Vitamin D Supplementation in Multiple Sclerosis

Study Overview
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Brief Summary
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Low vitamin D levels have been shown to increase a person's risk of developing multiple sclerosis (MS), and patients with MS who have lower vitamin D levels are at increased risk of having attacks. However, it is not known if giving supplemental vitamin D to those with MS reduces the risk of attacks, and some research suggests that vitamin D could even be harmful to people with MS. In this clinical trial, patients with relapsing-remitting MS will receive high-dose or low-dose oral vitamin D in addition to an approved therapy for MS, glatiramer acetate. Patients will be evaluated for two years, and the effect of high-dose vitamin D supplementation on the rate of MS attacks and on the number of new lesions and change in brain volume on MRI will be determined. Establishing this association will have major implications for the treatment of individuals with MS throughout the world.

Detailed Description
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Vitamin D insufficiency has recently emerged as a risk factor for susceptibility to multiple sclerosis (MS). The investigator's observational data suggest that lower vitamin D levels in patients with relapsing-remitting MS are associated with a higher subsequent relapse rate. However, it is unknown if providing vitamin D supplementation to such patients leads to a reduction in the risk of an exacerbation. Historically, several nutritional supplements that appeared to be helpful in observational studies of various diseases did not demonstrate a benefit or were harmful in randomized trials. Further, a vitamin D response element was recently identified in the promoter region of Human Leukocyte Antigen (HLA)-DRB1*15, the gene believed to be critical to initiating the autoimmune response in MS, and 1, 25-dihydroxyvitamin D3 increases the expression of the gene in vitro, suggesting that vitamin D supplementation could even be harmful in established MS. This is a randomized, double-blind trial of high- versus low-dose vitamin D3 supplementation as an add-on to glatiramer acetate in 172 patients with relapsing-remitting MS. Subjects will be randomized to 600 IU or 5000 IU of oral vitamin D3 daily for two years. A standardized brain MRI scan will be performed at baseline and at the end of the first and second years. The impact of high-dose vitamin D supplementation on the number of relapses, the number of new lesions on brain MRI, and the change in brain volume will be assessed. Establishing these associations will have major implications for the treatment of patients with MS throughout the world and will provide rationale for further investigations of the role of vitamin D in the immunopathogenesis of MS, possibly leading to the identification of new therapeutic targets.

Official Title
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A Randomized Controlled Trial of Vitamin D Supplementation in Multiple Sclerosis

Conditions
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Relapsing Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: Vitamin D3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must meet Magnetic Resonance Imaging in MS (MAGNIMS) criteria for relapsing-remitting MS Age 18 to 50 years Expanded Disability Status Scale (EDSS) score ≤ 4.0 MS disease duration ≤ 10 years if McDonald Relapse Remitting Multiple Sclerosis (RRMS;) ≤ 1 year if meets MAGNIMS RRMS criteria but not McDonald RRMS criteria If the patient meets the McDonald RRMS criteria (rather than McDonald Clinically Isolated Syndrome (CIS) that is now classified as MAGNIMS MS): Must have had one clinical attack in past two years and at least one new silent T2 or gadolinium-enhancing lesion on brain MRI within the past year OR Must have had two clinical attacks in past two years, one of which occurred in the past year Females of child-bearing age must be willing to use at least one form of pregnancy prevention throughout the study. Must have had a 25-hydroxyvitamin D level of ≥ 15 ng/mL within past 30 days Must be willing to stop taking additional supplemental vitamin D, except as part of a multivitamin, and must be willing to not take cod liver oil. Exclusion Criteria: Not be pregnant or nursing No ongoing renal or liver disease No known history of nephrolithiasis, hypercalcemia, sarcoidosis or other serious chronic illness including cancer (other than basal cell or squamous cell carcinoma of the skin), cardiac disease, or HIV. No ongoing hyperthyroidism or active infection with Mycobacterium species No known gastrointestinal disease (ulcerative colitis, Crohn's disease, celiac disease/gluten intolerance) or use of medications associated with malabsorption. No history of self-reported alcohol or substance abuse in past six months. No prior history of treatment with rituximab, any chemotherapeutic agent, or total lymphoid irradiation. No treatment in the past six months with natalizumab, fingolimod, or fumarate. If patient has received glatiramer acetate, they have not been exposed to more than three months of treatment. No treatment with other unapproved therapies for MS. No use of interferon beta or glatiramer acetate therapy for one month prior to screening No use of more than 1,000 IU vitamin D3 daily in the three months prior to screening No condition that would limit the likelihood of completing the MRI procedures No use of thiazide diuretics, digoxin, diltiazem, verapamil, cimetidine, heparin, low-molecular weight heparin, phenytoin, phenobarbital, carbamazepine, routine corticosteroids (eg scheduled monthly steroids, daily, etc), rifampin, or cholestyramine. No steroids within a month of screening. Not suicidal at screening visit (ineligible if answers yes to question 1 of screening Columbia Suicide Severity Rating Scale (C-SSRS) in PAST 2 MONTHS; or answers yes to questions 2-5 on C-SSRS for PAST 6 MONTHS; or answers yes to suicidal attempts or preparatory attempts in PAST 5 YEARS , http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225130.pdf). Serum calcium >0.2 mg/dL above upper limit of normal.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low-dose vitamin D3<br> | Drug: Vitamin D3<br>* Patients will be assigned to low dose (600 IU/day) versus high-dose (5000 IU/day) of vitamin D3 as an add-on therapy to glatiramer acetate (Copaxone).<br>|
| Active Comparator: High-dose vitamin D3<br> | Drug: Vitamin D3<br>* Patients will be assigned to low dose (600 IU/day) versus high-dose (5000 IU/day) of vitamin D3 as an add-on therapy to glatiramer acetate (Copaxone).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects That Experience a Relapse | Confirmed relapse defined as new or worsening symptoms referable to the central nervous system, lasting at least 24 hours, occurring at least 30 days since the prior attack, accompanied by worsening of the EDSS (>= 0.5 points) or in the Functional Systems (FS) scales (2 points on at least one FS scale or 1 point on >= two FS scales). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Relapse Rate | Average relapses per year | 2 years | 
| Number of Relapses Requiring Treatment |  | 2 years | 
| Number of New or Enlarging T2 Lesions |  | 2 years | 
| Proportion of Participants With Sustained Disability Progression | The Expanded Disability Status Scale (EDSS) is an ordinal clinical rating scale based on a standard neurological examination and is used to measure global neurologic impairment in people with multiple sclerosis (MS). It ranges from a minimum of 0.0 (normal examination) to 10.0 (death due to MS) in half-point increments. A participant will be considered to have had sustained progression of disability if there is an increase in the EDSS score at month 12 by at least 1.0 point that is confirmed on the final examination one year later (month 24). | 2 years | 
| Change in Multiple Sclerosis Functional Composite (MSFC) Score | The Multiple Sclerosis Functional Composite (MSFC) is a three-part measure of disability for people with multiple sclerosis, including measures of leg function/ambulation, arm/hand function and cognitive function. The three independent measures have different units. We take the reciprocal of the arm/hand function test, and then convert all measures to Z-scores. The average of the Z-scores from each measure yields the MSFC composite Z-score. A Z-score of 0 represents the population mean and positive scores indicate less disability. The MSFC was measured at baseline and up to 4 more times over 2 years. | 2 years | 
| Change in Low-contrast Acuity | Low-contrast acuity was measured as binocular vision on a 2.5% Sloan chart at a distance of 2 meters. The chart is used to test the ability to discriminate gradually smaller gray letters with a 2.5% contrast level against a white background. The low-contrast acuity measure is scored as total letters read and ranges from 0 (no letters read) to 60 (all letters read). Low-contrast acuity was measured at baseline and up to 4 more times over 2 years and higher scores indicate better low-contrast acuity. | 2 years | 
| Change in Health-related Quality of Life | The Functional Assessment of Multiple Sclerosis (FAMS) questionnaire is the quality of life (QOL) instrument used in this trial. It consists of 44 questions and the total score has a possible range of 0 to 176, with higher scores indicating better QOL. The FAMS questionnaire was obtained at baseline and up to 4 more times over 2 years. | 2 years | 
| Change in Brain Parenchymal Volume |  | 2 years | 
| Change in Normalized Gray Matter Volume |  | 2 years | 
| Change in Cortical Thickness | Unable to analyze this outcome measure | 2 years | 
| Development of Hypercalcemia |  | 2 years | 
| Development of Nephrolithiasis |  | 2 years |