Clinical trial NCT01198132: 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
Official title: 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 µg 3 Times Weekly
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: Multiple Sclerosis Relapsing-Remitting
Relapsing Multiple Sclerosis (RMS)
Rebif
Vitamin D3
Cholecalciferol
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Merck Serono S.A.S, France
First posted: 2010-09-09
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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 microgram (mcg) \[Rebif\] 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.


Eligibility criteria: 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 mcg (or 22 mcg in case of intolerance to 44 mcg) 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 less than (\<) 75 nanomolar per liter (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, hypoparathyroidism, 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 greater than (\>) 2.5 \* upper limit of normal.
* Severe renal impairment defined as creatinine clearance below 30 milliliter per minute (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.

Primary outcomes:
measure: Annualized Relapse Rate
timeFrame: 2 years post treatment (IMP) administration
Secondary outcomes:
measure: Time to First Documented Relapse
timeFrame: 2 years post treatment (IMP) administration
measure: Mean Number of Relapses Per Subject
timeFrame: 2 years post treatment (IMP) administration
measure: Number of Relapse-Free (Documented) Subjects
timeFrame: 2 years post treatment (IMP) administration
measure: Cumulative Probability of Progression of Disability (Kaplan-Meier Curves)
timeFrame: Baseline up to week 96
measure: Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI)
timeFrame: 2 years post treatment (IMP) administration
measure: Changes From Baseline in Measured Lesion Load (T2)
timeFrame: Baseline, Week 96
measure: Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96
timeFrame: Baseline, Week 96
measure: Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L)
timeFrame: 2 years post treatment (IMP) administration
measure: Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory
timeFrame: Baseline up to end of treatment (week 96)
Other outcomes:
Locations:
city: Montpellier
country: France
facility: CHU Hôpital Gui de Chauliac Service de Neurologie B
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Camu W, Lehert P, Pierrot-Deseilligny C, Hautecoeur P, Besserve A, Jean Deleglise AS, Payet M, Thouvenot E, Souberbielle JC. Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE). Neurol Neuroimmunol Neuroinflamm. 2019 Aug 6;6(5):e597. doi: 10.1212/NXI.0000000000000597. Print 2019 Sep.