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    Clinical Trial Results:
    Phase II triple blind placebo controlled RCT of simvastatin treatment for autism in young children with Neurofibromatosis Type 1

    Summary
    EudraCT number
    		 2012-005742-38
    Trial protocol
    		 GB  
    Global end of trial date
    30 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2020
    First version publication date
    13 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R02145
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC reference: 13/NW/0111
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Oxford Road, Manchester, United Kingdom,
    Public contact
    Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, research.sponsor@mft.nhs.uk
    Scientific contact
    Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, research.sponsor@mft.nhs.uk
    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 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall research aim is to determine whether treatment with statins improves the ASD phenotype in children with NF1 autism. This aim of this study is to test: -Acceptability and feasibility of involvement for families of children with NF1 ASD -The feasibility and acceptability of the assessment protocol -Treatment effects on intermediate and endpoint behavioural phenotype measures and imaging parameters The hypothesis is that treatment with statins in young children with NF1 autism will be: -Feasible, safe and acceptable to families -Associated with signals of change in brain imaging parameters -Associated with signals of change in autism and other behavioural symptoms
    Protection of trial subjects
    Risks and burdens identified to the participants include the burden of travel to research site, possible distress caused by blood tests and brain scan and the risk associated with the treatment. The protocol has been designed to reduce these risks as following: Burden of travel: The study has been designed with careful consideration of the burden on the participants. The trial team has sought to keep the burden of the treatment visits and intervention to the absolute minimum possible whilst at the same time ensuring safety of participants. The initial screening will be via postal questionnaire and the followup at 16 weeks via a telephone call in order to reduce the number of participant visits. Possible distress due to blood tests and brain scan: Experienced paediatric nurses will carry out blood tests. Play therapist will be used to help explain the procedures to the children in a developmentally appropriate way. Risks associated with medication: Stringent monitoring of adverse effects of medication will be carried out during the course of treatment. This will include both verbal enquiry as well as blood tests. The statin expert on the team (AM) has extensive clinical experience of the use of statins in very young children. He will be available for advice and for monitoring the results of the blood tests. Confidentiality; The research team will have access to person identifiable information only when they receive the screening pack back from parents. No person identifiable information will be used in any publication/advertisement of the trial. Parents will be explained that all the assessments will be confidential and that confidentiality will be maintained at all times other than when the participant is identified as being at serious risk (such as child protection issues). In such cases, the information will be discussed with the CI and anonymously discussed with the child protection lead nurse at MFT.
    Background therapy
    		 N/A
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2013
    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 Kingdom: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    34
    Adolescents (12-17 years)
    0
    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
    		 Recruitment start date: 30/09/2013 Recruitment end date: 30/11/2015 Territory: UK only

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 34
    Number of subjects completed
    		 30

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Reason: Number of subjects
    		 Not NF1 diagnosis: 2
    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    N/A - placebo

    Arm title
    		 Simvastatin
    Arm description
    		 Intervention arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    PL 00427/0146
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    0.5mg/kg/dau in a single dose or placebo for 4 weeks. Those showing no significant adverse events after 4 weeks, will be escalated to a dose of 1mg/kg/day to a maximum of 30 mg/day in a single daily dose for a further 8 weeks

    Number of subjects in period 1 [1]
    		Placebo Simvastatin
    Started
    16
    14
    Completed
    15
    11
    Not completed
    1
    3
         Lost to follow-up
    1
    2
         Consent withdrawn
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Four participants were withdrawn from the trial prior to randomisation: two withdrew and two proved not to have NF1 diagnosis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Simvastatin
    Reporting group description
    		 Intervention arm

    Reporting group values
    		 Placebo Simvastatin Total
    Number of subjects
    		 16 14 30
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 16 14 30
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.28 ± 1.76 7.90 ± 1.90 -
    Gender categorical
    Units: Subjects
        Female
    		 2 4 6
        Male
    		 14 10 24
    Mutation
    Units: Subjects
        Inherited
    		 10 3 13
        De novo
    		 5 11 16
        Not recorded
    		 1 0 1
    Riccardi Scale
    Units: Subjects
        one
    		 3 4 7
        two
    		 12 5 17
        three
    		 0 4 4
        four
    		 1 1 2
    Parent-Nominated Target Symptoms: Hyperactivity
    Units: Subjects
        Yes
    		 6 7 13
        No
    		 10 7 17
    Parent-nominated target symptoms: Agression
    Units: Subjects
        Yes
    		 6 7 13
        No
    		 10 7 17
    Parent-nominated target symptoms: Social inappropriateness
    Units: Subjects
        Yes
    		 9 9 18
        No
    		 7 5 12
    Parent-nominated target symptoms: Problems with communication
    Units: Subjects
        Yes
    		 3 2 5
        No
    		 13 12 25
    Parent-nominated target symptoms: Inflexibility/obsessionality
    Units: Subjects
        Yes
    		 7 2 9
        No
    		 9 12 21
    Parent-nominated target characteristics: Learning problems
    Units: Subjects
        Yes
    		 1 2 3
        No
    		 15 12 27
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 29.85 ± 8.51 25.76 ± 6.08 -
    Social Responsiveness Scale: T Score
    Units: Scale
        arithmetic mean (standard deviation)
    		 83.06 ± 7.58 82.93 ± 8.67 -
    Social interaction
    Autism Diagnostic interview scale: Total A
    Units: Scale
        arithmetic mean (standard deviation)
    		 18.88 ± 5.08 16.29 ± 5.08 -
    Social communication
    Autism diagnostic interview: Total B
    Units: Scale
        arithmetic mean (standard deviation)
    		 14.19 ± 4.37 14.00 ± 4.02 -
    Restricted repetitive behaviours
    Autism diagnostic interview: Total C
    Units: Scale
        arithmetic mean (standard deviation)
    		 5.88 ± 2.78 5.93 ± 2.64 -
    ADOS: Social affect
    Units: scale
        arithmetic mean (standard deviation)
    		 10.13 ± 3.26 9.29 ± 3.24 -
    ADOS: RRB
    Units: Scale
        arithmetic mean (standard deviation)
    		 1.88 ± 1.63 2.14 ± 1.74 -
    ADOS: Total
    Units: Score
        arithmetic mean (standard deviation)
    		 12.00 ± 3.81 11.57 ± 3.96 -
    WASI verbal IQ
    n= 26
    Units: score
        arithmetic mean (standard deviation)
    		 81.57 ± 12.99 90.00 ± 11.24 -
    Aberrant Behaviour Checklist: Irritability
    Units: Score
        arithmetic mean (standard deviation)
    		 19.40 ± 10.38 24.21 ± 9.36 -
    Aberrant Behaviour Checklist: Lethargy
    Units: Score
        arithmetic mean (standard deviation)
    		 14.20 ± 8.36 16.08 ± 6.85 -
    Aberrant behaviour checklist: Stereotypy
    Units: Score
        arithmetic mean (standard deviation)
    		 4.87 ± 3.56 7.29 ± 5.04 -
    Aberrant Behaviour Checklist: Hyperactivity
    Units: Score
        arithmetic mean (standard deviation)
    		 24.07 ± 13.04 30.21 ± 8.75 -
    Aberrant Behaviour Checklist: Inappropriate speech
    Units: Score
        arithmetic mean (standard deviation)
    		 5.93 ± 3.15 7.43 ± 3.61 -
    Clinical Global Impression: Severity of illness
    Units: Score
        arithmetic mean (standard deviation)
    		 3.88 ± 0.885 3.57 ± 0.646 -
    Conners 3 Parent Rating Scale: Inattention
    Units: Score
        arithmetic mean (standard deviation)
    		 79.73 ± 12.13 80.71 ± 9.36 -
    Conners 3 Parent Rating Scale: Hyperactivity
    Units: score
        arithmetic mean (standard deviation)
    		 71.87 ± 14.75 81.14 ± 8.88 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Simvastatin
    Reporting group description
    		 Intervention arm

    Primary: Parent defined target symptoms (PDTS)

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    End point title
    		 Parent defined target symptoms (PDTS) [1]
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: These are descriptive endpoints only
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    14
    12
    Units: Scale
        arithmetic mean (standard deviation)
    3.516 ± 1.768
    3.250 ± 1.684
    No statistical analyses for this end point

    Primary: Completed imaging assessments

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    End point title
    		 Completed imaging assessments [2]
    End point description
    End point type
    Primary
    End point timeframe
    Study duraton
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: These are descriptive endpoints only
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    16
    14
    Units: Subjects
        Yes
    15
    11
        No
    1
    3
    No statistical analyses for this end point

    Secondary: ABC: Irritability

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    End point title
    		 ABC: Irritability
    End point description
    Individual components of the ABC scale
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    16.40 ± 10.82
    22.31 ± 12.14
    Statistical analysis title
    		 ABC: Irritabililty
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.61
         upper limit
    		 7.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.2

    Secondary: ABC: Lethargy

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    End point title
    		 ABC: Lethargy
    End point description
    Component of the ABC scale
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    12
    Units: Scale
        arithmetic mean (standard deviation)
    10.53 ± 9.61
    15.25 ± 10.30
    Statistical analysis title
    		 ABC: Lethargy
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.09
         upper limit
    		 11.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.92

    Secondary: ABC: Stereotypy

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    End point title
    		 ABC: Stereotypy
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    3.93 ± 3.63
    7.77 ± 5.83
    Statistical analysis title
    		 ABC: Stereotypy
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.98
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.32

    Secondary: ABC: Hyperactivity

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    End point title
    		 ABC: Hyperactivity
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    11
    Units: Scale
        arithmetic mean (standard deviation)
    19.13 ± 13.17
    28.77 ± 12.83
    Statistical analysis title
    		 ABC: Hyperactivity
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 11.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.65

    Secondary: ABC: Inappropriate speech

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    End point title
    		 ABC: Inappropriate speech
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    11
    Units: Scale
        arithmetic mean (standard deviation)
    4.80 ± 2.54
    7.15 ± 3.31
    Statistical analysis title
    		 ABC: Inappropriate speech
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 3.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95

    Secondary: 25% reduction irritability scale

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    End point title
    		 25% reduction irritability scale
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Subjects
        yes
    5
    6
    No statistical analyses for this end point

    Secondary: Conners: Inattention

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    End point title
    		 Conners: Inattention
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    74.53 ± 14.16
    80.38 ± 10.08
    Statistical analysis title
    		 Conners: Inattention
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.96
         upper limit
    		 11.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.21

    Secondary: Conners: Hyperactivity

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    End point title
    		 Conners: Hyperactivity
    End point description
    End point type
    Secondary
    End point timeframe
    12 Weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    69.40 ± 17.12
    78.31 ± 13.51
    Statistical analysis title
    		 Conners: Hyperactivity
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.09
         upper limit
    		 6.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.63

    Secondary: Conners: Learning problems

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    End point title
    		 Conners: Learning problems
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    65.40 ± 12.91
    73.69 ± 15.71
    Statistical analysis title
    		 Conners: Learning problems
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.13
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.89

    Secondary: Conners: Executive function

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    End point title
    		 Conners: Executive function
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    68.20 ± 16.24
    76.00 ± 11.66
    Statistical analysis title
    		 Conners: Executive function
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.51
         upper limit
    		 10.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.34

    Secondary: Conners: Aggression

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    End point title
    		 Conners: Aggression
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    68.40 ± 20.86
    72.77 ± 17.09
    Statistical analysis title
    		 Conners: Aggression
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.05
         upper limit
    		 10.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.61

    Secondary: Conners: Peer relations

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    End point title
    		 Conners: Peer relations
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    15
    13
    Units: Scale
        arithmetic mean (standard deviation)
    83.89 ± 11.53
    86.08 ± 8.73
    Statistical analysis title
    		 Conners: Peer relations
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.45
         upper limit
    		 7.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.97

    Secondary: Responders

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    End point title
    		 Responders
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    14
    12
    Units: Subjects
        PDTS score < 3
    2
    5
    No statistical analyses for this end point

    Secondary: Global improvement

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    End point title
    		 Global improvement
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    14
    12
    Units: Scale
        arithmetic mean (standard deviation)
    3.57 ± 0.852
    3.00 ± 0.739
    No statistical analyses for this end point

    Secondary: Treatment responder

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    End point title
    		 Treatment responder
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    14
    14
    Units: Subjects
        Yes
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events will be recorded and reported at each study visit. Serious Adverse Event (SAE) forms. SAEs and SUSARs will be reported to the sponsor in accordance with the relevant local SOPs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Simvastatin
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Simvastatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo Simvastatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    14 / 14 (100.00%)
    General disorders and administration site conditions
    General disorder
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 14 (7.14%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    4 / 16 (25.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory system disorder
         subjects affected / exposed
    4 / 16 (25.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    2
    Skin and subcutaneous tissue disorders
    Dermatologic system disorders
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 14 (21.43%)
         occurrences all number
    6
    3
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    5 / 16 (31.25%)
    7 / 14 (50.00%)
         occurrences all number
    13
    7
    Musculoskeletal and connective tissue disorders
    Musculoskeletal system disorder
         subjects affected / exposed
    4 / 16 (25.00%)
    2 / 14 (14.29%)
         occurrences all number
    4
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2013
    Protocol version 3.0 Endpoint outcome measures - added Effect on neurocognitive functions as assessed by the judgement of line orientation task and paired associate learning task. First trial visit (week 0) - added Cognitive functions will be assessed using the following neurocognitive measures: Judgement of line orientation task and paired associate learning task (20 minutes), removed genotyping, added Participants will be given stickers to positively reinforce the successful completion of the task. They will also be given a token of appreciation for their time and effort on the trial. Treatment procedures at 4 week visit - added genotyping, removed mononuclear PMAPKinase activity Trial treatment endpoint at 12 weeks - added Behavioural phenotype measures, Blood tests plasma lipids, liver function tests, renal function tests and creatine kinase, mononuclear PMAPkinase activity, Participants will be given a token of appreciation for their time and effort on the trial. Measuring trial endpoints - added Cognitive symptoms (baseline and 12 week end point) Assessed using the judgement of line orientation task, paired associate learning task. Data Collection - added Participants’ cognitive functions will be assessed using the judgement of line orientation task and paired associate learning task and this will be recorded in the case record form.
    30 May 2014
    Protocol version 4.0 Amendment to patient recruitment age range, from 5-8 years to 4.5- 10.5 years. Cognitive assessment measures added at baseline and 12 weeks (Judgement of line orientation task & Paired associates learning task) Procedure for imaging - If it deemed appropriate, due to difficulties in week 0, the participant may require part of the scan or the entire scan to be performed at week 4. 4 week visit (+/- 7 days) - If required brain imaging will be undertaken on the MRI scanner at the CRF without contrast injections or sedation, with support from CRF staff, nursing and play specialists (e.g. if scan at week 0 was incomplete or inadequate)

    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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