Vitamin D Supplementation in Multiple Sclerosis

• Annualized relapse rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Number of relapses requiring treatment [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Number of new T2 lesions [ Time Frame: In the two-year study, compared to baseline ] [ Designated as safety issue: No ]
• Occurrence of sustained disability progression [ Time Frame: At years 1 and 2, compared to baseline ] [ Designated as safety issue: No ]
  A patient will be considered to have had sustained progression of disability if there is an increase in the Expanded Disability Status Scale score at month 12 by at least 1.0 point that is confirmed on the final examination one year later.
• Change in MS Functional Composite Score [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in low-contrast acuity [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in health-related quality of life [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in brain parenchymal volume [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in normalized gray matter volume [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in cortical thickness [ Time Frame: Over the two year study compared to baseline ] [ Designated as safety issue: No ]
• Development of hypercalcemia/related adverse effects [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Annualized relapse rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Number of relapses requiring treatment [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Number of new T2 lesions [ Time Frame: In the two-year study, compared to baseline ] [ Designated as safety issue: No ]
• Occurrence of sustained disability progression [ Time Frame: At years 1 and 2, compared to baseline ] [ Designated as safety issue: No ]
  A patient will be considered to have had sustained progression of disability if there is an increase in the Expaned Disability Status Scale score at month 12 by at least 1.0 point that is confirmed on the final examination one year later.
• Change in MS Functional Composite Score [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in low-contrast acuity [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in health-related quality of life [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in brain parenchymal volume [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in normalized gray matter volume [ Time Frame: Over the two-year study compared to baseline ] [ Designated as safety issue: No ]
• Change in cortical thickness [ Time Frame: Over the two year study compared to baseline ] [ Designated as safety issue: No ]
• Development of hypercalcemia/related adverse effects [ Time Frame: 2 years ] [ Designated as safety issue: No ]

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.

Vitamin D insufficiency has recently emerged as a risk factor for susceptibility to multiple sclerosis (MS). Our 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 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.

• Active Comparator: Low-dose vitamin D3
  Intervention: Drug: Vitamin D3
• Active Comparator: High-dose vitamin D3
  Intervention: Drug: Vitamin D3

Inclusion Criteria:

1. Must meet MAGNIMS criteria for relapsing-remitting MS
2. Age 18 to 50 years
3. EDSS score ≤ 4.0
4. MS disease duration ≤ 10 years if McDonald RRMS; ≤ 1 year if meets MAGNIMS RRMS criteria but not McDonald RRMS criteria

5. If the patient meets the McDonald RRMS criteria (rather than McDonald 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
6. Females of child-bearing age must be willing to use at least one form of pregnancy prevention throughout the study.
7. Must have had a 25-hydroxyvitamin D level of ≥ 15 ng/mL within past 30 days
8. 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:

1. Not be pregnant or nursing
2. No ongoing renal or liver disease
3. 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.
4. No ongoing hyperthyroidism or active infection with Mycobacterium species
5. No known gastrointestinal disease (ulcerative colitis, Crohn's disease, celiac disease/gluten intolerance) or use of medications associated with malabsorption.
6. No history of self-reported alcohol or substance abuse in past six months.
7. 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.
8. No use of interferon beta or glatiramer acetate therapy for one month prior to screening
9. No use of more than 1,000 IU vitamin D3 daily in the three months prior to screening
10. No condition that would limit the likelihood of completing the MRI procedures
11. 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.
12. No steroids within a month of screening.
13. 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).
14. Serum calcium >0.2 mg/dL above upper limit of normal.

• Oregon Health and Science University
• University of California, San Francisco
• Washington University School of Medicine
• Mount Sinai School of Medicine
• University of Pennsylvania
• Yale University
• The Cleveland Clinic
• University of Rochester
• Stanford University
• University of Virginia
• Swedish Medical Center
• Anne Arundel Health System Research Institute
• Stony Brook University
• Columbia University
• University of Massachusetts, Worcester