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    Clinical Trial Results:
    A randomised placebo-controlled study of the safety and tolerability of a retinoid-X receptor agonist's ability to promote remyelination in people with relapsing-remitting multiple sclerosis already on interferon-beta therapy: a phase 2a trial

    Summary
    EudraCT number
    		 2014-003145-99
    Trial protocol
    		 GB  
    Global end of trial date
    17 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2021
    First version publication date
    01 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCMROne
    Additional study identifiers
    ISRCTN number
    		 ISRCTN14265371
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust & University of Cambridge
    Sponsor organisation address
    Hills Road, Cambridge, United Kingdom,
    Public contact
    Clinical Trials Regulatory Manager, Cambridge Clinical Trials Unit, +44 1223 348158, cctu@addenbrookes.nhs.uk
    Scientific contact
    Clinical Trials Regulatory Manager, Cambridge Clinical Trials Unit, +44 1223 348158, cctu@addenbrookes.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to establish the safety and tolerability of bexarotene in the treatment of relapsing remitting multiple sclerosis.
    Protection of trial subjects
    Adverse events were captured at every visit, and all adverse events were recorded on the case report form and reported in accordance with the trial protocol. Any serious adverse events were reviewed in a blinded fashion by the trial steering committee, which included the chief investigator, principal investigator from each site, statistician, Professor Robin Franklin (scientific advisor) or deputy, a thyroid advisor, a lipid advisor, and representatives from the funder and Sponsor. Weekly (for the first month) then monthly fasting full blood count (FBC), thyroid function tests, liver function tests and lipid profile were performed and assessed by a clinician.
    Background therapy
    		 None
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 56
    Worldwide total number of subjects
    56
    EEA total number of subjects
    56
    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)
    56
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All participants were recruited from the UK.

    Pre-assignment
    Screening details
    		 Potential participants were identified from multiple sclerosis clinics at the participating sites. Potential participants were also referred from other specialist centres. Full inclusion/exclusion criteria are outlined in the trial protocol.

    Pre-assignment period milestones
    Number of subjects started
    		 56
    Number of subjects completed
    		 52

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Excluded: Insufficient T2 lesions at MRI: 2
    Reason: Number of subjects
    		 Excluded: EDSS > 6.0: 2
    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, Data analyst, Assessor
    Blinding implementation details
    A web-based randomisation system was used for randomisation and assigned a sequential patient number and a corresponding 'patient pack' number, used to select treatment to be dispensed (bexarotene or placebo), which was visually indistinguishable at the point of issue to the patient. MRI scans were labelled with two unique and random numbers (no patient identifiable information) to ensure the investigator analysing the scan remained blinded to treatment group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bexarotene (active)
    Arm description
    		 Bexarotene 300mg/m2 daily as a single dose with the evening meal, reduced, if poorly tolerated, to a minimum of 100mg/m2/day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bexarotene
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The standard dose of bexarotene was initially 300mg/m2 orally daily as a single dose with a meal, which may subsequently be titrated down to a minimum of 100 mg/m2 depending on tolerability. The dose would be rounded down to the nearest available number of whole capsules. The dose was capped at a maximum of 10 capsules daily and body surface area calculated using the DuBois method.

    Arm title
    		 Placebo
    Arm description
    		 Placebo capsules to match active IMP
    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 capsules to match active IMP

    Number of subjects in period 1 [1]
    		Bexarotene (active) Placebo
    Started
    26
    26
    Completed
    25
    24
    Not completed
    1
    2
         Consent withdrawn by subject
    1
    -
         Did not tolerate MRI (did not receive placebo)
    -
    1
         Acute relapse (did not receive placebo)
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline period only includes participants who were randomised to receive treatment. 4 participants who had consented were excluded prior to randomisation.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bexarotene (active)
    Reporting group description
    		 Bexarotene 300mg/m2 daily as a single dose with the evening meal, reduced, if poorly tolerated, to a minimum of 100mg/m2/day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo capsules to match active IMP

    Reporting group values
    		 Bexarotene (active) Placebo Total
    Number of subjects
    		 26 26 52
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 26 26 52
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 15 15 30
        Male
    		 11 11 22
    Subject analysis sets

    Subject analysis set title
    Primary efficacy endpoint
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with follow-up data (as the metrics are change metrics so could not include those who declined follow-up)

    Subject analysis set title
    Pre-defined exploratory endpoint
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with follow-up data (as the metrics are change metrics so could not include those who declined follow-up).

    Subject analysis sets values
    		 Primary efficacy endpoint Pre-defined exploratory endpoint
    Number of subjects
    49
    49
    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)
    49
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Bexarotene (active)
    Reporting group description
    		 Bexarotene 300mg/m2 daily as a single dose with the evening meal, reduced, if poorly tolerated, to a minimum of 100mg/m2/day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo capsules to match active IMP

    Subject analysis set title
    Primary efficacy endpoint
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with follow-up data (as the metrics are change metrics so could not include those who declined follow-up)

    Subject analysis set title
    Pre-defined exploratory endpoint
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with follow-up data (as the metrics are change metrics so could not include those who declined follow-up).

    Primary: Difference in mean within-patient change in lesional MTR in those lesions falling below the within-patient median (“submedian lesions”)

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    End point title
    		 Difference in mean within-patient change in lesional MTR in those lesions falling below the within-patient median (“submedian lesions”)
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Analysed by patient.
    End point type
    Primary
    End point timeframe
    6 month trial period (change between baseline (month 0) and month 6 scans)
    End point values
    		 Bexarotene (active) Placebo Primary efficacy endpoint
    Number of subjects analysed
    25
    24
    49
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.25 (-0.13 to 0.63)
    0.09 (-0.25 to 0.43)
    0.16 (-0.39 to 0.71)
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by patient.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.554 [2]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [1] - The patient-level change in mean lesional MTR between baseline and month 6 for those lesions whose MTR was below the within-patient median at baseline
    [2] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of submedian lesions (defined by cohort-level median)

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    End point title
    		 The change in mean MTR of submedian lesions (defined by cohort-level median)
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 923, Placebo = 662, Overall subject analysis set = 1585.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [3]
    24 [4]
    49 [5]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.35 (0.22 to 0.48)
    -0.07 (-0.20 to 0.06)
    0.30 (-0.18 to 0.78)
    Notes
    [3] - Number of lesions in group = 923
    [4] - Number of lesions in group = 662
    [5] - Number of lesions in group = 1585
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene = 923, Placebo = 662, Subject Analysis Set = 1585.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.223 [6]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [6] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of supramedian lesions (defined by cohort-level median)

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    End point title
    		 The change in mean MTR of supramedian lesions (defined by cohort-level median)
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 1023, Placebo = 562, Overall subject analysis set = 1585.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [7]
    24 [8]
    49 [9]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    -0.31 (-0.42 to -0.20)
    -0.18 (-0.30 to -0.06)
    -0.04 (-0.52 to 0.43)
    Notes
    [7] - Lesion numbers = 1023
    [8] - Lesion numbers = 562
    [9] - Lesion numbers = 1585
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.854 [10]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [10] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of periventricular lesions

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    End point title
    		 The change in mean MTR of periventricular lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 205, Placebo = 151, Overall subject analysis set = 356.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [11]
    24 [12]
    49 [13]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    -0.31 (-0.54 to -0.08)
    -0.18 (-0.39 to 0.03)
    -0.02 (-0.58 to 0.55)
    Notes
    [11] - Number of lesions in group = 205
    [12] - Number of lesions in group = 151
    [13] - Number of lesions in group = 356
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.953 [14]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [14] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of deep white matter lesions

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    End point title
    		 The change in mean MTR of deep white matter lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 593, Placebo = 356, Overall subject analysis set = 949.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [15]
    24 [16]
    49 [17]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    -0.03 (-0.17 to 0.11)
    0.01 (-0.13 to 0.15)
    -0.06 (-0.56 to 0.44)
    Notes
    [15] - Number of lesions in group = 593
    [16] - Number of lesions in group = 356
    [17] - Number of lesions in group = 949
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.81 [18]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [18] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of juxtacortical lesions

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    End point title
    		 The change in mean MTR of juxtacortical lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 82, Placebo = 53, Overall subject analysis set = 135.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [19]
    24 [20]
    49 [21]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.09 (-0.28 to 0.46)
    -0.16 (-0.74 to 0.42)
    0.29 (-0.44 to 1.01)
    Notes
    [19] - Number of lesions in group = 82
    [20] - Number of lesions in group = 53
    [21] - Number of lesions in group = 135
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.441 [22]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [22] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of leucocortical lesions

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    End point title
    		 The change in mean MTR of leucocortical lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 649, Placebo = 389, Overall subject analysis set = 1038.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [23]
    24 [24]
    49 [25]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.00 (-0.16 to 0.16)
    -0.02 (-0.18 to 0.14)
    -0.04 (-0.54 to 0.46)
    Notes
    [23] - Number of lesions in group = 649
    [24] - Number of lesions in group = 389
    [25] - Number of lesions in group = 1038
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.864 [26]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [26] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of cortical grey matter lesions

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    End point title
    		 The change in mean MTR of cortical grey matter lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 47, Placebo = 43, Overall subject analysis set = 90.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [27]
    24 [28]
    49 [29]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.68 (-0.05 to 1.41)
    -0.35 (-1.26 to 0.56)
    0.93 (0.12 to 1.75)
    Notes
    [27] - Number of lesions in group = 47
    [28] - Number of lesions in group = 43
    [29] - Number of lesions in group = 90
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.03 [30]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [30] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of deep grey matter lesions

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    End point title
    		 The change in mean MTR of deep grey matter lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 7, Placebo = 9, Overall subject analysis set = 16.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [31]
    24 [32]
    49 [33]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.49 (-1.59 to 2.57)
    -1.41 (-2.23 to -0.59)
    1.93 (0.28 to 3.59)
    Notes
    [31] - Number of lesions in group = 7
    [32] - Number of lesions in group = 9
    [33] - Number of lesions in group = 16
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.027 [34]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [34] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of mixed deep grey matter and white matter lesions

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    End point title
    		 The change in mean MTR of mixed deep grey matter and white matter lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 217, Placebo = 158, Overall subject analysis set = 375.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [35]
    24 [36]
    49 [37]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.10 (-0.14 to 0.34)
    -0.24 (-0.46 to -0.02)
    0.41 (-0.15 to 0.97)
    Notes
    [35] - Number of lesions in group = 217
    [36] - Number of lesions in group = 158
    [37] - Number of lesions in group = 375
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.16 [38]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [38] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of brainstem lesions

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    End point title
    		 The change in mean MTR of brainstem lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 64, Placebo = 24, Overall subject analysis set = 88.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [39]
    24 [40]
    49 [41]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.24 (-0.40 to 0.88)
    -1.21 (-1.85 to -0.57)
    1.75 (0.86 to 2.63)
    Notes
    [39] - Number of lesions in group = 64
    [40] - Number of lesions in group = 24
    [41] - Number of lesions in group = 88
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0003 [42]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [42] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in mean MTR of cerebellar lesions

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    End point title
    		 The change in mean MTR of cerebellar lesions
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by lesion using a nested model with patient random intercepts. Lesion numbers: Bexarotene (active) = 82, Placebo = 41, Overall subject analysis set = 123.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [43]
    24 [44]
    49 [45]
    Units: percentage units
        arithmetic mean (confidence interval 95%)
    0.04 (-0.45 to 0.53)
    -0.31 (-0.78 to 0.16)
    -0.03 (-0.79 to 0.74)
    Notes
    [43] - Number of lesions in group = 82
    [44] - Number of lesions in group = 41
    [45] - Number of lesions in group = 123
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by lesion using a nested model with patient random intercepts.
    Comparison groups
    Placebo v Bexarotene (active)
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.947 [46]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [46] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in the P100 latency of the visual evoked potential for all eyes

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    End point title
    		 The change in the P100 latency of the visual evoked potential for all eyes
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by eye using a nested model with patient random intercepts. Eye numbers: Bexarotene (active) = 42, Placebo = 44, Overall subject analysis set = 86.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [47]
    24 [48]
    49 [49]
    Units: ms
        arithmetic mean (confidence interval 95%)
    -2.00 (-3.88 to -0.12)
    0.70 (-0.69 to 2.09)
    -2.85 (-5.75 to 0.05)
    Notes
    [47] - Number of eyes in group = 42
    [48] - Number of eyes in group = 44
    [49] - Number of eyes in group = 86
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by eye using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.054 [50]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [50] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in the P100 latency of the visual evoked potential for eyes with baseline latency >118ms

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    End point title
    		 The change in the P100 latency of the visual evoked potential for eyes with baseline latency >118ms
    End point description
    Adjusted bexarotene-placebo difference (95% CI)
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6). Data was analysed by eye using a nested model with patient random intercepts. Eye numbers: Bexarotene (active) = 29, Placebo = 22, Overall subject analysis set = 51.
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [51]
    24 [52]
    49 [53]
    Units: ms
        arithmetic mean (confidence interval 95%)
    -3.46 (-5.93 to -0.99)
    0.40 (-1.30 to 2.10)
    -4.06 (-7.68 to -0.44)
    Notes
    [51] - Number of eyes in group = 29
    [52] - Number of eyes in group = 22
    [53] - Number of eyes in group = 51
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by eye using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.028 [54]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [54] - Statistical significance refers to p<0·05.

    Other pre-specified: The change in the P100 latency of the visual evoked potential for eyes with baseline latency >118ms and no history of optic neuritis in previous 5 years

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    End point title
    		 The change in the P100 latency of the visual evoked potential for eyes with baseline latency >118ms and no history of optic neuritis in previous 5 years
    End point description
    Adjusted bexarotene-placebo difference (95% CI). Data was analysed by eye using a nested model with patient random intercepts. Eye numbers: Bexarotene (active) = 26, Placebo = 17, Overall subject analysis set = 43.
    End point type
    Other pre-specified
    End point timeframe
    6 months (baseline (month 0) to month 6)
    End point values
    		 Bexarotene (active) Placebo Pre-defined exploratory endpoint
    Number of subjects analysed
    25 [55]
    24 [56]
    49 [57]
    Units: ms
        arithmetic mean (confidence interval 95%)
    -3.87 (-6.55 to -1.19)
    0.08 (-1.88 to 2.04)
    -4.75 (-8.80 to -0.71)
    Notes
    [55] - Number of eyes in group = 26
    [56] - Number of eyes in group = 17
    [57] - Number of eyes in group = 43
    Statistical analysis title
    		 Other pre-specified analysis
    Statistical analysis description
    Treatment effect was estimated using multiple regression of the outcome measure on a group indicator with the following prespecified trial covariates: the baseline value of the outcome measure and the four binary minimisation factors: age (≤ 40 /> 40 years), gender, trial centre/scanner (London/Edinburgh) and EDSS (≤ 4·0/> 4·0 score). Data was analysed by eye using a nested model with patient random intercepts.
    Comparison groups
    Bexarotene (active) v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.032 [58]
    Method
    		 Multiple regression
    Confidence interval
    Notes
    [58] - Statistical significance refers to p<0·05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the point of informed consent (screening) to end of trial participation (month 9)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Bexarotene (active)
    Reporting group description
    		 Bexarotene 300mg/m2 daily as a single dose with the evening meal, reduced, if poorly tolerated, to a minimum of 100mg/m2/day

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo capsules to match active IMP

    Serious adverse events
    		 Bexarotene (active) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 24 (4.17%)
         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
    		 Bexarotene (active) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 26 (100.00%)
    17 / 24 (70.83%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 26 (23.08%)
    4 / 24 (16.67%)
         occurrences all number
    6
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Shortness of breath
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Sore throat
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Low mood
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Transaminitis
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Weight loss
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 26 (53.85%)
    8 / 24 (33.33%)
         occurrences all number
    14
    8
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Multiple sclerosis pseudo relapse
         subjects affected / exposed
    1 / 26 (3.85%)
    4 / 24 (16.67%)
         occurrences all number
    1
    4
    Lhermitte's sign
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Cerebellar infarction
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Neuropathic pain
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Muscle spasticity aggravated
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Memory disturbance
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    10 / 26 (38.46%)
    0 / 24 (0.00%)
         occurrences all number
    10
    0
    Lymphopenia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Eye disorders
    Dry eyes
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dry lips
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Ulceration of mouth
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    5 / 26 (19.23%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Diarrhoea
         subjects affected / exposed
    4 / 26 (15.38%)
    4 / 24 (16.67%)
         occurrences all number
    4
    4
    Constipation
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Epigastric pain
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    13 / 26 (50.00%)
    1 / 24 (4.17%)
         occurrences all number
    13
    1
    Pruritis
         subjects affected / exposed
    7 / 26 (26.92%)
    0 / 24 (0.00%)
         occurrences all number
    7
    0
    Skin desquamation
         subjects affected / exposed
    5 / 26 (19.23%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Dry skin
         subjects affected / exposed
    4 / 26 (15.38%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Acne
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Facial flushing
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Urinary frequency
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Stiffness joints
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    URTI
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    LRTI
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    UTI
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Shingles
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Coryzal symptoms
         subjects affected / exposed
    3 / 26 (11.54%)
    4 / 24 (16.67%)
         occurrences all number
    3
    4
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    24 / 26 (92.31%)
    0 / 24 (0.00%)
         occurrences all number
    24
    0
    Secondary hypothyroidism
         subjects affected / exposed
    26 / 26 (100.00%)
    0 / 24 (0.00%)
         occurrences all number
    26
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 May 2016
    1. The changes outlined to study title, eligibility criteria, study procedures (including MRI) and safety information have been carried out to reflect: a. Lack of scientific justification to exclude participants on other MS first-line (ABN category 1) disease-modifying therapies b. Renewed UK guidance for alcohol intake in adults c. Revised SmPC for Bexarotene d. MTR outcome measure is now possible to standardise between sites e. Local nursing practices 2. Owing to a period of temporary closure at the Royal Free Pharmacy Manufacturing Unit, manufacture (i.e. over-encapsulation of Bexarotene and production of matched-placebo) may require outsourcing and the protocol has been amended to reflect this. The Royal Free Pharmacy Manufacturing Unit will, however, remain responsible for QP batch certification of the finished product. 3. To reduce the number of study visits for participants (and thus burden of the research) by revising recruitment procedures to invite participants to attend their screening visit in a fasted state for purpose of blood sample collection. 4. Typographical errors in the protocol have been rectified.
    22 May 2017
    Changes to the patient eligibility criteria, following further advice from the Trial Management Group: 1. Patient age requirement now 18-50 (previously 30-50). 2. Kurtzke EDSS requirement now 0.0-6.0 (previously 3.0-6.0). 3. Removed previous requirement of ‘at least one relapse in the two years prior to screening’. 4. Changed definition of RSI in Section 11.1.6.
    17 Jan 2018
    1. Changes to the patient eligibility criteria, following the first meeting of the Trial Steering Committee. 2. To specify that the review of a patient’s screening visit results, and the subsequent documentation of the patient’s eligibility to enter the trial, can be performed by ‘an Investigator’, rather than only the ‘Chief or Principal Investigator’. 3. To specify that the blood samples for measuring peripheral immune markers will only be taken at the Cambridge site, not at the Edinburgh participating site. 4. To introduce an EDSS assessment at the Month 9 trial visit (Visit 11). 5. Definition of ‘weekly’ and ‘monthly’ in trial visit scheduling. 6. Minor text changes to cover: frequency of TSC meetings; frequency of meetings between Chief Investigator and trial Lipid Advisor; storage freezer temperature settings; correction of typographical errors.

    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
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