A Multicentre Study of the Efficacy and Safety of Supplementary Treatment With Cholecalciferol in Patients With Relapsing Multiple Sclerosis Treated With Subcutaneous Interferon Beta-1a 44 µg 3 Times Weekly (CHOLINE)

• Time to first documented relapse [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Mean number of relapses per subject per year [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Number of relapse-free (documented) subjects [ Time Frame: after two years of treatment ] [ Designated as safety issue: No ]
• Cumulative probability of progression of disability (Kaplan-Meier curves) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Number of new or extended lesions by T1- and T2-weighted MRI [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Changes in measured lesion load (T2) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Measurement and evaluation of cognitive ability by Paced auditory serial addition task (PASAT) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Change in quality of life (QoL) using EQ-5D (EuroQoL-5 dimension questionnaire) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Safety of the treatment assessed by recording of adverse events, clinical laboratory evaluations (blood biochemistry and urinalysis) and vital signs [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: Yes ]

• Time to first documented relapse [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Mean number of relapses per subject per year [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Number of relapse-free (documented) subjects [ Time Frame: after two years of treatment ] [ Designated as safety issue: No ]
• Cumulative probability of progression of disability (Kaplan-Meier curves) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Number of new or extended lesions by T1- and T2-weighted MRI [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Changes in measured lesion load (T2), number of new lesions (T1 gadolinium activity and black holes) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Measurement and evaluation of cognitive ability by Paced auditory serial addition task (PASAT) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Change in quality of life (QoL) using EQ-5D (EuroQoL-5 dimension questionnaire) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: No ]
• Safety of the treatment assessed by recording of adverse events and clinical laboratory evaluations (blood biochemistry and urinalysis) [ Time Frame: After 2 years of treatment ] [ Designated as safety issue: Yes ]

The aim of this multicentre, randomised, double-blind, placebo-controlled study is to evaluate the efficacy and safety of supplementary treatment with cholecalciferol (vitamin D3) in subjects with relapsing multiple sclerosis (R MS) treated with subcutaneous (s.c.) interferon beta-1a 44 µg (Rebif) 3 times weekly. The subjects will be divided into 2 groups, one receiving cholecalciferol 100,000 IU twice monthly along with Rebif treatment and the other group will be on placebo along with Rebif treatment. A total of 200 subjects will be recruited in 20-30 centres in France.

• Experimental: Group 1
  100 subjects will receive 100,000 IU twice monthly, i.e. one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) during the 96 weeks treatment period along with s.c. Rebif 3 times weekly.
  Intervention: Dietary Supplement: Cholecalciferol (Vitamin D3)
• No Intervention: Group 2
  100 subjects will receive the placebo under identical conditions along with s.c. Rebif 3 times weekly.

Inclusion Criteria:

• Diagnosis of RRMS according to Poser criteria (clinically definite multiple sclerosis [CDMS] or laboratory supported definite multiple sclerosis [LSDMS]) or according to McDonald criteria (2005).
• Subjects aged between 18 and 65 years.
• Treated with interferon beta-1a 44 µg (or 22 µg in case of intolerance to 44 µg) 3 times weekly subcutaneously for 4 months ± (2 months) at the randomization visit (V1).
• Expanded disability status scale (EDSS) score between 0 and 5.
• At least one documented episode during the last two year.
• Stable disease with no episodes over the last 30 days.
• Serum 25-hydroxyvitamin D < 75 nmol/l at randomization visit.

• Women must not be pregnant or breast-feeding, and women of childbearing age must meet the following criteria:

  • Surgically sterilised, or
  • Using a highly effective contraceptive method throughout the entire duration of the study. A highly effective contraceptive method is defined as a method with a very low failure rate (i.e. < 1 % per year) with regular and appropriate use, e.g. implants, injectable contraceptives, combined oral contraceptives, coil, abstinence or vasectomised partner.
  • Menopausal women may be included.
• Affiliated to French healthcare insurance.
• Subjects must be ready and able to provide informed consent and comply with the protocol requirements.

Exclusion Criteria:

• Hormonal abnormalities associated with vitamin D other than low dietary intake or reduced exposure to sun, for example malabsorption (coeliac disease, Whipple's disease, inflammatory bowel disease, intestinal derivation, short bowel syndrome), cirrhosis, nephrotic syndrome, hyperthyroidism, rickets, hypoparathyreosis, cancer, granulomatous diseases (sarcoidosis, silicosis) and lymphomas known at the initial visit.
• Patients with osteoporosis or known osteopenia.
• Use of medicines affecting vitamin D metabolism other than corticosteroids, e.g. anticonvulsants (phenobarbital, primidone, phenytoin), rifampicin, isoniazid, ketoconazole, 5-FU and leucovorin, or thiazide diuretics.
• Previous or ongoing hypercalcaemia.
• Situations involving increased susceptibility to hypercalcaemia, e.g. known cardiac arrhythmia or cardiac disease, treatment with digitalis, renal lithiasis.
• Any contraindication to the treatment (cholecalciferol) stated in the summary of product characteristics.
• Moderate renal impairment defined as creatinine clearance between 30 and 60 ml/min.
• An active episode during the month prior to inclusion in the study.
• Inadequate liver function, defined as total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 * upper limit of normal.
• Severe renal impairment defined as creatinine clearance below 30 ml/min.
• Inadequate marrow reserves, defined as white blood cells < 0.5 * lower limit of normal.
• Serious or acute heart disease such as uncontrolled cardiac arrhythmia, uncontrolled angina, cardiomyopathy or uncontrolled congestive heart failure.
• History of severe depression, or attempted suicide or ongoing suicidal ideation.
• Epilepsy inadequately controlled by treatment.
• Ongoing or previous alcohol or drug abuse (within the last two years).
• Major medical or psychiatric disease which, in the opinion of investigator, would place the subject at risk or could adversely affect compliance with the study protocol.
• Known hypersensitivity to gadolinium and/or known inability to undergo MRI.
• Any medical condition requiring chronic treatment with systemic corticosteroids.
• Participation in any other studies involving other study products over the 30 days prior to inclusion in this study.
• Legal incapacity or limited legal capacity.