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    Clinical Trial Results:
    Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome or early multiple sclerosis and healthy control participants. An exploratory randomised double blind placebo controlled study

    Summary
    EudraCT number
    		 2012-000635-68
    Trial protocol
    		 IE  
    Global end of trial date
    09 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2018
    First version publication date
    04 Dec 2018
    Other versions
    Summary report(s)
    		 Effects of vitamin D3 in clinically isolated syndrome and healthy control participants: A double-blind randomised controlled trial
    Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2012CIS/VD/SVUH
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01728922
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College Dublin
    Sponsor organisation address
    Belfield, Dublin, Ireland,
    Public contact
    Neurology Department, St Vincent's University Hospital, 00353 12214179, n.neuadcc@st-vincents.ie
    Scientific contact
    Neurology Department, St Vincent's University Hospital, 00353 12214179, n.neuadcc@st-vincents.ie
    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
    05 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effects of vitamin D supplementation at two doses a) 4,667 IU daily b) 9,333 IU daily compared to c) placebo over a four and six-month period on the frequency of CD4 T cell subsets and cytokine responses by PBMC in 1) patients with the clinically isolated syndrome or early MS not treated with disease modifying therapies 2) healthy control participants
    Protection of trial subjects
    All patients provided written informed consent to participate in the study prior to being screened. Patients were free to withdraw from the study at any time without giving a reason. Patients were advised that if they requested to withdraw from the study, at any time during the trial, then this would have no negative consequences. The investigator could also withdraw patients from the trial if they deemed it appropriate for safety or ethical reasons or if it was considered to be to be detrimental to the well-being of the patient. Safety monitoring: Blood biochemistry including LFTs, U&E and serum calcium were measured at all study visits. In addition serum parathyroid hormone was assessed at screening. Serum or urine pregnancy testing in women of child-bearing potential was performed at screening and baseline visits.
    Background therapy
    		 -
    Evidence for comparator
    		 There is thus accumulating evidence that vitamin D deficiency increases susceptibility to MS and that vitamin D supplementation reduces disease activity by immunomodulatory mechanisms. It seems probable that serum vitamin D levels of greater than 100nmol/L are required to produce the immunological effects of vitamin D. Recent studies have suggested that despite supplementation it is difficult to achieve adequate levels of vitamin D in people with MS and showed different responses to supplementation raising the possibility of a different vitamin D pharmacokinetics in people with MS compared to controls. Thus, in MS patients with vitamin D deficiency, doses of 5000 to 10,000 IU/day are likely to be needed to achieve the desired immunological response. Most patients with RRMS, once diagnosed, commence treatment with first line disease modifying therapies (DMTs). Several RCTs are underway examining the effects vitamin D supplementation in RRMS patients already receiving first-line DMTs on clinical and MRI outcomes. In the UK and Ireland patients with the clinically isolated syndrome (CIS) are not usually commenced on DMTs until there is clinical or MRI evidence of dissemination in time. One may recruit these CIS patients, at risk of developing RRMS, into trials of potentially therapeutic agents in order to examine the efficacy of a therapy in preventing the development of clinically definite multiple sclerosis. We have therefore designed this RCT in order to examine, over a 24-week treatment period, in CIS patients and healthy control participants, randomized to either of two doses of vitamin D (5000 or 10,000 IU) or placebo, the effects on immunological measures as a primary outcome. In addition, in the CIS patients clinical and MRI efficacy measures will be secondary outcomes.
    Actual start date of recruitment
    02 Apr 2012
    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
    Ireland: 67
    Worldwide total number of subjects
    67
    EEA total number of subjects
    67
    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)
    67
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were screened against inclusion and exclusion criteria following discussion of the trial and provision of signed, fully informed consent.

    Pre-assignment
    Screening details
    		 39 healthy participants and 32 participants with clinical isolated syndrome were randomised into three trial arms each: placebo, 5,000 IU vitamin D and 10,000 IU vitamin D.

    Period 1
    Period 1 title
    Baseline Visit
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Patients, healthy control participants, and study staff, with the exception of the hospital pharmacist and internal monitor were blinded until the study database was locked at the end of the trial. The IMP and the placebo were identical in appearance, as was the labeling and packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Healthy control - placebo
    Arm description
    		 Healthy participants randomised to be receiving placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One placebo dose daily

    Arm title
    		 CIS - placebo
    Arm description
    		 Participants with clinical isolated syndrome randomised to be receiving placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One placebo dose daily

    Arm title
    		 Healthy control - 5,000 IU vitamin D
    Arm description
    		 Healthy participants randomised to be receiving 5,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Arm title
    		 CIS - 5,000 IU vitamin D
    Arm description
    		 Participants with clinical isolated syndrome randomised to be receiving 5,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Arm title
    		 Healthy control - 10,000 IU vitamin D
    Arm description
    		 Healthy participants randomised to be receiving 10,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Arm title
    		 CIS - 10,000 IU vitamin D
    Arm description
    		 Participants with clinical isolated syndrome randomised to be receiving 10,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Number of subjects in period 1
    		Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Started
    12
    7
    13
    10
    13
    12
    Completed
    11
    7
    13
    10
    13
    12
    Not completed
    1
    0
    0
    0
    0
    0
         Consent withdrawn by subject
    1
    -
    -
    -
    -
    -
    Period 2
    Period 2 title
    Study Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Patients, healthy control participants, and study staff, with the exception of the hospital pharmacist and internal monitor were blinded until the study database was locked at the end of the trial. The IMP and the placebo were identical in appearance, as was the labeling and packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Healthy control - placebo
    Arm description
    		 Healthy participants receiving placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One placebo dose daily

    Arm title
    		 CIS - placebo
    Arm description
    		 Participants with clinical isolated syndrome receiving placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One placebo dose daily

    Arm title
    		 Healthy control - 5,000 IU vitamin D
    Arm description
    		 Healthy participants receiving 5,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Arm title
    		 CIS - 5,000 IU vitamin D
    Arm description
    		 Participants with clinical isolated syndrome receiving 5,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Arm title
    		 Healthy control - 10,000 IU vitamin D
    Arm description
    		 Healthy participants receiving 10,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Arm title
    		 CIS - 10,000 IU vitamin D
    Arm description
    		 Participants with clinical isolated syndrome receiving 10,000 IU vitamin D
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Vigantol, Cholecalciferol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Enteral use
    Dosage and administration details
    One 10,000 IU vitamin D3 dose daily

    Number of subjects in period 2
    		Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Started
    11
    7
    13
    10
    13
    12
    Completed
    11
    7
    13
    10
    11
    12
    Not completed
    0
    0
    0
    0
    2
    0
         Consent withdrawn by subject
    -
    -
    -
    -
    1
    -
         Protocol deviation
    -
    -
    -
    -
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Healthy control - placebo
    Reporting group description
    		 Healthy participants randomised to be receiving placebo

    Reporting group title
    CIS - placebo
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving placebo

    Reporting group title
    Healthy control - 5,000 IU vitamin D
    Reporting group description
    		 Healthy participants randomised to be receiving 5,000 IU vitamin D

    Reporting group title
    CIS - 5,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving 5,000 IU vitamin D

    Reporting group title
    Healthy control - 10,000 IU vitamin D
    Reporting group description
    		 Healthy participants randomised to be receiving 10,000 IU vitamin D

    Reporting group title
    CIS - 10,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving 10,000 IU vitamin D

    Reporting group values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D Total
    Number of subjects
    		 12 7 13 10 13 12 67
    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
    Units: years
        arithmetic mean (standard deviation)
    		 29.1 ( 4.7 ) 34.3 ( 10.6 ) 30.3 ( 3.7 ) 32.7 ( 4.6 ) 30.5 ( 5.1 ) 37.2 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 6 10 5 6 8 45
        Male
    		 2 1 3 5 7 4 22
    Ever smoked
    Has the study subject ever smoked?
    Units: Subjects
        Yes
    		 4 3 3 5 2 7 24
        No
    		 8 4 10 5 11 5 43
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.6 ( 4.3 ) 26.7 ( 4.2 ) 23.5 ( 3.3 ) 26.3 ( 3.4 ) 25.4 ( 3.2 ) 30.6 ( 5.6 ) -
    IFN-γ+ CD4+ proliferating T cells
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 4.9 (2.5 to 7.5) 4.7 (4.3 to 5.6) 8.5 (5 to 10.9) 5.8 (3.3 to 6.8) 9.3 (7 to 12.6) 7.3 (1.2 to 10.3) -
    Il-17+ CD4+ proliferating T-cells
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 0.8 (0.3 to 1.5) 0.3 (0.2 to 0.9) 1 (0.5 to 1.6) 1.1 (0.6 to 2.9) 0.6 (0.4 to 0.9) 0.8 (0.1 to 2) -
    IFN-γ from stimulated PBMCs
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    		 5852 (746 to 14895) 183 (60 to 420) 6954 (1671 to 10836) 514 (259 to 1618) 8735 (2307 to 22084) 341 (124 to 1230) -
    IL-17 from stimulated PBMCs
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    		 512 (80 to 1420) 1090 (621 to 1776) 169 (33 to 1006) 317 (208 to 989) 153 (72 to 1487) 1208 (595 to 1587) -
    IL-10 from stimulated PBMCs
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    		 1528 (407 to 7274) 1192 (562 to 1438) 1571 (321 to 3657) 1596 (618 to 2174) 3093 (466 to 6130) 1271 (361 to 1599) -
    Seasonally adjusted serum 25(OH)D concentrations
    Units: nnmol/L
        arithmetic mean (standard deviation)
    		 49.5 ( 17 ) 53.7 ( 15.8 ) 57.2 ( 20.7 ) 51.5 ( 16.9 ) 45.6 ( 8.8 ) 55.2 ( 16.8 ) -
    Plasma parathyroid hormone concentration
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 5.0 ( 2.0 ) 3.3 ( 1.0 ) 4.2 ( 1.1 ) 2.6 ( 0.6 ) 4.8 ( 1.9 ) 3.2 ( 1.7 ) -
    Serum calcium concentrations
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.3 ( 0.1 ) 2.4 ( 0.1 ) 2.3 ( 0.1 ) 2.4 ( 0.1 ) 2.3 ( 0.1 ) 2.4 ( 0.1 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Healthy control - placebo
    Reporting group description
    		 Healthy participants randomised to be receiving placebo

    Reporting group title
    CIS - placebo
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving placebo

    Reporting group title
    Healthy control - 5,000 IU vitamin D
    Reporting group description
    		 Healthy participants randomised to be receiving 5,000 IU vitamin D

    Reporting group title
    CIS - 5,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving 5,000 IU vitamin D

    Reporting group title
    Healthy control - 10,000 IU vitamin D
    Reporting group description
    		 Healthy participants randomised to be receiving 10,000 IU vitamin D

    Reporting group title
    CIS - 10,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving 10,000 IU vitamin D
    Reporting group title
    Healthy control - placebo
    Reporting group description
    		 Healthy participants receiving placebo

    Reporting group title
    CIS - placebo
    Reporting group description
    		 Participants with clinical isolated syndrome receiving placebo

    Reporting group title
    Healthy control - 5,000 IU vitamin D
    Reporting group description
    		 Healthy participants receiving 5,000 IU vitamin D

    Reporting group title
    CIS - 5,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome receiving 5,000 IU vitamin D

    Reporting group title
    Healthy control - 10,000 IU vitamin D
    Reporting group description
    		 Healthy participants receiving 10,000 IU vitamin D

    Reporting group title
    CIS - 10,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome receiving 10,000 IU vitamin D

    Primary: The Effects of Oral Vitamin D Compared to Placebo on the Percentage IFN-γ+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline.

    		 Close Top of page
    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on the Percentage IFN-γ+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline. [1]
    End point description
    This outcome measure will be assessed at 16 weeks and compared to baseline.
    End point type
    Primary
    End point timeframe
    assessed at 16 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    5.9 (1.4 to 12.6)
    7 (4.3 to 9)
    6.5 (3.1 to 11.5)
    4.9 (3.6 to 10.2)
    11.3 (3.3 to 13.1)
    7 (2.3 to 8.6)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on the Percentage IFN-γ+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline.

    		 Close Top of page
    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on the Percentage IFN-γ+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline. [2]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 24 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    6.2 (3.8 to 12.6)
    6 (1.1 to 7.3)
    8.2 (4.8 to 12.3)
    6.4 (4.7 to 8.6)
    8.9 (4.5 to 12.3)
    5.1 (2.5 to 7.6)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on the Percentage IL-17+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline.

    		 Close Top of page
    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on the Percentage IL-17+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline. [3]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 16 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    0.8 (0.3 to 1.9)
    0.6 (0.2 to 1.9)
    0.6 (0.3 to 0.9)
    1.4 (0.8 to 2.9)
    0.5 (0.3 to 1.2)
    1.3 (0.6 to 3.2)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on the Percentage IL-17+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline.

    		 Close Top of page
    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on the Percentage IL-17+ CD4+ Proliferating T-cells as a Fraction of Total T-cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline. [4]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 24 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    1.3 (0.4 to 2.8)
    0.8 (0 to 13)
    0.5 (0.3 to 1.7)
    1.7 (0.5 to 2.4)
    0.7 (0.5 to 1.6)
    0.7 (0.3 to 2.9)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on IFN-γ Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline.

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    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on IFN-γ Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline. [5]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 16 weeks
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    6129 (1179 to 16005)
    103 (0 to 842)
    2160 (1780 to 8896)
    1303 (414 to 1910)
    6918 (2664 to 20006)
    757 (191 to 1739)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on IFN-γ Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline.

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    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on IFN-γ Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline. [6]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 24 weeks
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    7620 (2969 to 17173)
    450 (13 to 810)
    8253 (3860 to 16915)
    698 (299 to 1957)
    8948 (2905 to 21193)
    484 (160 to 2161)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on IL-17 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline

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    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on IL-17 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline [7]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 16 weeks
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    90 (34 to 1795)
    1606 (762 to 3160)
    190 (77 to 1265)
    669 (183 to 1066)
    230 (51 to 1487)
    1098 (781 to 2303)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on IL-17 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline

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    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on IL-17 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline [8]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 24 weeks
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    473 (119 to 2081)
    1399 (665 to 1850)
    267 (152 to 1012)
    805 (211 to 2151)
    416 (149 to 1525)
    1676 (628 to 2078)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on IL-10 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline

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    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on IL-10 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 16 Weeks Compared to Baseline [9]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 16 weeks
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    1793 (153 to 2556)
    1213 (658 to 2176)
    958 (250 to 2356)
    1146 (667 to 1682)
    1201 (489 to 3365)
    1183 (84 to 2052)
    No statistical analyses for this end point

    Primary: The Effects of Oral Vitamin D Compared to Placebo on IL-10 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline.

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    End point title
    		 The Effects of Oral Vitamin D Compared to Placebo on IL-10 Concentrations in Peripheral Blood Mononuclear Cells in Patients With CIS and Healthy Control Participants (HCP) at 24 Weeks Compared to Baseline. [10]
    End point description
    End point type
    Primary
    End point timeframe
    Assessed at 24 weeks
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis performed was within-group baseline to endpoint testing. This type of analysis is statistically invalid in the context of randomised controlled trials and its input is not supported by EudraCT. Please refer to the results paper for review of the results of the statistical analysis.
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    13
    12
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    1452 (615 to 3838)
    881 (302 to 2528)
    1616 (416 to 2865)
    1001 (735 to 2003)
    3251 (1023 to 5908)
    1140 (140 to 1855)
    No statistical analyses for this end point

    Secondary: The Number of New T2 Lesions Compared to Baseline Among the Study Group.

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    End point title
    		 The Number of New T2 Lesions Compared to Baseline Among the Study Group.
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 24 weeks
    End point values
    		 CIS - placebo CIS - 5,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    7
    9
    10
    Units: lesions per participant
        arithmetic mean (standard deviation)
    0.6 ( 0.8 )
    1.4 ( 1.7 )
    0.4 ( 0.5 )
    No statistical analyses for this end point

    Secondary: The Number of New Gadolinium Enhancing Lesions Compared to Baseline Among the Study Group.

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    End point title
    		 The Number of New Gadolinium Enhancing Lesions Compared to Baseline Among the Study Group.
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 24 weeks
    End point values
    		 CIS - placebo CIS - 5,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    7
    9
    10
    Units: lesions per participant
        arithmetic mean (standard deviation)
    0.1 ( 0.4 )
    0.1 ( 0.3 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Number of Patients With New Disease Activity by MRI

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    End point title
    		 Number of Patients With New Disease Activity by MRI
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 24 weeks
    End point values
    		 CIS - placebo CIS - 5,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    7
    9
    10
    Units: participants
    3
    5
    5
    No statistical analyses for this end point

    Other pre-specified: Change in Seasonally-adjusted Serum 25(OH)D Levels at 16 Weeks

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    End point title
    		 Change in Seasonally-adjusted Serum 25(OH)D Levels at 16 Weeks
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Assessed at 16 weeks
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    11
    12
    Units: nmol/L
        arithmetic mean (standard deviation)
    4 ( 12 )
    7 ( 26 )
    83 ( 27 )
    81 ( 63 )
    152 ( 71 )
    121 ( 35 )
    Statistical analysis title
    		 Intergroup comparison at 16 weeks
    Statistical analysis description
    Comparison of 5,000 IU vitamin D arm and 10,000 IU vitamin D arm to placebo arm.
    Comparison groups
    Healthy control - placebo v Healthy control - 5,000 IU vitamin D v Healthy control - 10,000 IU vitamin D
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Intergroup comparison at 16 weeks
    Statistical analysis description
    Comparison of 5,000 IU vitamin D arm and 10,000 IU vitamin D arm to placebo arm.
    Comparison groups
    CIS - placebo v CIS - 5,000 IU vitamin D v CIS - 10,000 IU vitamin D
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Intergroup comparison at 16 weeks
    Statistical analysis description
    Comparison between 5,000 IU vitamin D arm and 10,000 IU vitamin D arm
    Comparison groups
    CIS - 5,000 IU vitamin D v CIS - 10,000 IU vitamin D
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 t-test, 2-sided
    Confidence interval

    Other pre-specified: Change in Seasonally-adjusted Serum 25(OH)D Levels at 24 Weeks

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    End point title
    		 Change in Seasonally-adjusted Serum 25(OH)D Levels at 24 Weeks
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Assessed at 24 weeks
    End point values
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Number of subjects analysed
    11
    7
    13
    10
    11
    12
    Units: nmol/L
        arithmetic mean (standard deviation)
    2 ( 14 )
    18 ( 34 )
    92 ( 35 )
    76 ( 57 )
    136 ( 71 )
    115 ( 51 )
    Statistical analysis title
    		 Intergroup comparison at 24 weeks
    Statistical analysis description
    Comparison of 5,000 IU vitamin D arm and 10,000 IU vitamin D arm to placebo arm.
    Comparison groups
    Healthy control - 10,000 IU vitamin D v Healthy control - 5,000 IU vitamin D v Healthy control - placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Intergroup comparison at 24 weeks
    Statistical analysis description
    Comparison between 5,000 IU vitamin D arm and 10,000 IU vitamin D arm
    Comparison groups
    Healthy control - 5,000 IU vitamin D v Healthy control - 10,000 IU vitamin D
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Intergroup comparison at 24 weeks
    Statistical analysis description
    Comparison of 5,000 IU vitamin D arm and 10,000 IU vitamin D arm to placebo arm.
    Comparison groups
    CIS - placebo v CIS - 5,000 IU vitamin D v CIS - 10,000 IU vitamin D
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Intergroup comparison at 24 weeks
    Statistical analysis description
    Comparison between 5,000 IU vitamin D arm and 10,000 IU vitamin D arm
    Comparison groups
    CIS - 5,000 IU vitamin D v CIS - 10,000 IU vitamin D
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed at each visit (9 visits) during the trial over the entire study period (30 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NA
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Healthy control - placebo
    Reporting group description
    		 Healthy participants randomised to be receiving placebo

    Reporting group title
    CIS - placebo
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving placebo

    Reporting group title
    Healthy control - 5,000 IU vitamin D
    Reporting group description
    		 Healthy participants randomised to be receiving 5,000 IU vitamin D

    Reporting group title
    CIS - 5,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving 5,000 IU vitamin D

    Reporting group title
    Healthy control - 10,000 IU vitamin D
    Reporting group description
    		 Healthy participants randomised to be receiving 10,000 IU vitamin D

    Reporting group title
    CIS - 10,000 IU vitamin D
    Reporting group description
    		 Participants with clinical isolated syndrome randomised to be receiving 10,000 IU vitamin D

    Serious adverse events
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Lumbar discectomy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Healthy control - placebo CIS - placebo Healthy control - 5,000 IU vitamin D CIS - 5,000 IU vitamin D Healthy control - 10,000 IU vitamin D CIS - 10,000 IU vitamin D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 13 (69.23%)
    8 / 9 (88.89%)
    6 / 13 (46.15%)
    8 / 11 (72.73%)
    10 / 13 (76.92%)
    10 / 12 (83.33%)
    Surgical and medical procedures
    Dental procedure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Banding haemorrhoids
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Temperature
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Weight loss
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Lightheadedness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
    3 / 11 (27.27%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    0
    3
    0
    1
    Shivering
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Missed oral contraceptive pill
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Immune system disorders
    Hay fever
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Vaginal thrush
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Delayed menstrual cycle
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    3 / 12 (25.00%)
         occurrences all number
    0
    1
    0
    0
    1
    3
    Depression
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Investigations
    Colonoscopy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 9 (33.33%)
    0 / 13 (0.00%)
    4 / 11 (36.36%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    1
    6
    0
    5
    1
    0
    Tingling/sensory symptoms
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    2 / 11 (18.18%)
    0 / 13 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    1
    0
    3
    0
    5
    Reduced visual acuity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Neuropathic pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Relapse
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Low iron
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Ear and labyrinth disorders
    Fullness of left ear
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye disorders
    Eye strain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Heartburn
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rectal bleeding
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sebaceous cyst
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Flushing
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    2 / 11 (18.18%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Elevated urea
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Knee injury
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscular pain
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 9 (22.22%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    2
    0
    1
    0
    4
    Bursitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
    2 / 11 (18.18%)
    5 / 13 (38.46%)
    4 / 12 (33.33%)
         occurrences all number
    4
    1
    1
    7
    5
    4
    Conjunctivitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Herpes simplex virus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 9 (11.11%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 9 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Athlete's foot
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Norovirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 9 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2014
    Inclusion/Exclusion criteria: Previous treatment with beta-interferons or glatiramer acetate or steroids in the last three months. Participants already taking supplemental vitamin D. In discussion with the study team we felt these changes will improve recruitment without impacting on the scientific integrity of the trial or the safety of the participants. The main reason for the change is that steroids are a mainstay of treatment of acute episodes (relapses) and a 3 month steroid washout was initially proposed to prevent any steroid hangover effect but on review this is too long and unnecessary. We also noted that a number of participants were taking very low doses of vitamin D having read about Clinically Isolated Syndrome on the internet or in multivitamin preparations. Given that there is no way of controlling for dietary vitamin D intake as a number of foods are now fortified it was felt that doses less than 1000IU per day would be noted but should not exclude participation in the trial. The changes are reflected below: Previous treatment with beta-interferons or glatiramer acetate in the last 3 months or steroids in the last 4 weeks. Participants already taking supplemental vitamin D at greater than 1000IU per day. We wish to clarify a typographical error with reference to the age range for controls. On both the synopsis and section 10.3.3 (version 8.0: 14/3/2012) screening procedures the age range is listed as 20-40 years, however under section 10.2.2 (version 8.0: 14/3/2012) inclusion criteria it is listed as 25-40 years. This has been corrected in the current protocol in all sections to read age range 20-40 years.
    28 Jul 2014
    Study assessments and procedures (Section 10.3): In the protocol (version 8.0: 14/3/2012) under section 10.3.1 Description of study assessments it states that height and weight will be measured at each visit. This has been amended that height (cm) and weight (kg) will only be assessed at the screening period. This is given the short duration of the study and the fact that there is no adjustment of dosing for weight, repeating this measure at each visit was felt to be unnecessary. In the text it says parathormone will be taken at screening, baseline, week 4, 8, 12, 16, 24 and end of study (week 28-30). This has been amended to show that parathormone will not be taken at week 12. Similarly vitamin D will not be measured at week 12. In the text to ensure uniformity where it refers to urea, electrolytes and creatinine this has been amended to U&E as this is the acronym used by the laboratory to incorporate all these measures and this has been added to the abbreviations section. This section has been re-ordered and rewritten to outline clearly what each study assessment involves (section 10.3.1), study end-point assessments (section 10.3.2) and what assessments are to be carried out at each visit (section 10.3.3) as there were some inconsistencies within the text and table 2: schedule of events it has also been updated. End of study visit was outlined in section 10.4 Definition of end of trial and this has now been moved to section 10.3.3.
    28 Jul 2014
    Discontinuation/Withdrawal of subjects from study treatment (Section 10.4): The current protocol (version 8.0: 14/3/2012) reads: Patients who discontinue the study will be requested to attend for all remaining study visits including end-point and end of study assessments. Patients who become pregnant will not have any endpoints assessed (MRI, Cliniical). The only exception to this requirement is when a subject withdraws consent for all study procedures. A modified visit schedule has been proposed for patients who discontinue the study drug. It is proposed that these patients attend an end of treatment visit within 2 weeks of stopping the medication and an end of study visit 4-6 weeks later. These patients will no longer require immunology or MRI scanning as part of the study protocol as these will be impossible to interpret in relation to the study objectives due to potential confounders (ie pregnancy, commencement of DMT’s).
    28 Jul 2014
    Serious adverse event (Section 12.1.3): Planned hospitalisation for an elective procedure unrelated to the study drug does not need to be reported as an SAE.

    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/28975037
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