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    Clinical Trial Results:
    A Multicentre, Randomised, Double-blind, Placebo-controlled Study of the Efficacy of Supplementary Treatment With Cholecalciferol (Vitamin D3) in Patients With Relapsing- Multiple Sclerosis (RMS) Treated With Subcutaneous Interferon Beta-1a 44 mcg 3 Times Weekly

    Summary
    EudraCT number
    		 2009-013695-46
    Trial protocol
    		 FR  
    Global end of trial date
    12 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jan 2017
    First version publication date
    21 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    701068-524
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01198132
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    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
    30 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study the efficacy and safety of supplementary treatment with cholecalciferol (vitamin D3) in patients with relapsing multiple sclerosis (RMS) treated with subcutaneous interferon beta 1a 44 microgram (mcg) 3 times weekly.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 129
    Worldwide total number of subjects
    129
    EEA total number of subjects
    129
    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)
    129
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 129 subjects were randomized. Out of which 126 subjects treated in the study and 90 subjects completed the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cholecalciferol
    Arm description
    		 Subjects received Cholecalciferol 100,000 IU one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with subcutaneous Rebif 44 mcg 3 times a week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cholecalciferol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Cholecalciferol 100,000 IU one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with subcutaneous Rebif 44 mcg 3 times a week.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.

    Number of subjects in period 1
    		Cholecalciferol Placebo
    Started
    63
    66
    Completed
    45
    45
    Not completed
    18
    21
         Physician decision
    5
    4
         Consent withdrawn by subject
    4
    5
         Sign/symptoms of underlying disease
    2
    1
         Abnormal/clinically significant biologic
    1
    1
         Other Un-specified
    3
    6
         Adverse event, non-fatal
    -
    1
         Lack of efficacy
    2
    3
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cholecalciferol
    Reporting group description
    		 Subjects received Cholecalciferol 100,000 IU one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with subcutaneous Rebif 44 mcg 3 times a week.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.

    Reporting group values
    		 Cholecalciferol Placebo Total
    Number of subjects
    		 63 66 129
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.5 ( 9.29 ) 36.9 ( 8.34 ) -
    Gender, Male/Female
    Units: subjects
        Female
    		 50 39 89
        Male
    		 13 27 40

    End points

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    End points reporting groups
    Reporting group title
    Cholecalciferol
    Reporting group description
    		 Subjects received Cholecalciferol 100,000 IU one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with subcutaneous Rebif 44 mcg 3 times a week.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.

    Subject analysis set title
    All Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received Cholecalciferol (Vitamin D3) 100 000 International units (IU) [1 IU - 1 IU biological equivalent of 0.025 microgram (mcg) cholecalciferol] one dose every two week orally (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with sub-cutaneous injection of Rebif 44 mcg 3 times a week and subjects received matching placebo to Cholecalciferol once every two weeks orally along with sub-cutaneous injection of Rebif 44 mcg 3 times weekly.

    Primary: Reduction in Rate of Relapse

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    End point title
    		 Reduction in Rate of Relapse [1]
    End point description
    Relapse rate was expressed as rate ratio between the two groups. Relapse rate was calculated for each treatment group as follows: the number of relapses observed during the trial period divided by the number of subject years at risk. Intent-to-treat (ITT) set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    2 years post treatment (Investigational Medicinal product: IMP) administration
    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: Due to database constraint, a separate document has been attached presenting the statistical analysis for this endpoint.
    End point values
    		 All Subjects
    Number of subjects analysed
    129
    Units: ratio
        number (confidence interval 95%)
    0.8 (0.48 to 1.32)
    Attachments
    		 Untitled (Filename: Statistical Analysis 1.pdf)
    No statistical analyses for this end point

    Secondary: Time to First Documented Relapse

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    End point title
    		 Time to First Documented Relapse
    End point description
    Time to First Documented Relapse was calculated using Kaplan-Meier survival methods. ITT set included all randomized subjects. Here "Number of participant analyzed" signifies those subjects who were evaluable for this outcome measure. Here "99999" signifies Median and Confidence interval could not be calculated due to a limited number of events.
    End point type
    Secondary
    End point timeframe
    2 years post treatment (IMP) administration
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    61
    65
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (60.1 to 99999)
    No statistical analyses for this end point

    Secondary: Mean Number of Relapses per Subject

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    End point title
    		 Mean Number of Relapses per Subject
    End point description
    Relapse rate was calculated for each treatment group as follows: the number of relapses observed during the trial period divided by the number of subject years at risk. ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    2 years post treatment (IMP) administration
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    63
    66
    Units: relapses
        median (full range (min-max))
    0 (0 to 3)
    0 (0 to 3)
    No statistical analyses for this end point

    Secondary: Number of Relapse-Free (Documented) Subjects

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    End point title
    		 Number of Relapse-Free (Documented) Subjects
    End point description
    The relapse-free patients after 2 years of treatment was calculated using Cochran-Mantel-Haenszel test using the site as control variable. ITT set included all randomized subjects. Here "Number of subjects analysed" those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    2 years post treatment (IMP) administration
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    45
    46
    Units: subjects
        number (not applicable)
    35
    27
    No statistical analyses for this end point

    Secondary: Cumulative Probability of Progression of Disability

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    End point title
    		 Cumulative Probability of Progression of Disability
    End point description
    Disability progression was assessed using Expanded disability status scale (EDSS). EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A one-point increase on the EDSS scale was considered as a progression in disability. The time to disability progression was summarized using Kaplan-Meier survival methods. ITT set included all randomized subjects. Here "Number of subjects analysed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    2 years post treatment (IMP) administration
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    60
    65
    Units: cumulative probability
        number (not applicable)
    12.7
    9.1
    No statistical analyses for this end point

    Secondary: Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI)

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    End point title
    		 Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI)
    End point description
    ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    2 years post treatment (IMP) administration
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    44 [2]
    41 [3]
    Units: lesions
    arithmetic mean (standard deviation)
        T1-weighted MRI
    0.4 ( 0.76 )
    1.9 ( 3.76 )
        T2-weighted MRI
    0.5 ( 0.79 )
    2 ( 4.71 )
    Notes
    [2] - Here "N" signifies number of participant analysed for this endpoint.
    [3] - Here "N" signifies number of participant analysed for this endpoint.
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Measured Lesion Load (T2)

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    End point title
    		 Changes From Baseline in Measured Lesion Load (T2)
    End point description
    Baseline defined as last value recorded prior to first intake of study drug. ITT set included all randomized subjects. Here “n” signifies those subjects who were evaluable for this outcome measure at the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    63
    66
    Units: cubic millimeter (mm^3)
    arithmetic mean (standard deviation)
        Baseline (n=49, 43)
    5305.4 ( 10858.86 )
    3520.1 ( 4954.44 )
        Change at Week 96 (n=44, 38)
    -315 ( 2523.97 )
    596.3 ( 2034.8 )
    No statistical analyses for this end point

    Secondary: Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT)

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    End point title
    		 Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT)
    End point description
    The Adapted Paced Auditory Serial Addition Task (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. The score for PASAT is the total number of correct answers (out of 60, for a total possible score ranging from 0-60 with higher score preferred as it indicates higher auditory processing speed) for each trial. The PASAT test score was summarized per treatment group at each visit. The variations compared to the baseline values was calculated and summarized. The variations between the baseline values and the values after 2 years between the treatment groups was compared using analysis of covariance methods including the baseline value as covariate. ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    2 years post treatment (IMP) administration
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    63
    66
    Units: units on a scale
        arithmetic mean (standard deviation)
    49.1 ( 10.88 )
    49.9 ( 10.48 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L)

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    End point title
    		 Change from Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L)
    End point description
    The EQ-5D health questionnaire is a generic self-reported health-related quality of life instrument that includes a 100 mm Visual Analog Scale (VAS) to measure the general health state, as well as 5 items corresponding to one dimension each: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In this study, the VAS scale is not collected and the version 3L of the scale was used: Each dimension had 3 possible levels: 1 = no problem, 2 = some problems and 3 = extreme problems. EQ-5D-3L weighted health state index exists that combines the score of the 5 dimensions and ranges from 0 to 1 (full health). The variables for the 5 dimensions of the EQ-5D descriptive system was named 'mobility','selfcare', 'activity', 'pain', and 'anxiety'. The 5 variables contained the values for the different dimensions in the EQ-5D health profile (i.e. 1, 2, or 3). ITT set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    2 years post treatment (IMP) administration
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    63
    66
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=60, 63)
    0.7834 ( 0.2409 )
    0.7937 ( 0.21447 )
        Change at Week 96 (n=43, 45)
    -0.0051 ( 0.13742 )
    0.0043 ( 0.19654 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory
    End point description
    A serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Clinical laboratory abnormalities are expected to be reported as adverse events if they met any criterion for seriousness, led to treatment discontinuation, required a medical intervention or were considered clinically significant by the investigator. Safety set included all subjects who receive at least one administration of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment (week 96)
    End point values
    		 Cholecalciferol Placebo
    Number of subjects analysed
    61
    65
    Units: subjects
    number (not applicable)
        TEAEs
    43
    35
        Serious TEAEs
    11
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline till the end of the study (week 96)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cholecalciferol
    Reporting group description
    		 Subjects received Cholecalciferol 100,000 IU one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with subcutaneous Rebif 44 mcg 3 times a week.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.

    Serious adverse events
    		 Cholecalciferol Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 61 (18.03%)
    10 / 65 (15.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced complete
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plastic surgery to the face
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy on contraceptive
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy on oral contraceptive
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy after post coital contraception
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foetal death
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal mass
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Psoriatic arthropathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         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
    		 Cholecalciferol Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 61 (65.57%)
    31 / 65 (47.69%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Vascular disorders
    Arterial disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 65 (3.08%)
         occurrences all number
    4
    3
    Cyst
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 61 (1.64%)
    5 / 65 (7.69%)
         occurrences all number
    1
    5
    Injection site erythema
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Injection site pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Injection site reaction
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 65 (3.08%)
         occurrences all number
    1
    2
    Malaise
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Social circumstances
    Menopause
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 65 (0.00%)
         occurrences all number
    4
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Erectile dysfunction
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Menorrhagia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 65 (6.15%)
         occurrences all number
    1
    4
    Pulmonary hypertension
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Snoring
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Depression
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 65 (4.62%)
         occurrences all number
    6
    3
    Depressive symptom
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Stress
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Creatinine urine increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Normetanephrine urine increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Serum ferritin increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Urine calcium/creatinine ratio increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Breast injury
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 65 (0.00%)
         occurrences all number
    4
    0
    Head injury
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Ligament sprain
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Limb injury
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Skin abrasion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Spinal column injury
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Tooth fracture
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 65 (1.54%)
         occurrences all number
    4
    1
    Migraine
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 65 (1.54%)
         occurrences all number
    3
    1
    Optic neuritis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Radiculitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphopenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Aphthous stomatitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 65 (3.08%)
         occurrences all number
    0
    2
    Dental discomfort
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    3
    Dry skin
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Erythema nodosum
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Skin necrosis
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    3
    0
    Skin reaction
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    Articular calcification
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 65 (6.15%)
         occurrences all number
    1
    4
    Bronchitis viral
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 65 (6.15%)
         occurrences all number
    1
    4
    Gingivitis
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    Hordeolum
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 65 (1.54%)
         occurrences all number
    4
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 65 (6.15%)
         occurrences all number
    4
    6
    Oral candidiasis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Paronychia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    2
    Sinusitis
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 65 (3.08%)
         occurrences all number
    1
    2
    Tooth abscess
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Tooth infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Tracheobronchitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 61 (6.56%)
    4 / 65 (6.15%)
         occurrences all number
    4
    5
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Metabolic syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 65 (3.08%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2009
    - Specified the equivalent daily dose of Uvedose in IU for the group A. - Specified that the number of new T1-weighted lesions and MRI variation parameters (brain volume, volume of T2 lesions, total number of Gd-enhanced lesions, volume of hypo-intense lesions) were summarized at visits V1 and V6 (week 96) by treatment group
    30 Oct 2009
    - Added “Patients with osteoporosis or known osteopenia” as an exclusion criterion
    09 Dec 2009
    - Replaced 25 Hydroxyvitamin-D3 (25(OH)D) by 25-hydroxyvitamin D (25(OH)D) - Removed spinal IRM, added a central review of the MRI, changed the text regarding the method of measuring the change in brain volume (defined as any change in normalized brain volume between baseline and final assessment parameters), described the MRI procedure (2 CD, anonymisation of the data, and 1 CD sent to the centralized reviewer).
    08 Jun 2010
    - Added changes requested by the Data Safety Monitoring Board (DSMB) on the safety assessments: Removed “measure of albumin in urine samples.” - Added conditions for the premature discontinuation: lithiasis with clinical and/or radiological expression and adjustment of clinically significant laboratory abnormalities - Added renal lithiasis expressed clinically or discovered by accident, during an X-ray examination as AEs potentially related to Vitamin D overdose - Removed bony side events as a clinical events of hypercalcemia and replaced by the following General clinical signs: bilateral renal lithiasis with nephrocalcinosis; gastroduodenal ulcer; acute calcifying pancreatitis; hypertension; articular chondrocalcinosis; signs of chronic hypercalcemia, and add nausea, vomiting, anorexia
    01 Jun 2011
    - Changed to allow the 22mcg dose for Rebif in the clinical study (44mcg dose is the recommended dose however the 22mcg dose is recommended if the highest dose is not tolerated) and to increase the window time from 2 to 4 months for the subject selection in order to allow a better tolerance prior the randomization visit (V2) as flu-syndromes and tiredness are more important at the beginning of the treatment. The inclusion criteria was modified accordingly - Corrected exclusion criteria ”Inadequate marrow reserves, defined as white blood cells inferior to 0.5 x lower limit of normal” and not “superior to" - Specified that Rebif has exception drug status requiring special monitoring during treatment and prescribed by a specialized physician (neurologist) - Added vitamin D-enriched food supplements without consulting the Investigator as prohibited medications - DSMB committee requested to add “corrected calcemia” in addition of “calcemia” for the clinically significant laboratory abnormalities. - Corrected to allow a biological re-test as needed prior the subject randomization and extension of the screening period from 8 to 17 weeks in case of biological re-tests.

    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
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