Vitamin D Supplementation in Multiple Sclerosis

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.

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/U
CM225130.pdf).

- Serum calcium >0.2 mg/dL above upper limit of normal.