Vitamin D Supplementation in Multiple Sclerosis

NCT ID: NCT01490502

Last Updated: 2022-09-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 172 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-03-31
• Study Completion Date: 2021-05-15

Brief Summary

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

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.

Conditions

Relapsing Remitting Multiple Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Low-dose vitamin D3

Group Type: ACTIVE_COMPARATOR

Vitamin D3

Intervention Type: DRUG

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).

High-dose vitamin D3

Group Type: ACTIVE_COMPARATOR

Vitamin D3

Intervention Type: DRUG

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).

Interventions

Vitamin D3

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).

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Oregon Health and Science University

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Icahn School of Medicine at Mount Sinai

OTHER

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: collaborator

University of Rochester

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: collaborator

Swedish Medical Center

OTHER

Sponsor Role: collaborator

Anne Arundel Health System Research Institute

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

University of Massachusetts, Worcester

OTHER

Sponsor Role: collaborator

Dignity Health

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ellen M Mowry, MD, MCR

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Dignity Health Medical Foundation

Carmichael, California, United States

University of California, San Francisco

San Francisco, California, United States

Stanford University

Stanford, California, United States

Yale University

New Haven, Connecticut, United States

Anne Arundel Health System Research Institute

Annapolis, Maryland, United States

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

University of Massachusetts

Worcester, Massachusetts, United States

Washington University St. Louis

St Louis, Missouri, United States

Columbia University

New York, New York, United States

Mount Sinai School of Medicine

New York, New York, United States

University of Rochester

Rochester, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

Oregon Health Sciences University

Portland, Oregon, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Virginia

Charlottesville, Virginia, United States

Swedish Medical Center

Seattle, Washington, United States

Countries

United States

References

Cassard SD, Fitzgerald KC, Qian P, Emrich SA, Azevedo CJ, Goodman AD, Sugar EA, Pelletier D, Waubant E, Mowry EM. High-dose vitamin D3 supplementation in relapsing-remitting multiple sclerosis: a randomised clinical trial. EClinicalMedicine. 2023 Apr 13;59:101957. doi: 10.1016/j.eclinm.2023.101957. eCollection 2023 May.

Reference Type: DERIVED

PMID: 37125397 (View on PubMed)

Bhargava P, Cassard S, Steele SU, Azevedo C, Pelletier D, Sugar EA, Waubant E, Mowry EM. The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. Contemp Clin Trials. 2014 Nov;39(2):288-93. doi: 10.1016/j.cct.2014.10.004. Epub 2014 Oct 12.

Reference Type: DERIVED

PMID: 25311447 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

NA_00049137

Identifier Type: -

Identifier Source: org_study_id