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    Clinical Trial Results:
    A Phase II randomised placebo controlled clinical trial of Simvastatin in patients with secondary progressive multiple sclerosis

    Summary
    EudraCT number
    		 2006-006347-31
    Trial protocol
    		 GB  
    Global end of trial date
    14 Nov 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MSTC-001 (MS-STAT)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00647348
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensingston Campus, London, United Kingdom, SW7 2AZ
    Public contact
    David Wilkie, Imperial College London, +44 02083830675, d.wilkie@imperial.ac.uk
    Scientific contact
    David Wilkie, Imperial College London, +44 02083830675, d.wilkie@imperial.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
    01 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Nov 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether Simvastatin at a dose of 80mg can reduce the rate of whole brain atrophy as measured by MRI over a 2-year time period when compared with placebo.
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jan 2008
    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: 140
    Worldwide total number of subjects
    140
    EEA total number of subjects
    140
    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)
    140
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited at three neuroscience centres in the UK between Jan 2008, and Nov 2011

    Pre-assignment
    Screening details
    		 140 participants enrolled to the study

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Simvastatin 80mg OD
    Arm description
    		 Participants received Simvastatin 80mg OD
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    80mg daily, two 40 mg tablets inside opaque hard gelatine capsules received one tablet per day for the first month before having two per day from then on for 24 months

    Arm title
    		 Placebo
    Arm description
    		 Participants received Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    80mg daily, two 40 mg tablets inside opaque hard gelatine capsules received one tablet per day for the first month before having two per day from then on for 24 months

    Number of subjects in period 1
    		Simvastatin 80mg OD Placebo
    Started
    70
    70
    Completed
    67
    64
    Not completed
    3
    6
         Lost to follow-up
    3
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Simvastatin 80mg OD
    Reporting group description
    		 Participants received Simvastatin 80mg OD

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received Placebo

    Reporting group values
    		 Simvastatin 80mg OD Placebo Total
    Number of subjects
    		 70 70 140
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 70 70 140
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 51.5 ( 7 ) 51.1 ( 6.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 49 48 97
        Male
    		 21 22 43

    End points

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    End points reporting groups
    Reporting group title
    Simvastatin 80mg OD
    Reporting group description
    		 Participants received Simvastatin 80mg OD

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received Placebo

    Primary: Percentage Change in Whole Brain Volume

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    End point title
    		 Percentage Change in Whole Brain Volume
    End point description
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 Simvastatin 80mg OD Placebo
    Number of subjects analysed
    66
    64
    Units: percentage of brain volumen change
        geometric mean (standard deviation)
    0.288 ( 0.521 )
    0.584 ( 0.498 )
    Statistical analysis title
    		 Changes in Whole Brain Volume
    Comparison groups
    Simvastatin 80mg OD v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.003
    Method
    		 BBSI=brain boundary shift integral
    Confidence interval
    Notes
    [1] - intention-to-treat analysis

    Secondary: Evaluation of Disability (EDSS)

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    End point title
    		 Evaluation of Disability (EDSS)
    End point description
    Score (0 to 10), lower score less disability and better progression. For EDSS, mean score at 24 months was compared between treatment groups using an ANCOVA model adjusting for baseline score and minimisation variables.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Simvastatin 80mg OD Placebo
    Number of subjects analysed
    67
    61
    Units: score on scale
        geometric mean (standard deviation)
    5.93 ( 1.11 )
    6.35 ( 0.83 )
    Statistical analysis title
    		 Evaluation of Disability (EDSS)
    Comparison groups
    Simvastatin 80mg OD v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - EDSS, mean score at 24 months was compared between treatment groups using an ANCOVA model adjusting for baseline score and minimisation variables.

    Secondary: Evaluation of Disability (MSFC Z Score)

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    End point title
    		 Evaluation of Disability (MSFC Z Score)
    End point description
    Negative value implies worsening and a positive value implies improvement.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Simvastatin 80mg OD Placebo
    Number of subjects analysed
    58
    49
    Units: Score on scale
        geometric mean (standard deviation)
    -0.78 ( 2.06 )
    -1.21 ( 2.59 )
    No statistical analyses for this end point

    Secondary: Evaluation of Disability (MSFC Walk)

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    End point title
    		 Evaluation of Disability (MSFC Walk)
    End point description
    The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Simvastatin 80mg OD Placebo
    Number of subjects analysed
    62
    54
    Units: foot per second
        geometric mean (standard deviation)
    1.83 ( 1.61 )
    1.55 ( 1.19 )
    No statistical analyses for this end point

    Secondary: Evaluation of Disability (MSFC Peg Test)

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    End point title
    		 Evaluation of Disability (MSFC Peg Test)
    End point description
    The patient is seated at a table with a small, shallow container holding nine pegs and a wood or plastic block containing nine empty holes. On a start command when a stopwatch is started, the patient picks up the nine pegs one at a time as quickly as possible, puts them in the nine holes, and, once they are in the holes, removes them again as quickly as possible one at a time, replacing them into the shallow container. The total time to complete the task is recorded.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Simvastatin 80mg OD Placebo
    Number of subjects analysed
    61
    54
    Units: speed per second
        geometric mean (standard deviation)
    0.033 ( 0.01 )
    0.033 ( 0.01 )
    No statistical analyses for this end point

    Secondary: Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Total Score)

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    End point title
    		 Disease Impact Specific to the Disease and Rated by the Patient (MSIS-29 Questionnaire Total Score)
    End point description
    The MSIS-29 is a 29-item self-report measure with 20 items associated with a physical scale and 9 items with a psychological scale. Items ask about the impact of MS on day-to-day life in the past two weeks. All items have 5 response options: 1 "not at all" to 5"extremely". Each of the two scales is scored by summing the responses across items, then converting to a 0-100 scale where 100 indicates a greater impact of the disease on daily function (worse health).
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Simvastatin 80mg OD Placebo
    Number of subjects analysed
    66
    57
    Units: score on a scale
        geometric mean (standard deviation)
    70.1 ( 15.6 )
    76.1 ( 16.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Simvastatin 80mg OD
    Reporting group description
    		 Participants received Simvastatin 80mg OD

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received Placebo

    Serious adverse events
    		 Simvastatin 80mg OD Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 70 (12.86%)
    14 / 70 (20.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Increased spasticity
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizures
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sub-arachnoid haemorrhage
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral encephalitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Grade 3 relapse (requiring hospital admission)
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 70 (7.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Lesion Biopsy
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendectomy
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    2 / 70 (2.86%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Simvastatin 80mg OD Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 70 (70.00%)
    54 / 70 (77.14%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 70 (4.29%)
    10 / 70 (14.29%)
         occurrences all number
    3
    10
    Relapse
         subjects affected / exposed
    17 / 70 (24.29%)
    17 / 70 (24.29%)
         occurrences all number
    17
    17
    cramp
         subjects affected / exposed
    12 / 70 (17.14%)
    10 / 70 (14.29%)
         occurrences all number
    12
    10
    Increase spasticity
         subjects affected / exposed
    0 / 70 (0.00%)
    7 / 70 (10.00%)
         occurrences all number
    0
    7
    Worsening mobility
         subjects affected / exposed
    9 / 70 (12.86%)
    8 / 70 (11.43%)
         occurrences all number
    9
    8
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    7 / 70 (10.00%)
    13 / 70 (18.57%)
         occurrences all number
    7
    13
    Infections and infestations
    Urinary infection
         subjects affected / exposed
    9 / 70 (12.86%)
    8 / 70 (11.43%)
         occurrences all number
    9
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24655729
    http://www.ncbi.nlm.nih.gov/pubmed/28600189
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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