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    Clinical Trial Results:
    Towards Onset Prevention of COGnitive decline in adults with Down syndrome (the TOP-COG study)

    Summary
    EudraCT number
    		 2011-001564-21
    Trial protocol
    		 GB  
    Global end of trial date
    14 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions
    Summary report(s)
    		 2011-001564-21 summary

    Trial information

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    Trial identification
    Sponsor protocol code
    GN09CP301
    Additional study identifiers
    ISRCTN number
    		 ISRCTN67338640
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NRS reference: NRS11/CG06, IRAS project code: 77898, Portfolio ID: 11619, MREC reference: 11/AL/0200, Sponsor reference: GN09CP301
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow and Clyde
    Sponsor organisation address
    J B Russell House, Gartnavel Royal Hospital, 1055 Great Western Road, Glasgow, United Kingdom, G12 0XH
    Public contact
    Joanne McGarry Academic Research Coordinator, NHS Greater Glasgow & Clyde, +44 (0)141 314 4011, Joanne.McGarry@ggc.scot.nhs.uk
    Scientific contact
    Joanne McGarry Academic Research Coordinator, NHS Greater Glasgow & Clyde, +44 (0)141 314 4011, Joanne.McGarry@ggc.scot.nhs.uk
    Sponsor organisation name
    University of Glasgow
    Sponsor organisation address
    University Avenue, Glasgow, United Kingdom, G12 8QQ
    Public contact
    Dr Debra Stuart, University of Glasgow, debra.stuart@glasgow.ac.uk
    Scientific contact
    Dr Debra Stuart, University of Glasgow, debra.stuart@glasgow.ac.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
    18 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aims of the study are to gather the data needed to design a full-scale multi-centred RCT of oral simvastatin 40mg a day. The principal research questions are: What are the: (1) trial recruitment/retention rates and recruitment sources, (2) rates of tolerability/safety of oral simvastatin 40mg a day, (3) most sensitive instruments to detect early cognitive decline in adults with Down syndrome, and (4) perceptions of adults with Down syndrome and their carers on deciding whether to participate, on randomisation, and their experience of the assessments?
    Protection of trial subjects
    Participants were fully informed of the time required to participate before making a decision. The primary study researcher was experienced in working with adults with intellectual disabilities. Interviews were conducted in participants' homes where requested. Capillary blood tests and saliva collection were offered in place of venous blood sampling. Participants underwent baseline measurements followed by a comprehensive check at 6-12 weeks after starting treatment to identify any initial adverse events.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Feb 2012
    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
    United Kingdom: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    0
    Adults (18-64 years)
    21
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The setting was the general community of Scotland, UK; specifically, the health board areas of Greater Glasgow and Clyde, Lothian, Tayside, Lanarkshire and Borders. Recruitment was from multiple sources within the general community, Down Syndrome Scotland, Local Authorities and National Health Service clinical services.

    Pre-assignment
    Screening details
    		 Inclusion: Down syndrome; aged ≥ 50 yrs/Exclusion: no consent; unable to comply with protocol, including tissue samples; dementia; diabetes; clinically evident atherosclerotic disease; at risk of cardiovascular disease; liver disease; chronic renal insufficiency; statin therapy; previous statin SAE; unable to avoid grapefruit juice; excess alcohol

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 One capsule of placebo at night for 12 months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One oral placebo capsule at night by mouth

    Arm title
    		 Simvastatin
    Arm description
    		 Simvastatin 40mg at night by oral administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Simvastatin 40mg at night by oral administration. Swallowed whole, not chewed.

    Number of subjects in period 1
    		Placebo Simvastatin
    Started
    11
    10
    Completed
    11
    10
    Period 2
    Period 2 title
    12 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject
    Blinding implementation details
    Randomisation conducted by the Robertson Centre for Biostatistics and information communicated directly with the Pharmacy Production Unit. On receipt of a prescription, the study drugs were posted directly to participants. The active drug and placebo were over-encapsulated, identical in appearance and similar in weight

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 One capsule of placebo at night for 12 months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One oral placebo capsule at night by mouth

    Arm title
    		 Simvastatin
    Arm description
    		 Simvastatin 40mg at night by oral administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Simvastatin 40mg at night by oral administration. Swallowed whole, not chewed.

    Number of subjects in period 2
    		Placebo Simvastatin
    Started
    11
    10
    Completed
    5
    3
    Not completed
    6
    7
         Carer concerned about drug
    -
    3
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    2
    -
         Lost to follow-up
    2
    3
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 One capsule of placebo at night for 12 months

    Reporting group title
    Simvastatin
    Reporting group description
    		 Simvastatin 40mg at night by oral administration

    Reporting group values
    		 Placebo Simvastatin Total
    Number of subjects
    		 11 10 21
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 53.67 ( 3.16 ) 54.68 ( 3.10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5 10
        Male
    		 6 5 11
    Intellectual disability
    Units: Subjects
        Mild ID
    		 4 0 4
        Moderate ID
    		 3 4 7
        Severe ID
    		 4 5 9
        Profound ID
    		 0 1 1
    Apolipoprotein E gene
    Apolipoprotein E (APOE)
    Units: Subjects
        APOE ε3/2
    		 1 1 2
        APOE ε3/3
    		 7 6 13
        APOE ε4/3
    		 3 3 6
    Cholesterol
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 5.3 ( 0.8 ) 5.1 ( 0.5 ) -
    Quality of Life
    EuroQol 5 Dimension Questionnaire (EQ-5D) health utility
    Units: Score
        arithmetic mean (standard deviation)
    		 0.81 ( 0.29 ) 0.54 ( 0.38 ) -
    Adaptive Behaviour Scale total score
    Units: Score
        arithmetic mean (standard deviation)
    		 224 ( 39 ) 177 ( 50 ) -
    Townsend Scale total score
    Units: Score
        arithmetic mean (standard deviation)
    		 8.2 ( 3.0 ) 9.3 ( 4.3 ) -
    Neuropsychological Assessement of Dementia in Individuals with Intellectual Disabilities (NADIID)
    Memory for Objects test
    Units: Score
        arithmetic mean (standard deviation)
    		 5.7 ( 2.3 ) 4.0 ( 2.4 ) -
    Selective Attention Cancellation Test
    Overall score
    Units: Score
        arithmetic mean (standard deviation)
    		 17.0 ( 9.3 ) 25.3 ( 25.0 ) -
    Cambridge Neuropsychological Test Automated Battery (CANTAB) pattern recognition memory
    Units: % correct
        arithmetic mean (standard deviation)
    		 61.5 ( 23.5 ) 56.6 ( 12.3 ) -
    Cats and Dogs switching condition
    Time taken
    Units: Time
        arithmetic mean (standard deviation)
    		 58.8 ( 36.3 ) 40.5 ( 22.0 ) -
    Cats and Dogs switching condition
    Number of errors
    Units: Number of errors
        arithmetic mean (standard deviation)
    		 4.1 ( 5.3 ) 11.0 ( 7.6 ) -
    Tower of London test
    Revised for learning disabilities
    Units: Total score
        arithmetic mean (standard deviation)
    		 21.7 ( 8.5 ) 20.7 ( 8.0 ) -
    Cued Recall Test
    Units: Total score
        arithmetic mean (standard deviation)
    		 34.1 ( 4.5 ) 21.2 ( 12.7 ) -
    Category Fluency Test
    Number correct
    Units: Number
        arithmetic mean (standard deviation)
    		 12.1 ( 4.2 ) 8.0 ( 4.2 ) -
    Category Fluency Test
    Number repeated
    Units: Number
        arithmetic mean (standard deviation)
    		 0.7 ( 1.1 ) 2.6 ( 1.7 ) -
    Category Fluency Test
    Number of errors
    Units: Number
        arithmetic mean (standard deviation)
    		 0.3 ( 0.5 ) 0.0 ( 0.0 ) -
    Story Recall Test
    Free recall
    Units: Score
        arithmetic mean (standard deviation)
    		 5.8 ( 3.7 ) 5.0 ( 6.3 ) -
    Story Recall Test
    Cued recall
    Units: Score
        arithmetic mean (standard deviation)
    		 4.4 ( 2.7 ) 2.4 ( 4.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 One capsule of placebo at night for 12 months

    Reporting group title
    Simvastatin
    Reporting group description
    		 Simvastatin 40mg at night by oral administration
    Reporting group title
    Placebo
    Reporting group description
    		 One capsule of placebo at night for 12 months

    Reporting group title
    Simvastatin
    Reporting group description
    		 Simvastatin 40mg at night by oral administration

    Primary: Recruitment

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    End point title
    		 Recruitment [1]
    End point description
    Monthly numbers screened and recruited
    End point type
    Primary
    End point timeframe
    12 months
    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: Between-group analyses were not conducted for this end point. Instead, descriptive statistics were used to describe the total study cohort.
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    11
    10
    Units: Number of patients
        Month 1
    2
    1
        Month 2
    2
    1
        Month 3
    0
    0
        Month 4
    0
    0
        Month 5
    0
    0
        Month 6
    1
    1
        Month 7
    0
    0
        Month 8
    3
    2
        Month 9
    0
    0
        Month 10
    1
    2
        Month 11
    0
    2
        Month 12
    2
    1
    No statistical analyses for this end point

    Primary: Retention

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    End point title
    		 Retention [2]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to 12 months
    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: Between-group analyses were not conducted for this end point. Instead, descriptive statistics were used to describe the total study cohort.
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    11
    10
    Units: Proportion of participants
        Included in analysis
    9
    7
        Lost to follow-up
    2
    3
    No statistical analyses for this end point

    Primary: Recruitment and retention

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    End point title
    		 Recruitment and retention [3]
    End point description
    Number of participants recruited per base general population size
    End point type
    Primary
    End point timeframe
    12 months
    Notes
    [3] - 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: Between-group analyses were not conducted for this end point. Instead, descriptive statistics were used to describe the total study cohort.
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    11
    10
    Units: Number of participants
    9
    7
    No statistical analyses for this end point

    Secondary: Neuropsychological Assessment of Dementia in Individuals with Intellectual Disabilities

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    End point title
    		 Neuropsychological Assessment of Dementia in Individuals with Intellectual Disabilities
    End point description
    Memory for Objects test
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    6
    Units: Score
        arithmetic mean (standard deviation)
    4.9 ( 2.6 )
    5.3 ( 2.7 )
    Statistical analysis title
    		 Memory for Objects test
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.047
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 3.96
    Variability estimate
    Standard error of the mean

    Secondary: Selective Attention Cancellation Test

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    End point title
    		 Selective Attention Cancellation Test
    End point description
    Overall score
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    3
    Units: Score
        arithmetic mean (standard deviation)
    18.8 ( 11.6 )
    21.7 ( 8.4 )
    Statistical analysis title
    		 Selective Attention Cancellation Test
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.669
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.36
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -29.2
         upper limit
    		 18.45
    Variability estimate
    Standard error of the mean

    Secondary: Cambridge Neuropsychological Test Automated Battery (CANTAB)

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    End point title
    		 Cambridge Neuropsychological Test Automated Battery (CANTAB)
    End point description
    % correct
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    4
    5
    Units: Score
        arithmetic mean (standard deviation)
    67.3 ( 17.4 )
    57.0 ( 12.2 )
    Statistical analysis title
    		 CANTAB pattern recognition memory
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.118
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -32.6
         upper limit
    		 1.31
    Variability estimate
    Standard error of the mean

    Secondary: Cats and Dogs switching condition

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    End point title
    		 Cats and Dogs switching condition
    End point description
    Time taken
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    8
    5
    Units: Time
        arithmetic mean (standard deviation)
    47.0 ( 31.5 )
    44.0 ( 10.9 )
    Statistical analysis title
    		 Cats & Dogs switching condition (time taken)
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.94
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.74
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -44.5
         upper limit
    		 41
    Variability estimate
    Standard error of the mean

    Secondary: Cats and Dogs switching condition

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    End point title
    		 Cats and Dogs switching condition
    End point description
    Number of errors
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    8
    7
    Units: Number
        arithmetic mean (standard deviation)
    7.0 ( 8.2 )
    7.8 ( 7.5 )
    Statistical analysis title
    		 Cats & Dogs switching condition (number of errors)
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.417
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 3.09

    Secondary: Tower of London test

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    End point title
    		 Tower of London test
    End point description
    Revised for learning disabilities
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    6
    Units: Score
        arithmetic mean (standard deviation)
    24.8 ( 13.6 )
    20.3 ( 11.7 )
    Statistical analysis title
    		 Tower of London test
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.429
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.71
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -18.4
         upper limit
    		 6.9
    Variability estimate
    Standard error of the mean

    Secondary: Cued Recall Test

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    End point title
    		 Cued Recall Test
    End point description
    Total score
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    7
    5
    Units: Score
        arithmetic mean (standard deviation)
    28.7 ( 13.0 )
    12.8 ( 14.2 )
    Statistical analysis title
    		 Cued Recall Test
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.451
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 46.07
    Variability estimate
    Standard error of the mean

    Secondary: Category Fluency Test

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    End point title
    		 Category Fluency Test
    End point description
    Number correct
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    6
    Units: Number
        arithmetic mean (standard deviation)
    9.2 ( 3.9 )
    8.2 ( 6.1 )
    Statistical analysis title
    		 Category Fluency Test (number correct)
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.685
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.46
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.92
         upper limit
    		 7.84
    Variability estimate
    Standard error of the mean

    Secondary: Category Fluency Test

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    End point title
    		 Category Fluency Test
    End point description
    Number repeated
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    5
    Units: Number
        arithmetic mean (standard deviation)
    1.0 ( 1.1 )
    1.6 ( 1.1 )
    Statistical analysis title
    		 Category Fluency Test (number repeated)
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.189
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.87
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 0.26
    Variability estimate
    Standard error of the mean

    Secondary: Category Fluency Test

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    End point title
    		 Category Fluency Test
    End point description
    Number of errors
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    5
    Units: Number
        arithmetic mean (standard deviation)
    0.1 ( 0.3 )
    0.2 ( 0.5 )
    Statistical analysis title
    		 Category Fluency Test (number of errors)
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.653
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 25.23
    Variability estimate
    Standard error of the mean

    Secondary: Story Recall Test

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    End point title
    		 Story Recall Test
    End point description
    Free recall
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    8
    5
    Units: Number
        arithmetic mean (standard deviation)
    3.6 ( 3.3 )
    3.0 ( 4.2 )
    Statistical analysis title
    		 Story Recall Test (Free recall)
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.488
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.72
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.39
         upper limit
    		 1.94
    Variability estimate
    Standard error of the mean

    Secondary: Story Recall Test

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    End point title
    		 Story Recall Test
    End point description
    Cued recall
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    8
    5
    Units: Number
        arithmetic mean (standard deviation)
    3.9 ( 3.0 )
    2.6 ( 3.7 )
    Statistical analysis title
    		 Story Recall Test (cued recall)
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.413
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.03
         upper limit
    		 2.24
    Variability estimate
    Standard error of the mean

    Secondary: Change in Aβ40

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    End point title
    		 Change in Aβ40
    End point description
    Change over 12 months: simvastatin group compared to placebo group
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Simvastatin
    Number of subjects analysed
    6
    Units: pmol/L
        number (not applicable)
    -24.4
    No statistical analyses for this end point

    Secondary: Change in Aβ42

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    End point title
    		 Change in Aβ42
    End point description
    Change over 12 months: simvastatin group compared to placebo group
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Simvastatin
    Number of subjects analysed
    6
    Units: pmol/l
        number (not applicable)
    -0.26
    No statistical analyses for this end point

    Secondary: Change in Aβ42/Aβ40 ratio

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    End point title
    		 Change in Aβ42/Aβ40 ratio
    End point description
    Change over 12 months: simvastatin group compared to placebo group
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Simvastatin
    Number of subjects analysed
    6
    Units: ratio
        number (not applicable)
    -0.02
    No statistical analyses for this end point

    Other pre-specified: Cholesterol

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    End point title
    		 Cholesterol
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    7
    Units: mmol/l
        arithmetic mean (standard deviation)
    5.4 ( 0.7 )
    4.7 ( 0.7 )
    No statistical analyses for this end point

    Other pre-specified: EuroQoL 5 Dimension Questionnaire (EQ-5D)

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    End point title
    		 EuroQoL 5 Dimension Questionnaire (EQ-5D)
    End point description
    EQ-5D health utility
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    7
    Units: Score
        arithmetic mean (standard deviation)
    0.75 ( 0.29 )
    0.68 ( 0.25 )
    No statistical analyses for this end point

    Other pre-specified: Adaptive Behaviour Scale (ABS)

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    End point title
    		 Adaptive Behaviour Scale (ABS)
    End point description
    Total score
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    7
    Units: Score
        arithmetic mean (standard deviation)
    214 ( 38 )
    170 ( 56 )
    No statistical analyses for this end point

    Other pre-specified: Townsend Scale

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    End point title
    		 Townsend Scale
    End point description
    Total score
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Simvastatin
    Number of subjects analysed
    9
    7
    Units: Score
        arithmetic mean (standard deviation)
    8.1 ( 3.4 )
    11.3 ( 3.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 month treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 One capsule of placebo at night for 12 months

    Reporting group title
    Simvastatin
    Reporting group description
    		 Simvastatin 40mg at night by oral administration

    Serious adverse events
    		 Placebo Simvastatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (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
    		 Placebo Simvastatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 10 (30.00%)
    Injury, poisoning and procedural complications
    Leg injury
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Episodic diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Endocrine disorders
    Thyroid dysfunction
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2011
    Protocol amendment, addressing points raised by the MHRA during its review. Within NHS GG&C, the amended protocol (version 3) was approved as part of Health Board management approval.
    05 Apr 2012
    Protocol version 4 Replacement of outcome measure instrument - 'Cats and Dogs test' in place of 'Delayed Matching to Sample test' No baseline interviews conducted yet so no participant recall required.
    16 May 2012
    Protocol v5 - Revised medication supply process - Revised unblinding process - Clarification of data sharing, to facilitate drug supply - Additional exclusion criterion
    03 Dec 2013
    Protocol version 7 Revised exclusion criteria and expected Adverse Reactions, following a change to the Summary of Product Characteristics and subsequently updated Reference Safety Information.
    21 Jan 2014
    Protocol version 8 Inclusion of sub-study assessing cognitive performance tools, for patients otherwise ineligible for the full study. No drug therapy involved.

    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.
    Recruitment was challenging. However, valuable feasibility data was obtained, allowing the possibility of designing a full-scale Randomised Controlled Trial, with a realistic recruitment strategy & seeking an appropriate level of funding to implement

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27473843
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