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    Clinical Trial Results:
    A phase 3 randomised, double blind, clinical trial investigating the effectiveness of repurposed simvastatin compared to placebo, in secondary progressive multiple sclerosis, in slowing the progression of disability

    Summary
    EudraCT number
    		 2017-003328-56
    Trial protocol
    		 GB  
    Global end of trial date
    26 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2026
    First version publication date
    07 Jan 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTU/2014/107
    Additional study identifiers
    ISRCTN number
    		 ISRCTN82598726
    US NCT number
    		 NCT03387670
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    Chief Investigator, University College London, +44 2031087414, j.chataway@ucl.ac.uk
    Scientific contact
    Chief Investigator, University College London, +44 2031087414, j.chataway@ucl.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
    11 Oct 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jul 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the effect of daily use simvastatin (80mg) versus placebo on disability progression at 6 monthly intervals in patients with Secondary Progressive MS (SPMS). Disability progression will be assessed based on change in Expanded Disability Status Scores (EDSS) compared to baseline. The hypothesis is that repurposed simvastatin (80mg) is a disease modifying treatment for patients with SPMS.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures (SOPs), the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, and the National Health Service (NHS) Research Governance Framework for Health and Social Care. The potential hepatic effects and risk of myopathy in simvastatin use and provision for stopping or modifiying treatment if these events occurred were made in the trial protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2017
    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: 964
    Worldwide total number of subjects
    964
    EEA total number of subjects
    0
    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)
    932
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from 31 neuroscience centres and district general hospitals in the UK. The eligibility of each patient was reviewed on the observations and bloods taken for screening.

    Pre-assignment
    Screening details
    		 1079 participants were assessed for eligibility and 964 were randomised. The reasons for exclusions were: 94 ineligible, 16 patient choice and 5 unknown reason. Written informed consent to be was obtained, after explanation of the aims, methods, benefits and potential hazards of the trial and BEFORE any trial-specific procedures were performed.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Participants and investigators, including pharmacy, treating and independent assessing neurologists, were masked to treatment allocation. To maintain masking, an online randomisation system was used. This issued a five-digit code to identify the concealed bottles of treatment (tablets of the same colour and size), either simvastatin or placebo, for the site pharmacy to dispense at each dosing visit according to the patient's allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Simvastatin
    Arm description
    		 Oral 80 mg simvastatin (initially 40 mg at randomisation, then escalated after 1 month if tolerated) taken once daily at night
    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
    Oral 80 mg simvastatin (initially 40 mg at randomisation, then escalated after 1 month if tolerated) taken once daily at night.

    Arm title
    		 Placebo
    Arm description
    		 Oral placebo (initially 1 capsule at randomisation, then escalated after 1 month to 2 capsules if tolerated), taken once daily at night.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (1x tablet taken once daily at night for 1 month from Baseline (Month 0). Followed by Placebo (2x tablet taken once daily at night) for 35 months from Visit 3 (Month 1) to Visit 10 (Month 36). For those patients who have not had a confirmed EDSS progression event by Visit 10 (Month 36), they will be invited to an additional 3 visits to Visit 13 (Month 54) to continue Placebo (2x tablet taken once daily at night).

    Number of subjects in period 1
    		Simvastatin Placebo
    Started
    482
    482
    Completed
    425
    412
    Not completed
    57
    70
         Consent withdrawn by subject
    28
    32
         Unable to complete safety monitoring
    1
    6
         Adverse event, non-fatal
    14
    14
         Started contraindicated medication
    -
    1
         Ill health
    6
    9
         Safety concerns
    3
    1
         Started statins
    -
    3
         Died
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 Oral 80 mg simvastatin (initially 40 mg at randomisation, then escalated after 1 month if tolerated) taken once daily at night

    Reporting group title
    Placebo
    Reporting group description
    		 Oral placebo (initially 1 capsule at randomisation, then escalated after 1 month to 2 capsules if tolerated), taken once daily at night.

    Reporting group values
    		 Simvastatin Placebo Total
    Number of subjects
    		 482 482 964
    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 at randomisation
    Units: years
        arithmetic mean (standard deviation)
    		 54.2 ( 6.8 ) 54.4 ( 6.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 353 351 704
        Male
    		 129 131 260
    Ethnic origin
    Units: Subjects
        White
    		 463 466 929
        Asian or Asian British
    		 12 9 21
        Black or Black British
    		 1 3 4
        Mixed
    		 6 3 9
        Unknown
    		 0 1 1
    Relapse in last 12 months
    Has the participant had a relapse in the last 12 months before randomisation
    Units: Subjects
        Yes
    		 25 24 49
        No
    		 457 458 915
    Expanded Disability Status Scale step score
    Expanded Disability Status Scale step score at randomistion
    Units: Subjects
        4 to 5.5
    		 140 135 275
        6.0
    		 177 177 354
        6.5
    		 165 170 335
    Symbol Digit Modalities Test Z score ≤–1·5
    Number and % of participants with Z score of under ≤–1·5 on the Symbol Digit Modalities Test.
    Units: Subjects
        ≤–1·5
    		 270 253 523
        >-1.5
    		 204 217 421
        Missing
    		 8 12 20
    California Verbal Learning Test-II Z score ≤–1.5
    Units: Subjects
        ≤–1.5
    		 171 176 347
        >-1.5
    		 302 294 596
        Missing
    		 9 12 21
    Brief Visuospatial Memory Test-Revised Z score ≤–1.5
    Units: Subjects
        ≤–1.5
    		 55 57 112
        >-1.5
    		 415 401 816
        Missing
    		 12 24 36
    Siponimod
    On siponimod treatment at randomisation
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 481 482 963
    Multiple Sclerosis Duration
    Years since onset of multiple sclerosis
    Units: Years
        arithmetic mean (standard deviation)
    		 22.3 ( 9.4 ) 23.4 ( 9.4 ) -
    Secondary progressive multiple sclerosis duration
    Years since onset of secondary progressive multiple sclerosis
    Units: Years
        arithmetic mean (standard deviation)
    		 7.0 ( 4.7 ) 7.2 ( 5.0 ) -
    Total cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 5.4 ( 1.1 ) 5.4 ( 1.1 ) -
    Timed 25-foot walk speed
    Speed at completing the 2 trials of the MSFC timed 25 foot walk at the baseline visit
    Units: feet per second
        arithmetic mean (standard deviation)
    		 2.2 ( 1.2 ) 2.2 ( 1.2 ) -
    9 hole peg test speed
    Speed at completing the MSFC nine hole peg test
    Units: s-1 x 100
        arithmetic mean (standard deviation)
    		 3.3 ( 1.0 ) 3.4 ( 1.0 ) -
    Multiple sclerosis impact scale physical score
    Multiple sclerosis impact scale physical score out of 100
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    		 54.3 ( 19.4 ) 54.6 ( 19.2 ) -
    Multiple sclerosis impact scale psychological score
    Multiple sclerosis impact scale psychological score out of 100
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    		 38.4 ( 21.6 ) 40.2 ( 22.5 ) -
    Multiple Sclerosis Walking Scale-12 version 2
    Multiple Sclerosis Walking Scale-12 version 2 score out of 100
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    		 67.9 ( 18.0 ) 66.7 ( 18.4 ) -
    Modified Fatigue Impact Scale 21
    Modified Fatigue Impact Scale 21 score out of 100
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    		 57.5 ( 19.2 ) 57.0 ( 19.5 ) -
    Chalder Fatigue Questionnaire
    Chalder Fatigue Questionnaire score out of 100
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    		 52.8 ( 18.6 ) 52.3 ( 19.0 ) -
    Sloan low contrast visual acuity 100% contrast
    Number of letters identified on Sloan chart at 100% contrast, out of 60
    Units: Letters
        arithmetic mean (standard deviation)
    		 51.3 ( 10.1 ) 51.1 ( 10.4 ) -
    Sloan low contrast visual acuity 2.5% contrast
    Number of letters correctly identified on Sloan low contrast visual acuity 2.5% contrast
    Units: Letters
        arithmetic mean (standard deviation)
    		 26.3 ( 13.0 ) 25.9 ( 13.2 ) -
    Sloan low contrast visual acuity 1.25% contrast
    Number of letters correctly identified on Sloan low contrast visual acuity at 1.25% contrast
    Units: Letters
        arithmetic mean (standard deviation)
    		 13.7 ( 12.1 ) 13.7 ( 12.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 Oral 80 mg simvastatin (initially 40 mg at randomisation, then escalated after 1 month if tolerated) taken once daily at night

    Reporting group title
    Placebo
    Reporting group description
    		 Oral placebo (initially 1 capsule at randomisation, then escalated after 1 month to 2 capsules if tolerated), taken once daily at night.

    Subject analysis set title
    Per-protocol high dose
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Includes participants who complied with high dose treatment. Patients were considered compliant with their randomised intervention if they took the protocol dose on at least 90% of days over the first 3 years of follow-up, or until date of confirmed progression, death, or withdrawal if these happened before 3 years.

    Subject analysis set title
    Per-protocol high/low dose
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Includes participants who complied with high or low dose treatment. Patients were considered compliant with their randomised intervention if they took the either low (40mg/1 capsule) or high (80mg/2 capsules) dose on at least 90% of days over the first 3 years of follow-up, or until date of confirmed progression, death, or withdrawal if these happened before 3 years.

    Subject analysis set title
    COVID-19 sensitivity analysis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were included where they were randomised before the start of COVID-19-related public health restrictions (before March 16, 2020) and attended an in-person visit at month 36 after the end of COVID-19 related public health restrictions in the UK (after July 19, 2021).

    Primary: Confirmed disability progression up to 4·5 years

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    End point title
    		 Confirmed disability progression up to 4·5 years
    End point description
    The primary endpoint was confirmed disability progression up to 4·5 years. Progression of disability was defined as an increase of at least 1 point if EDSS score at baseline visit was less than 6·0, or an increase of 0·5 point if EDSS score at baseline visit was 6·0 or more. The initial disability progression event was finalised as a confirmed event if the increase in EDSS persisted to at the next visit at least 6 months later. The time of confirmed progression was defined as when the initial disability progression occurred.
    End point type
    Primary
    End point timeframe
    Up to 4.5 years from randomisation
    End point values
    		 Simvastatin Placebo Per-protocol high dose Per-protocol high/low dose COVID-19 sensitivity analysis
    Number of subjects analysed
    482
    482
    646
    681
    615
    Units: Progression
        Yes
    192
    173
    264
    274
    203
        No
    290
    309
    382
    407
    412
    Statistical analysis title
    		 Primary endpoint: confirmed disability progression
    Statistical analysis description
    The primary endpoint, confirmed disability progression on EDSS, was compared between the simvastatin and placebo treatment using a Cox proportional hazards model. The estimated hazard ratio (HR) along with its 95% confidence interval (CI) and Wald test p value was obtained. The model stratified by centre and adjusted for the other variables included in the minimisation process (sex, age, and baseline EDSS).
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    964
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.39
    Notes
    [1] - Two-sided p-value from a Wald test against the null hypothesis that the hazard ratio is equal to 1
    Statistical analysis title
    		 Sensitivity analysis including unconfirmed events
    Statistical analysis description
    Simvastatin and placebo groups were compared using a Cox proportional hazards model that stratified by centre and adjusted for the other variables included in the minimisation process (sex, age, and baseline EDSS). In this analysis progression events were additionally included where participant ended follow-up before the event could be confirmed.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    964
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.32 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.33
    Notes
    [2] - Sensitivity analysis for the primary endpoint
    [3] - Two-sided p-value from a Wald test against the null hypothesis that the hazard ratio is equal to 1
    Statistical analysis title
    		 Per-protocol analysis, high dose
    Statistical analysis description
    The primary endpoint, confirmed disability progression on EDSS, was compared between the simvastatin and placebo treatment using a Cox proportional hazards model. The estimated hazard ratio (HR) along with its 95% confidence interval (CI) and Wald test p value was obtained. The model stratified by centre and adjusted for the other variables included in the minimisation process (sex, age, and baseline EDSS).
    Comparison groups
    Simvastatin v Placebo v Per-protocol high dose
    Number of subjects included in analysis
    1610
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.38
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.43
    Notes
    [4] - Per-protocol analysis including participants who complied with high dose treatment
    Statistical analysis title
    		 Per-protocol analysis, low/high dose
    Statistical analysis description
    The primary endpoint, confirmed disability progression on EDSS, was compared between the simvastatin and placebo treatment using a Cox proportional hazards model. The estimated hazard ratio (HR) along with its 95% confidence interval (CI) and Wald test p value was obtained. The model stratified by centre and adjusted for the other variables included in the minimisation process (sex, age, and baseline EDSS).
    Comparison groups
    Simvastatin v Placebo v Per-protocol high/low dose
    Number of subjects included in analysis
    1645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.37
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.42
    Notes
    [5] - Per-protocol analysis including participants who complied with high or low dose treatment
    Statistical analysis title
    		 Covid-19 sensitivity analysis
    Statistical analysis description
    A mixed-effects logistic regression model was used to compare the placebo and simvastatin group at 3 years on unconfirmed progression on the EDSS step score. Analysis adjusted for sex, age, and baseline EDSS and included a random effect for site.
    Comparison groups
    Simvastatin v Placebo v COVID-19 sensitivity analysis
    Number of subjects included in analysis
    1579
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.45

    Secondary: Multicomponent disability progression

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    End point title
    		 Multicomponent disability progression
    End point description
    Progression by 3 years on a multicomponent measure. Disability progression (and subsequently confirmed) on one or more of EDSS, timed 25-foot walk (T25FW), or the 9 hole peg test (9HPT). Progression on the EDSS was defined as a 0·5 point increase if baseline EDSS ≥6 or 1·0 point increase if baseline EDSS <6. Progression on the MSFC walk was defined as either: A) ≥20% increase in average 25ft walk time; or B) becoming unable to complete either of the trials of the 25ft walk due to disability. Progression on the 9HPTwas defined as either: A) ≥20% decrease in the average 9HPT time; B) becoming unable to complete either of the right handed trials of the 9HPT; or C) becoming unable to complete either of the left handed trials of the 9HPT.
    End point type
    Secondary
    End point timeframe
    Up to 3 years.
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    446 [6]
    442 [7]
    Units: Progression
        Yes
    261
    242
        No
    185
    200
    Notes
    [6] - Participants were only included where they had a valid measure of the outcome
    [7] - Participants only included where they had a valid measure of the outcome
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    A mixed-effects logistic regression model was used to compare the groups at 3 years on subsequently confirmed disability progression on the multicomponent measure. Analysis adjusted for sex, age, and baseline EDSS and included a random effect for site.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    888
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.53

    Secondary: Multicomponent disability progression: EDSS

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    End point title
    		 Multicomponent disability progression: EDSS
    End point description
    Progression by 3 years on EDSS (and subsequently confirmed) for participants with data on multicomponent measure of disability progression. Progression on the EDSS was defined as per the primary outcome: a 0·5 point increase if baseline EDSS ≥6 or 1·0 point increase if baseline EDSS <6.
    End point type
    Secondary
    End point timeframe
    Up to 3 years from randomisation
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    446
    442
    Units: Progression
        Yes
    166
    150
        No
    276
    292
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    A mixed-effects logistic regression model was used to compare the groups at 3 years on subsequently confirmed disability progression on the multicomponent measure. Analysis adjusted for sex, age, and baseline EDSS and included a random effect for site.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    888
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.52

    Secondary: Multicomponent disability progression: Timed 25-foot walk

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    End point title
    		 Multicomponent disability progression: Timed 25-foot walk
    End point description
    Progression by 3 years on timed 25-foot walk (and subsequently confirmed). Analysis includes participants with data on the multicomponent measure of disability progression. Progression on the MSFC walk was defined as either: A) ≥20% increase in average 25ft walk time; or B) becoming unable to complete either of the trials of the 25ft walk due to disability.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    446
    442
    Units: Progression
        Yes
    158
    145
        No
    288
    297
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    A mixed-effects logistic regression model was used to compare the groups at 3 years on confirmed disability progression. Analysis adjusted for sex, age, and baseline EDSS and included a random effect for site.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    888
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.52

    Secondary: Multicomponent disability progression: 9 hole peg test

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    End point title
    		 Multicomponent disability progression: 9 hole peg test
    End point description
    Progression by 3 years (and subsequently confirmed) on the 9 hole peg test (9HPT). Progression on the 9HPTwas defined as either: A) ≥20% decrease in the average 9HPT time; B) becoming unable to complete either of the right handed trials of the 9HPT; or C) becoming unable to complete either of the left handed trials of the 9HPT.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    446
    442
    Units: Progression
        Yes
    51
    32
        No
    395
    410
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    A mixed-effects logistic regression model was used to compare the groups at 3 years. Analysis adjusted for sex, age, and baseline EDSS and included a random effect for site.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    888
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 2.69

    Secondary: Modified Rankin Scale

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    End point title
    		 Modified Rankin Scale
    End point description
    Disability progression on the mRS, defined as any increase between baseline and 3 years.
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    413
    393
    Units: Progression
        Yes
    165
    148
        No
    248
    245
    Statistical analysis title
    		 Mixed effects logistic regression
    Statistical analysis description
    A mixed-effects logistic regression model was used to compare the groups at 3 years. Analysis adjusted for sex, age, and baseline EDSS and included a random effect for site.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    806
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.47

    Secondary: Multiple Sclerosis Functional Composite Z score

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    End point title
    		 Multiple Sclerosis Functional Composite Z score
    End point description
    Multiple Sclerosis Functional Composite (MSFC) Z score comprising the timed 25-foot walk, 9 hole peg test and Symbol Digit Modalities Test. Z score is standardised using the baseline of the MS-STAT2 study.
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    402
    383
    Units: Z score
        arithmetic mean (standard deviation)
    -0.3 ( 1.2 )
    -0.3 ( 1.2 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. Bias corrected and accelerated bootstrap 95% CI based on 2000 replications were used for inference.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.14
    Notes
    [8] - P-value inferred from 95% confidence intervals.

    Secondary: Timed 25ft walk speed

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    End point title
    		 Timed 25ft walk speed
    End point description
    Analysis of the 25ft walk used the reciprocal of the average 25ft walk time. Where a trial could not be completed due to disability the maximum possible time of 180 seconds was imputed
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    389
    373
    Units: Feet per second
        arithmetic mean (standard deviation)
    1.9 ( 1.2 )
    1.9 ( 1.3 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    762
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.1

    Secondary: 9-hole peg test speed

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    End point title
    		 9-hole peg test speed
    End point description
    Speed at completing the 9 hole peg test. Analysis of the 9HPT used was based on average 1/9HPT as defined in the MSFC manual. Where participants could not complete a trial due to disability the maximum possible time was imputed which was 300 seconds.
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    401
    383
    Units: seconds^-1 x 100
        arithmetic mean (standard deviation)
    3.3 ( 1.1 )
    3.3 ( 1.1 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    784
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.12

    Secondary: Symbol Digit Modalities Test score

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    End point title
    		 Symbol Digit Modalities Test score
    End point description
    Symbol Digit Modalities Test score out of 110
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    397
    377
    Units: Score from 0 to 110
        arithmetic mean (standard deviation)
    43.3 ( 13.9 )
    43.8 ( 13.7 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    774
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 1.06

    Secondary: Sloan Low Contrast Visual Acuity 100% contrast

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    End point title
    		 Sloan Low Contrast Visual Acuity 100% contrast
    End point description
    Number of letters correctly identified out of 60
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    389
    369
    Units: Letters
        arithmetic mean (standard deviation)
    50.5 ( 9.5 )
    50.0 ( 10.7 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. Bias corrected and accelerated bootstrap 95% CI based on 2000 replications were used for inference.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 1.16
    Notes
    [9] - P value inferred from 95% confidence intervals

    Secondary: Sloan Low Contrast Visual Acuity 2.5% contrast

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    End point title
    		 Sloan Low Contrast Visual Acuity 2.5% contrast
    End point description
    Number of letters correctly identified out of 60
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    388
    366
    Units: Letters
        arithmetic mean (standard deviation)
    25.6 ( 12.6 )
    24.5 ( 12.2 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. Bias corrected and accelerated bootstrap 95% CI based on 2000 replications were used for inference.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    754
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 1.81
    Notes
    [10] - P-value inferred from 95% confidence interval

    Secondary: Sloan Low Contrast Visual Acuity 1.25% contrast

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    End point title
    		 Sloan Low Contrast Visual Acuity 1.25% contrast
    End point description
    Number of letters correctly identified out of 60
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    376
    362
    Units: Letters
        arithmetic mean (standard deviation)
    12.7 ( 11.8 )
    12.8 ( 11.1 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. Bias corrected and accelerated bootstrap 95% CI based on 2000 replications were used for inference.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 0.76
    Notes
    [11] - P-value inferred from 95% confidence interval

    Secondary: California Verbal Learning Test-II

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    End point title
    		 California Verbal Learning Test-II
    End point description
    California Verbal Learning Test-II score out of 80
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    399
    378
    Units: Score from 0 to 80
        arithmetic mean (standard deviation)
    46.8 ( 13.0 )
    47.0 ( 13.3 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 1.24

    Secondary: Brief Visuospatial Memory Test-Revised

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    End point title
    		 Brief Visuospatial Memory Test-Revised
    End point description
    Brief Visuospatial Memory Test-Revised score out of 36
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    386
    366
    Units: Score from 0 to 36
        arithmetic mean (standard deviation)
    20.2 ( 8.7 )
    20.3 ( 9.3 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The groups were compared using a mixed effects linear regression for the outcome at baseline and 3 years, with the treatment effect at baseline constrained to zero. The model included an unstructured covariance matrix for the residuals. The minimisation variables (i.e., sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    752
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 1.22

    Secondary: Multiple sclerosis impact scale 29 version 2 Total

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    End point title
    		 Multiple sclerosis impact scale 29 version 2 Total
    End point description
    Total score out of 100 on the Multiple sclerosis impact scale 29 version 2
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    397
    387
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    51.1 ( 19.7 )
    50.5 ( 20.4 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The mean at 3 years was compared between the groups using mixed effects linear regression for the outcome at baseline, 1, 2 and 3 years. The model included an interaction between visit and treatment group, with the treatment effects at baseline constrained to be zero. The minimisation variables (sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. The model included an unstructured covariance matrix for the residuals by visit.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    784
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    1.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 3.68

    Secondary: Multiple sclerosis impact scale 29 version 2 physical score

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    End point title
    		 Multiple sclerosis impact scale 29 version 2 physical score
    End point description
    Multiple sclerosis impact scale 29 version 2 physical score out of 100
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    401
    389
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    56.8 ( 21.2 )
    55.3 ( 21.3 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The mean at 3 years was compared between the groups using mixed effects linear regression for the outcome at baseline, 1, 2 and 3 years. The model included an interaction between visit and treatment group, with the treatment effects at baseline constrained to be zero. The minimisation variables (sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. The model included an unstructured covariance matrix for the residuals by visit.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    790
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 4.22

    Secondary: Multiple sclerosis impact scale 29 version 2 psychological score

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    End point title
    		 Multiple sclerosis impact scale 29 version 2 psychological score
    End point description
    Multiple sclerosis impact scale 29 version 2 (out of 100)
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    411
    405
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    39.1 ( 22.8 )
    39.8 ( 23.8 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The mean at 3 years was compared between the groups using mixed effects linear regression for the outcome at baseline, 1, 2 and 3 years. The model included an interaction between visit and treatment group, with the treatment effects at baseline constrained to be zero. The minimisation variables (sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. The model included an unstructured covariance matrix for the residuals by visit.
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 3.32

    Secondary: Multiple Sclerosis Walking Scale 12

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    End point title
    		 Multiple Sclerosis Walking Scale 12
    End point description
    Multiple Sclerosis Walking Scale 12 score out of 100
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    394
    386
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    68.3 ( 21.0 )
    69.0 ( 20.9 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The mixed effects linear regression for the outcome at baseline, 1, 2 and 3 years included fixed effects for the interactions between visit and treatment group, minimisation variables and their interactions with visit. The treatment effect at baseline was constrained to zero. There was an unstructured covariance matrix for the residuals. Bias corrected and accelerated bootstrap 95% CI based on 2000 replications were used for inference.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.61
         upper limit
    		 0.74
    Notes
    [12] - P value inferred from 95% confidence intervals

    Secondary: Modified Fatigue Impact Scale 21

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    End point title
    		 Modified Fatigue Impact Scale 21
    End point description
    Modified Fatigue Impact Scale 21 score out of 100
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    391
    377
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    56.2 ( 20.9 )
    54.7 ( 21.7 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The mean at 3 years was compared between the groups using mixed effects linear regression for the outcome at baseline, 1, 2 and 3 years. The model included an interaction between visit and treatment group, with the treatment effects at baseline constrained to be zero. The minimisation variables (sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. The model included an unstructured covariance matrix for the residuals by visit.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 3.23

    Secondary: Chalder Fatigue Questionnaire

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    End point title
    		 Chalder Fatigue Questionnaire
    End point description
    Chalder Fatigue Questionnaire score out of 100
    End point type
    Secondary
    End point timeframe
    At 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    403
    398
    Units: Score from 0 to 100
        arithmetic mean (standard deviation)
    50.4 ( 18.2 )
    49.0 ( 18.1 )
    Statistical analysis title
    		 Mixed effects linear regression
    Statistical analysis description
    The mean at 3 years was compared between the groups using mixed effects linear regression for the outcome at baseline, 1, 2 and 3 years. The model included an interaction between visit and treatment group, with the treatment effects at baseline constrained to be zero. The minimisation variables (sex, age, and baseline EDSS) and their interactions with visit were included as fixed effects. The model included an unstructured covariance matrix for the residuals by visit.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    801
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean difference
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.04
         upper limit
    		 3.48

    Secondary: Relapses

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    End point title
    		 Relapses
    End point description
    Number of relapses
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Simvastatin Placebo
    Number of subjects analysed
    482
    482
    Units: Number
    98
    68
    Statistical analysis title
    		 Negative binomial regression
    Statistical analysis description
    Relapse rate was compared between the simvastatin and placebo groups using a mixed-effects negative binomial regression model with follow-up time for each participant included as an offset in the model. Analysis adjusted for sex, age, and baseline EDSS and included a random effect for site.
    Comparison groups
    Simvastatin v Placebo
    Number of subjects included in analysis
    964
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 Negative binomial regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.01

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation up to the end of each participant's follow-up, which was up to 4.5 years.
    Adverse event reporting additional description
    Non-serious adverse events are reported by system organ class.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 Oral 80 mg simvastatin (initially 40 mg at randomisation, then escalated after 1 month if tolerated) taken once daily at night

    Reporting group title
    Placebo
    Reporting group description
    		 Oral placebo (initially 1 capsule at randomisation, then escalated after 1 month to 2 capsules if tolerated), taken once daily at night.

    Serious adverse events
    		 Simvastatin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 482 (25.73%)
    117 / 482 (24.27%)
         number of deaths (all causes)
    5
    4
         number of deaths resulting from adverse events
    5
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    3 / 482 (0.62%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 482 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melanoma
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine Tumour
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal cancer
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    2 / 482 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tumour
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma
         subjects affected / exposed
    4 / 482 (0.83%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    deep vein thrombosis
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 482 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 482 (0.41%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right superior femoral artery thrombosis
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip replacement revision
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 482 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insertion of suprapubic catheter
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MS Autologous Stem Cell Transplant
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right foot bones fusion surgery
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma creation
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Finger surgery
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (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
    Reaction to COVID vaccine
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    hysteroscopy and polypectomy
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine bleeding
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma exacerbation
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia, parapneumonic effusion
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Attempted suicide
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic episode
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Elevated creatine kinase
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 482 (0.41%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity (raised ALT/AST)
    alternative assessment type: Systematic
         subjects affected / exposed
    11 / 482 (2.28%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    11 / 11
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 482 (2.49%)
    10 / 482 (2.07%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bone fracture
         subjects affected / exposed
    12 / 482 (2.49%)
    20 / 482 (4.15%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dislocated Shoulder
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suprapubic catheter insertion complications
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic head injury
         subjects affected / exposed
    0 / 482 (0.00%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    2 / 482 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emergency surgery for enlarged aorta - valve inserted (Aorta Dissection)
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Heart surgery for heart murmour
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 482 (0.21%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Functional decline due to progressive MS
         subjects affected / exposed
    2 / 482 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 482 (0.21%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Sclerosis relapse
         subjects affected / exposed
    8 / 482 (1.66%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudorelapse
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 482 (0.62%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    2 / 482 (0.41%)
    3 / 482 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transient ischemic attack
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Essential Thrombocythemia
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 482 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuritis
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Emergency surgery for glaucoma
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular hole repair left eye
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right retinal detachment
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric bleed
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 482 (0.41%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's Disease
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute bowel obstruction
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental abscess
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 482 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Entercolitis
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial intra-thoracic gastric volvus
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder removal
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder urgency
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney stone
         subjects affected / exposed
    3 / 482 (0.62%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emergency nephtostomy tube insertion
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phimosis
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severely reduced renal function
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 482 (0.41%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary Adrenal Insufficiency
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased mobility
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disc bulge
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Divarification of rectus muscle
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee surgery
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower back pain
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular pain
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metacarpophalangeal joint dislocation
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    2 / 482 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest infection
         subjects affected / exposed
    2 / 482 (0.41%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 infection
         subjects affected / exposed
    7 / 482 (1.45%)
    6 / 482 (1.24%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 482 (1.45%)
    2 / 482 (0.41%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 482 (0.41%)
    5 / 482 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected pressure sore
         subjects affected / exposed
    1 / 482 (0.21%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 482 (0.00%)
    4 / 482 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection of supra pubic catheter site
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection to skin of thumb
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 482 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 482 (0.41%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shingles
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    4 / 482 (0.83%)
    7 / 482 (1.45%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    16 / 482 (3.32%)
    19 / 482 (3.94%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 482 (0.21%)
    0 / 482 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 482 (0.00%)
    1 / 482 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Simvastatin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    427 / 482 (88.59%)
    423 / 482 (87.76%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    17 / 482 (3.53%)
    21 / 482 (4.36%)
         occurrences all number
    24
    24
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    15 / 482 (3.11%)
    22 / 482 (4.56%)
         occurrences all number
    16
    24
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    15 / 482 (3.11%)
    7 / 482 (1.45%)
         occurrences all number
    16
    7
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    119 / 482 (24.69%)
    128 / 482 (26.56%)
         occurrences all number
    164
    179
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    5 / 482 (1.04%)
    9 / 482 (1.87%)
         occurrences all number
    5
    9
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    14 / 482 (2.90%)
    22 / 482 (4.56%)
         occurrences all number
    16
    22
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    39 / 482 (8.09%)
    32 / 482 (6.64%)
         occurrences all number
    46
    55
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    23 / 482 (4.77%)
    26 / 482 (5.39%)
         occurrences all number
    27
    27
    Investigations
    Investigations
         subjects affected / exposed
    34 / 482 (7.05%)
    24 / 482 (4.98%)
         occurrences all number
    42
    26
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    168 / 482 (34.85%)
    157 / 482 (32.57%)
         occurrences all number
    303
    265
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    11 / 482 (2.28%)
    17 / 482 (3.53%)
         occurrences all number
    11
    16
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    145 / 482 (30.08%)
    136 / 482 (28.22%)
         occurrences all number
    210
    226
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    Additional description: Events for Blood and lymphatic system disorders SOC
         subjects affected / exposed
    11 / 482 (2.28%)
    6 / 482 (1.24%)
         occurrences all number
    12
    6
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    30 / 482 (6.22%)
    23 / 482 (4.77%)
         occurrences all number
    35
    26
    Eye disorders
    Eye disorders
         subjects affected / exposed
    25 / 482 (5.19%)
    30 / 482 (6.22%)
         occurrences all number
    31
    36
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    105 / 482 (21.78%)
    105 / 482 (21.78%)
         occurrences all number
    170
    142
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    6 / 482 (1.24%)
    1 / 482 (0.21%)
         occurrences all number
    6
    1
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    68 / 482 (14.11%)
    56 / 482 (11.62%)
         occurrences all number
    78
    66
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    25 / 482 (5.19%)
    15 / 482 (3.11%)
         occurrences all number
    26
    16
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    5 / 482 (1.04%)
    3 / 482 (0.62%)
         occurrences all number
    5
    3
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    157 / 482 (32.57%)
    148 / 482 (30.71%)
         occurrences all number
    220
    236
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    279 / 482 (57.88%)
    262 / 482 (54.36%)
         occurrences all number
    660
    598
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    9 / 482 (1.87%)
    13 / 482 (2.70%)
         occurrences all number
    9
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jan 2018
    Protocol update to v2.0 - Introduced a new exclusion criterion to prevent enrolment of patients with rare hereditary lactose-related disorders, add formal trial identifiers, and implement two additional fatigue questionnaires across all sites. It also establish three optional sub-studies (MRI, biomarker, and OCT), permit recruitment of healthy blood donors for the biomarker sub-study, and update procedures for obtaining consent and reporting serious events, including pregnancy notifications by male participants. Additional changes include switching from ABILHAND-56 to ABILHAND-23, updating oversight committee terminology, adding glossary terms, and making minor edits and formatting improvements throughout the protocol.
    02 Aug 2018
    Protocol update to v3.0 - Introduced updated branding and GDPR references, simplified and clarified inclusion criteria, and made broad refinements across governance, secondary outcomes, participant timelines, assessments, and operational procedures. It clarified eligibility, data collection processes, safety reporting, handling of intervention adherence, and follow-up procedures. Extensive updates were also made to the MRI, biomarker, and OCT sub-studies, including added eligibility criteria, clarified outcomes, and the addition of a new ABILHAND-23 sub-study.
    22 Jul 2019
    Protocol update to v4.0 - Updated exclusion criteria to include elbasvir, grazoprevir, recent cladribine, and to specify dimethyl fumarate, and corrected the primary outcome to reflect change in EDSS from baseline. Terminology was standardised, and laboratory-related sections were revised to add information on myopathy and clarify dose-modification strategies. Further updates refined contraindicated medications, the definition of trial end, and guidance for SLCVA testing and participant timelines, including limiting the FAB to a sub-study at UCLH and revising safety blood requirements. Safety reporting procedures were clarified, including updates to AE/SAE criteria and use of CTCAE V5, and adjustments were made to responsibilities for assessing expectedness. Additional changes included updating site maps, correcting references, expanding biomarker storage plans, refining OCT sub-study assessments, and adding a new FAB sub-study appendix.
    23 Mar 2020
    Protocol update to v5.0 - Clarified the schedule for safety blood testing, specifying that assessments would occur at Month 1 (40 mg tolerance), Month 3 (80 mg tolerance), and then at least annually from Month 6 to Month 36. It stated that patients unable to attend the Month 3 high-dose assessment should be de-escalated to 40 mg and re-challenged later if clinically appropriate. Once stable on the 80 mg dose, annual testing was considered sufficient unless clinical need required more frequent monitoring. It also established that no additional IMP would be dispensed if more than 12 months had passed since the last safety blood evaluation.
    11 Aug 2020
    Protocol update to v6.0 - Clarified the minimum required interval since an MS relapse for eligibility and added Ticagrelor and Daptomycin as exclusion and contraindicated medications, with related updates to laboratory abnormality guidance and dose re-challenge procedures. It allowed, in exceptional circumstances such as COVID-19, the combining of screening and baseline visits and permitted the Month 1 visit to be conducted remotely. Guidance on loss to follow-up was expanded to include categories of participation, and the map of expected MS-STAT2 sites was updated.
    17 Feb 2021
    Protcol update to v7.0 - updated the structured summary, trial team details, abbreviations, glossary and trial diagrams to reflect new protocol processes and definitions. It redefined the trial aim to assess whether disability progression could be slowed over the treatment period (rather than 3 years as previously), and revised the primary and secondary objectives and outcomes to include the additional trial visits, including clarification of EDSS comparisons and a shift to analysing the proportion of progression events. The design was amended to allow 1–3 additional six-monthly visits after Month 36 for patients without a confirmed progression event, with accompanying updates to the treatment schedule, participant timeline and processes for determining whether additional visits were required. Sample size calculations were revised, reducing the target sample due to recruitment impacts, and statistical methods were updated, including a new censor point for the primary outcome and changes to secondary outcome modelling. Finally, the analysis population description was updated to confirm that adherence would be assessed until each patient’s final visit.
    26 Feb 2024
    Protocol update to v8.0 - Updated the structured summary, staffing information, and background section to incorporate current prevalence data, cost estimates, limited UK use of Siponimod, and recent research on statin mechanisms. It removed the option for a 3–6-month confirmatory visit after an initial progression at Visit 10 so that all visits were treated consistently, as this had been updated within the previous amendment with the addition of vists 11-13, with corresponding wording removed across relevant sections. Additional detail was provided for secondary objectives, statistical subgroup analyses related to COVID-19, and outcome analysis methods, including corrections to terminology and clarification of health economic analyses. Expectations for in-person assessments at Baseline and Visit 10 were clarified, Figure 2 was updated to reflect final site selection, and the MRI sub-study was revised to include QSM and MTV advanced imaging techniques.

    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/39284697
    http://www.ncbi.nlm.nih.gov/pubmed/41045938
    http://www.ncbi.nlm.nih.gov/pubmed/35945550
    http://www.ncbi.nlm.nih.gov/pubmed/40631687
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    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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