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    Clinical Trial Results:
    Efficacy of Vitamin D Supplementation in relapsing-remitting Multiple Sclerosis

    Summary
    EudraCT number
    		 2011-002785-20
    Trial protocol
    		 DE  
    Global end of trial date
    26 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 May 2022
    First version publication date
    28 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EVIDIMS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité - University Hospital of Berlin
    Sponsor organisation address
    Lindenberger Weg 80, Berlin, Germany, 13125
    Public contact
    Herr PD Dr. med. Jan-Markus Dörr, Charité - Universitätsmedizin Berlin Campus Buch Experimental and Clinical Research Center (ECRC), 0049 30450660162, jan-markus.doerr@charite.de
    Scientific contact
    Herr Univ.-Prof. Dr. Friedemann Paul, Charité - Universitätsmedizin Berlin Campus Buch Experimental and Clinical Research Center (ECRC), 0049 30450639705, friedemann.paul@charite.de
    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
    26 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess efficacy of Vitamin D supplementation in relapsing-remitting Multiple Sclerosis
    Protection of trial subjects
    The study is approved by the local ethics committee and the German Competent Authority (Federal Institute for Drugs and Medical Devices) and is registered at both the European Union Drug Regulating Authorities . The study will be conducted in accordance to the Declaration of Helsinki in its currently applicable version, the guidelines of the International Conference on Harmonization of Good Clinical Practice (ICH-GCP), and the applicable German laws. All participants will be required to give informed written consent. The trial will be monitored according to ICH-GCP.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2011
    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
    Germany: 53
    Worldwide total number of subjects
    53
    EEA total number of subjects
    53
    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)
    53
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Nevertheless, unforeseen recruitment difficulties such as the contemporaneous approval of oral MS drugs and a highly comparative environment with a large number of recruiting clinical trials may explain why, despite a fairly long recruitment period of 45 months, only 53 patients were randomized.

    Pre-assignment
    Screening details
    		 53 Patients were screened for eligibility

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Substantial efforts are made to maintain blinding: Since high-dose formulation (oil) does not match the low-dose formulation (tablet), patients in the high-dose arm will take 400 IU tablets in addition to 20.000 IU oil, whereas patients in the lowdose arm will receive an identical volume of placebo-oil in addition to a 400 IU tablet.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VD-high-dose Group
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vigantol® Öl 20.000 I.E./ml COLECALCIFEROL
    Investigational medicinal product code
    SUB06794MIG
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    will receive 20.400 IU cholecalciferol orally every other day. Since high-dose formulation (oil) does not match the low-dose formulation (tablet), patients in the high-dose arm will take 400 IU tablets in addition to 20.000 IU oil

    Investigational medicinal product name
    Dekristol® 400-Tabletten COLECALCIFEROL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    patients in the high-dose arm will take 400 IU tablets in addition to 20.000 IU oil

    Arm title
    		 VD-low-dose Group+PBO
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    identical volume of placebo-oil in addition to a 400 IU tablet

    Investigational medicinal product name
    Dekristol® 400-Tabletten COLECALCIFEROL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    patients in the low-dose arm will take 400 IU tablets with placebo-oil

    Number of subjects in period 1
    		VD-high-dose Group VD-low-dose Group+PBO
    Started
    28
    25
    Completed
    21
    17
    Not completed
    7
    8
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    1
    -
         personal reasons
    1
    5
         Protocol deviation
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VD-high-dose Group
    Reporting group description
    		 -

    Reporting group title
    VD-low-dose Group+PBO
    Reporting group description
    		 -

    Reporting group values
    		 VD-high-dose Group VD-low-dose Group+PBO Total
    Number of subjects
    		 28 25 53
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41 ( 2.1 ) 45 ( 1.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 20 17 37
        Male
    		 8 8 16
    Disease course
    RRMS: relapsing remitting MS; CIS: clinically isolated syndrome
    Units: Subjects
        RRMS
    		 26 25 51
        CIS
    		 2 0 2
    disease duration onset to screening
    Units: months
        arithmetic mean (standard deviation)
    		 97 ( 14.4 ) 125 ( 16.8 ) -
    Mean BMI at screening
    BMI: body mass index;
    Units: Score
        arithmetic mean (standard deviation)
    		 27.2 ( 1.3 ) 25.5 ( 0.9 ) -
    Mean EDSS at screening
    EDSS: Expanded Disability Status Scale
    Units: Score
        arithmetic mean (full range (min-max))
    		 2.0 (0 to 5) 2.5 (0 to 6) -
    Mean 25OH vitamin D serum level
    Units: (ng/ml
        arithmetic mean (standard deviation)
    		 18.8 ( 1.9 ) 17.8 ( 1.7 ) -
    Mean T2w lesion count (n)
    Units: count
        arithmetic mean (standard deviation)
    		 52.6 ( 6.7 ) 76.1 ( 10.7 ) -
    Mean T2w lesion volume
    Units: ml
        arithmetic mean (standard deviation)
    		 4.6 ( 0.9 ) 10.4 ( 1.9 ) -
    Mean brain parenchymal fraction
    Units: ml
        arithmetic mean (standard deviation)
    		 1163.1 ( 25.8 ) 1121.3 ( 18.1 ) -
    Mean thalamus volume
    Units: ml
        arithmetic mean (standard deviation)
    		 15.5 ( 0.4 ) 14.4 ( 0.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    VD-high-dose Group
    Reporting group description
    		 -

    Reporting group title
    VD-low-dose Group+PBO
    Reporting group description
    		 -

    Primary: the number of new T2-weighted (T2w) hyperintense lesions

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    End point title
    		 the number of new T2-weighted (T2w) hyperintense lesions
    End point description
    End point type
    Primary
    End point timeframe
    after 18 months
    End point values
    		 VD-high-dose Group VD-low-dose Group+PBO
    Number of subjects analysed
    28
    25
    Units: Count
    arithmetic mean (standard error)
        Mean T2w lesion
    53.4 ( 7.3 )
    84.1 ( 13.5 )
        change from baseline
    1.3 ( 0.1 )
    2.1 ( 1.4 )
    Statistical analysis title
    		 T2w count after 18 months
    Comparison groups
    VD-high-dose Group v VD-low-dose Group+PBO
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 T2w change from baseline
    Comparison groups
    VD-high-dose Group v VD-low-dose Group+PBO
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 MANCOVA
    Confidence interval

    Secondary: T2w lesion volume after 18 months

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    End point title
    		 T2w lesion volume after 18 months
    End point description
    End point type
    Secondary
    End point timeframe
    after 18 months
    End point values
    		 VD-high-dose Group VD-low-dose Group+PBO
    Number of subjects analysed
    28
    25
    Units: ml
    arithmetic mean (standard error)
        T2w lesion
    4.6 ( 0.9 )
    10.4 ( 1.9 )
    Statistical analysis title
    		 T2w lesion volume after 18 months
    Comparison groups
    VD-high-dose Group v VD-low-dose Group+PBO
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 T2w lesion volume change from baseline
    Comparison groups
    VD-high-dose Group v VD-low-dose Group+PBO
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 MANCOVA
    Confidence interval

    Secondary: brain parenchymal fraction after 18 months

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    End point title
    		 brain parenchymal fraction after 18 months
    End point description
    End point type
    Secondary
    End point timeframe
    after 18 months
    End point values
    		 VD-high-dose Group VD-low-dose Group+PBO
    Number of subjects analysed
    28
    25
    Units: ml
    arithmetic mean (standard error)
        BPF
    1167.7 ( 25.9 )
    1126.6 ( 20.7 )
        change from baseline
    -9.3 ( 3.7 )
    -7.3 ( 2.6 )
    Statistical analysis title
    		 BPF after 18 months
    Comparison groups
    VD-low-dose Group+PBO v VD-high-dose Group
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 BPF change from baseline
    Comparison groups
    VD-high-dose Group v VD-low-dose Group+PBO
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 MANCOVA
    Confidence interval

    Secondary: brain volume after 18 months

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    End point title
    		 brain volume after 18 months
    End point description
    End point type
    Secondary
    End point timeframe
    after 18 months
    End point values
    		 VD-high-dose Group VD-low-dose Group+PBO
    Number of subjects analysed
    28
    25
    Units: percent
    arithmetic mean (standard error)
        brain volume changes (%)
    -0.61 ( 0.12 )
    -0.52 ( 0.1 )
    Statistical analysis title
    		 brain volume after 18 months
    Comparison groups
    VD-high-dose Group v VD-low-dose Group+PBO
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: thalamus volume after 18 months

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    End point title
    		 thalamus volume after 18 months
    End point description
    End point type
    Secondary
    End point timeframe
    after months
    End point values
    		 VD-high-dose Group VD-low-dose Group+PBO
    Number of subjects analysed
    28
    25
    Units: ml
    arithmetic mean (standard error)
        thalamus volume
    15.7 ( 0 )
    14.4 ( 0.5 )
        change from baseline
    0.41 ( 0.6 )
    0.41 ( 0.6 )
    No statistical analyses for this end point

    Secondary: cumulative number of new gdþ lesions

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    End point title
    		 cumulative number of new gdþ lesions
    End point description
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 VD-high-dose Group VD-low-dose Group+PBO
    Number of subjects analysed
    28
    25
    Units: cumulative number
        number gd+ lesions (V0–V6)
    2
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Own
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Total AE from both Arms
    Reporting group description
    		 -

    Serious adverse events
    		 Total AE from both Arms
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 53 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total AE from both Arms
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 53 (75.47%)
    Musculoskeletal and connective tissue disorders
    musculoskeletal complaints
         subjects affected / exposed
    15 / 53 (28.30%)
         occurrences all number
    15
    Infections and infestations
    respiratory infections
         subjects affected / exposed
    25 / 53 (47.17%)
         occurrences all number
    25

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2012
    update protocol Version 1.2 (09/01/2012), change in interpretation of scientific documents, addition of a new site
    25 Nov 2013
    Change of principal investigator at an exsting site, addition of a new site
    23 Dec 2013
    update protocol Version 1.3 (20/12/2013), changes in conduct of trial - due to changes in manufacturing of Viganto Öl I.E./ ml -we had to adjust the amount of drops to achieved the required dosage
    22 Jul 2015
    Recruitment stop

    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.
    Finally, the rather small sample size may well account for the lack of differences in both study arms during therapy with a drug that significantly reduces relapses and MRI activity.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32047645
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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