care in the North of the Netherlands.

    Pre-assignment
    Screening details
    		 238 eligible participants were found, based on their level of intellectual disability (IQ<70), aged over 6 years, risperidone use > 1 year, no psychosis, schizophrenia or bipolar disorder. 157 were advised by their physician not to participate and 56 refused participation by them self.

    Period 1
    Period 1 title
    baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    To ensure blinding both the intervention group and the control group will receive two bottles: bottle A with risperidone 1mg/ml and bottle B with either placebo or risperidone 1mg/ml. All participants will decrease the quantity used of bottle A with 12.5% every two weeks and will increase the quantity used of bottle B with 12.5% every two weeks. The pharmacy provided a list with allocation of randomisation numbers per arm to the producer of the medication. Randomisation numbers were prescribed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Discontinuation
    Arm description
    		 This arm discontinues risperidone to placebo with 12.5% every two weeks. After 14 weeks they use a placebo for 8 weeks, after which they were deblinded.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    All participants started the study at their original dosage, which was possible by switching to the liquid form of risperidone (1mg/ml). All received bottle A with risperidone 1mg/ml and bottle B with placebo. All participants decreased the quantity used of bottle A with 12.5% every two weeks and will increase the quantity used of bottle B with 12.5% every two weeks. Table 2 presents the discontinuation schedule of bottle A (active medication) to bottle B (active medication or placebo). Caregivers will be trained in the use of the discontinuation schedule and the use of the calibrated dispenser. Furthermore, they will be instructed to mix the solutions of bottle A and B and delude the mix with a compatible beverage.

    Arm title
    		 Control
    Arm description
    		 The control group were remained on their original dosage of risperidone. They received risperidone (1mg/ml) in both bottle A and B. After 24 weeks they were deblinded and were allowed to discontinue risperidone during a natural follow-up
    Arm type
    		 risperidone

    Investigational medicinal product name
    risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    To ensure blinding both the intervention group and the control group will receive two bottles: bottle A with risperidone 1mg/ml and bottle B with risperidone 1mg/ml. All participants will decrease the quantity used of bottle A with 12.5% every two weeks and will increase the quantity used of bottle B with 12.5% every two weeks. Caregivers will be trained in the use of the discontinuation schedule and the use of the calibrated dispenser. Furthermore, they will be instructed to mix the solutions of bottle A and B and delude the mix with a compatible beverage.

    Number of subjects in period 1
    		Discontinuation Control
    Started
    11
    14
    Completed
    11
    14
    Period 2
    Period 2 title
    Blind/discontinuation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    To ensure blinding both the intervention group and the control group will receive two bottles: bottle A with risperidone 1mg/ml and bottle B with either placebo or risperidone 1mg/ml. All participants will decrease the quantity used of bottle A with 12.5% every two weeks and will increase the quantity used of bottle B with 12.5% every two weeks.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Discontinuation
    Arm description
    		 This arm discontinues risperidone to placebo with 12.5% every two weeks. After 14 weeks they use a placebo for 8 weeks, after which they were deblinded.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid, Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    All participants started the study at their original dosage, which was possible by switching to the liquid form of risperidone (1mg/ml). All received bottle A with risperidone 1mg/ml and bottle B with placebo. All participants decreased the quantity used of bottle A with 12.5% every two weeks and will increase the quantity used of bottle B with 12.5% every two weeks. Table 2 presents the discontinuation schedule of bottle A (active medication) to bottle B (active medication or placebo). Caregivers will be trained in the use of the discontinuation schedule and the use of the calibrated dispenser. Furthermore, they will be instructed to mix the solutions of bottle A and B and delude the mix with a compatible beverage.

    Arm title
    		 Control
    Arm description
    		 The control group were remained on their original dosage of risperidone. They received risperidone (1mg/ml) in both bottle A and B. After 24 weeks they were deblinded and were allowed to discontinue risperidone during a natural follow-up
    Arm type
    		 risperidone

    Investigational medicinal product name
    risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    To ensure blinding both the intervention group and the control group will receive two bottles: bottle A with risperidone 1mg/ml and bottle B with risperidone 1mg/ml. All participants will decrease the quantity used of bottle A with 12.5% every two weeks and will increase the quantity used of bottle B with 12.5% every two weeks. Caregivers will be trained in the use of the discontinuation schedule and the use of the calibrated dispenser. Furthermore, they will be instructed to mix the solutions of bottle A and B and delude the mix with a compatible beverage.

    Number of subjects in period 2
    		Discontinuation Control
    Started
    11
    14
    Completed
    11
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Discontinuation
    Reporting group description
    		 This arm discontinues risperidone to placebo with 12.5% every two weeks. After 14 weeks they use a placebo for 8 weeks, after which they were deblinded.

    Reporting group title
    Control
    Reporting group description
    		 The control group were remained on their original dosage of risperidone. They received risperidone (1mg/ml) in both bottle A and B. After 24 weeks they were deblinded and were allowed to discontinue risperidone during a natural follow-up

    Reporting group values
    		 Discontinuation Control Total
    Number of subjects
    		 11 14 25
    Age categorical
    age was recorded at baseline in years.
    Units: Subjects
        Adolescents (12-17 years)
    		 5 5 10
        Adults (18-64 years)
    		 5 8 13
        From 65-84 years
    		 1 1 2
    Age continuous
    Age was recorded at baseline in years.
    Units: years
        arithmetic mean (standard deviation)
    		 33 ( 20.16 ) 28 ( 16.10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 4 6
        Male
    		 9 10 19
    Severity of intellectual disability
    severity of intellectual disability: mild, moderate, severe, profound
    Units: Subjects
        mild
    		 6 7 13
        moderate
    		 1 5 6
        severe
    		 4 2 6
        profound
    		 0 0 0
    use of other psychotropic drugs
    use of other psychotropic drugs
    Units: Subjects
        yes
    		 6 6 12
        no
    		 5 8 13
    start dosage of risperidone
    mean starting dosage of risperidone.
    Units: milligram(s)
        arithmetic mean (standard deviation)
    		 1.82 ( 1.28 ) 1.97 ( 1.14 ) -

    End points

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    End points reporting groups
    Reporting group title
    Discontinuation
    Reporting group description
    		 This arm discontinues risperidone to placebo with 12.5% every two weeks. After 14 weeks they use a placebo for 8 weeks, after which they were deblinded.

    Reporting group title
    Control
    Reporting group description
    		 The control group were remained on their original dosage of risperidone. They received risperidone (1mg/ml) in both bottle A and B. After 24 weeks they were deblinded and were allowed to discontinue risperidone during a natural follow-up
    Reporting group title
    Discontinuation
    Reporting group description
    		 This arm discontinues risperidone to placebo with 12.5% every two weeks. After 14 weeks they use a placebo for 8 weeks, after which they were deblinded.

    Reporting group title
    Control
    Reporting group description
    		 The control group were remained on their original dosage of risperidone. They received risperidone (1mg/ml) in both bottle A and B. After 24 weeks they were deblinded and were allowed to discontinue risperidone during a natural follow-up

    Primary: irritability

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    End point title
    		 irritability
    End point description
    Irritability is a sub scale of the Aberrant Behavior Checklist.
    End point type
    Primary
    End point timeframe
    measured at baseline, deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    15.36 (9.68 to 21.4)
    13.57 (8.54 to 18.61)
    14.18 (8.23 to 20.13)
    10.36 (5.08 to 15.63)
    Statistical analysis title
    		 irritability, mixed methods repeated measures
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.37 [1]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - there was no significant difference between the study arms over time on irritability.

    Secondary: lethargy

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    End point title
    		 lethargy
    End point description
    lethargy is a sub scale of the Aberrant Behavior Checklist
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    11.73 (5.02 to 18.44)
    11.07 (5.12 to 17.02)
    10.91 (4.44 to 17.38)
    6.86 (1.12 to 12.60)
    Statistical analysis title
    		 lethargy/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.345 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - no time*group effect

    Secondary: stereotypy

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    End point title
    		 stereotypy
    End point description
    stereotypy is a sub scale of the Aberrant Behavior Checklist
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    4.82 (1.32 to 8.32)
    5.29 (2.18 to 8.39)
    8.91 (5.44 to 12.38)
    2.57 (0.50 to 5.65)
    Statistical analysis title
    		 stereotypy MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.003 [3]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - stereotypy increased in the discontinuation group over time, compared to the control group.

    Secondary: hyperactivity

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    End point title
    		 hyperactivity
    End point description
    hyperactivity is a sub scale of the Aberrant Behavior Checklist
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    17.27 (10.44 to 24.10)
    19.14 (3.09 to 25.20)
    15.27 (8.87 to 21.68)
    12.86 (7.18 to 18.53)
    Statistical analysis title
    		 hyperactivity/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.16 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [4] - no group*time effect

    Secondary: inadequate speech

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    End point title
    		 inadequate speech
    End point description
    inadequate speech is a sub scale of the aberrant behaviour checklist
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    3.64 (1.62 to 5.65)
    4.57 (2.78 to 6.36)
    3.18 (1.11 to 5.26)
    2.43 (0.59 to 4.27)
    Statistical analysis title
    		 Inad/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.072 [5]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - no group*time effect

    Secondary: Dyskinesia/AIMS

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    End point title
    		 Dyskinesia/AIMS
    End point description
    Score on the Abnormal Involuntary Movement Scale
    End point type
    Secondary
    End point timeframe
    baseline and delblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: point
        arithmetic mean (confidence interval 95%)
    3.18 (1.09 to 5.27)
    0.93 (-0.96 to 2.78)
    4.46 (1.25 to 7.66)
    1.71 (-1.13 to 4.55)
    Statistical analysis title
    		 AIMS/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.65 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [6] - no group*time effect

    Secondary: Akathisia/BARS

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    End point title
    		 Akathisia/BARS
    End point description
    Barnes Akathisia Rating Scale
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    1.36 (0.41 to 2.32)
    0.79 (-0.06 to 1.63)
    01.7393 (0.43 to 3.03)
    0.93 (-0.22 to 2.08)
    Statistical analysis title
    		 BARS/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.73 [7]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [7] - no group*time effect

    Secondary: Parkinsonism/UPDRS

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    End point title
    		 Parkinsonism/UPDRS
    End point description
    Unified Parkinson's Disease Rating Scale-motor items.
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    1.55 (0.41 to 2.68)
    1.64 (0.63 to 2.65)
    1.27 (0.24 to 2.31)
    1.57 (0.65 to 2.49)
    Statistical analysis title
    		 UPDRS/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.75 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [8] - no group*time effect

    Secondary: autonomic symptoms/SCOPA-AUT

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    End point title
    		 autonomic symptoms/SCOPA-AUT
    End point description
    SCale for Outcomes of PArkonsons disease- Autonomic symptoms
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    28.6 (24.6 to 32.7)
    29.7 (25.7 to 33.7)
    32.7 (28.1 to 37.3)
    33.0 (28.5 to 37.5)
    Statistical analysis title
    		 SCOPA/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.52 [9]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - no group*time effect

    Secondary: waist circumference

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    End point title
    		 waist circumference
    End point description
    waist circumference in cm
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: cm
        arithmetic mean (confidence interval 95%)
    87.7 (76.2 to 99.2)
    83.3 (73.0 to 93.6)
    82.26 (71.24 to 93.29)
    82.4 (72.7 to 92.2)
    Statistical analysis title
    		 Waist/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.012 [10]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [10] - There is a significantly higher decrease in waist circumference in the discontinuation group over time, compared to the control group.

    Secondary: BMI

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    End point title
    		 BMI
    End point description
    Body Mass Index
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: kg/m^2
        arithmetic mean (confidence interval 95%)
    22.3 (18.5 to 26.2)
    23.1 (19.7 to 26.5)
    20.11 (16.61 to 23.61)
    22.8 (19.7 to 25.9)
    Statistical analysis title
    		 BMI/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.03 [11]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [11] - there was a significantly higher decrease in BMI in the discontinuation group, compared to the controls.

    Secondary: systolic blood pressure

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    End point title
    		 systolic blood pressure
    End point description
    systolic blood pressure
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: mm/HG
        arithmetic mean (confidence interval 95%)
    117 (108 to 126)
    115 (107 to 124)
    102 (93 to 111)
    114 (106 to 122)
    Statistical analysis title
    		 systolic/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.005 [12]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [12] - There was a significantly higher decrease in systolic blood pressure in the discontinuation group compared to the controls.

    Secondary: diastolic blood pressure

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    End point title
    		 diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: mm/HG
        arithmetic mean (confidence interval 95%)
    68 (62 to 75)
    71 (65 to 76)
    65 (58 to 71)
    70 (65 to 76)
    Statistical analysis title
    		 dias BP/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.48 [13]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [13] - no group*time effect

    Secondary: Sleepiness

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    End point title
    		 Sleepiness
    End point description
    Sleepiness measured with the Epworth Sleepiness Scale (ESS)
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: points
        arithmetic mean (confidence interval 95%)
    4.09 (1.65 to 6.53)
    3.43 (1.27 to 5.59)
    5.36 (1.69 to 9.04)
    4.07 (0.81 to 7.33)
    Statistical analysis title
    		 ESS/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.79 [14]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [14] - no group*time effect

    Secondary: weight

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    End point title
    		 weight
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    11
    14
    11
    14
    Units: kilogram(s)
        arithmetic mean (confidence interval 95%)
    67.6 (54.2 to 81.0)
    69.9 (58 to 81.7)
    61.7 (48.95 to 74.45)
    69.1 (57.8 to 81.7)
    Statistical analysis title
    		 weight/MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.046 [15]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [15] - there was a significantly higher decrease in weight in the discontinuation group, compared to the controls.

    Secondary: Glucose

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    End point title
    		 Glucose
    End point description
    Fasting glucose levels in mmol/l
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    8
    11
    8
    11
    Units: mmol/l
        number (confidence interval 95%)
    6.16 (5.65 to 6.68)
    5.38 (4.81 to 5.95)
    5.67 (5.13 to 6.22)
    5.35 (4.72 to 5.98)
    Statistical analysis title
    		 Glucose MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.31 [16]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [16] - There was no significant time*group effect

    Secondary: Total cholesterol

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    End point title
    		 Total cholesterol
    End point description
    fasting total cholesterol in mmol/l
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    8
    11
    8
    8
    Units: mmol/l
        arithmetic mean (confidence interval 95%)
    4.30 (3.79 to 4.81)
    3.96 (3.39 to 4.52)
    3.86 (3.39 to 4.32)
    3.93 (3.42 to 4.45)
    Statistical analysis title
    		 cholesterol MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.11 [17]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [17] - No significant group*time interaction

    Secondary: LDL Cholesterol

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    End point title
    		 LDL Cholesterol
    End point description
    fasting LDL cholesterol
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    8
    11
    8
    11
    Units: mmol/l
        arithmetic mean (confidence interval 95%)
    2.56 (2.11 to 3.00)
    2.39 (1.90 to 2.88)
    2.18 (1.79 to 2.57)
    2.22 (1.78 to 2.66)
    Statistical analysis title
    		 LDL MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.38 [18]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [18] - no significant time*group effect on LDL cholesterol levels

    Secondary: HDL Cholesterol

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    End point title
    		 HDL Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    8
    11
    8
    11
    Units: mmol/l
        arithmetic mean (confidence interval 95%)
    1.40 (1.21 to 1.59)
    1.27 (1.06 to 1.48)
    1.28 (1.08 to 1.48)
    1.20 (0.98 to 1.43)
    Statistical analysis title
    		 HDL MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.61 [19]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [19] - No significant time*group effect on HDL levels

    Secondary: Tryglycerides

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    End point title
    		 Tryglycerides
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    8
    11
    8
    11
    Units: mmol/l
        arithmetic mean (confidence interval 95%)
    1.05 (0.82 to 1.29)
    0.96 (0.70 to 1.22)
    1.05 (0.80 to 1.30)
    1.01 (0.73 to 1.29)
    Statistical analysis title
    		 Tryglycerides MMRM
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.66 [20]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [20] - No significant time*group effects on Triglyceride levels

    Secondary: Prolactin

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    End point title
    		 Prolactin
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    8
    11
    8
    11
    Units: mU/l
        arithmetic mean (confidence interval 95%)
    738 (532 to 944)
    629 (390 to 867)
    327 (144 to 509)
    626 (417 to 835)
    Statistical analysis title
    		 Prolactin MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.007 [21]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [21] - There was a significant time*group effect for prolactin levels, showing a favourable effect in the discontinuation group, compared to the control group.

    Secondary: Testosterone

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    End point title
    		 Testosterone
    End point description
    End point type
    Secondary
    End point timeframe
    baseline and deblinding
    End point values
    		 Discontinuation Control Discontinuation Control
    Number of subjects analysed
    8
    11
    8
    11
    Units: nmol/l
        arithmetic mean (confidence interval 95%)
    7.45 (4.77 to 11.8)
    9.65 (4.76 to 14.5)
    10.6 (4.77 to 16.43)
    9.48 (2.92 to 16.00)
    Statistical analysis title
    		 Testosterone MMRM
    Statistical analysis description
    The differences at baseline and week-24 between the discontinuation group and the continuation group were assessed with a mixed model for repeated measures with fixed effects for group, time and time*group. An unstructured covariance matrix was used. Analyses were done following the intention-to-treat principle.
    Comparison groups
    Discontinuation v Control v Discontinuation v Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.048 [22]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [22] - There was a significant group* time effect on testosterone levels, showing a favourable effect in the discontinuation group, compared to the control group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4th of January 2016 until 2nd of September 2017 (last patient deblinded)
    Adverse event reporting additional description
    When adverse effent occured, participant contacted their own physician and the primary researcher of that organization. The primary researcher would inform the coordinating investigator as soon as possible of the AE.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Discontinuation
    Reporting group description
    		 This arm discontinues risperidone to placebo with 12.5% every two weeks. After 14 weeks they use a placebo for 8 weeks, after which they were deblinded.

    Serious adverse events
    		 Discontinuation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Discontinuation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    Nervous system disorders
    Dyskinesia
    Additional description: Due to the withdrawal of risperidone, withdrawal dyskinesia can occur.
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    2

    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.
    The number of subjects included in the trial was substantially lower than anticipated. Furthermore, due to objections against participation by eligible participants physician, a selection bias can occur.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30609152
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    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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