Clinical trial NCT01490502: Vitamin D Supplementation in Multiple Sclerosis
Official title: A Randomized Controlled Trial of Vitamin D Supplementation in Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsing Remitting Multiple Sclerosis
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Oregon Health and Science University
name: University of California, San Francisco
name: Washington University School of Medicine
name: Icahn School of Medicine at Mount Sinai
name: University of Pennsylvania
name: Yale University
name: The Cleveland Clinic
name: University of Rochester
name: Stanford University
name: University of Virginia
name: Swedish Medical Center
name: Anne Arundel Health System Research Institute
name: Columbia University
name: University of Massachusetts, Worcester
name: Dignity Health
First posted: 2011-12-13
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Proportion of Subjects That Experience a Relapse
timeFrame: 2 years
Secondary outcomes:
measure: Annualized Relapse Rate
timeFrame: 2 years
measure: Number of Relapses Requiring Treatment
timeFrame: 2 years
measure: Number of New or Enlarging T2 Lesions
timeFrame: 2 years
measure: Proportion of Participants With Sustained Disability Progression
timeFrame: 2 years
measure: Change in Multiple Sclerosis Functional Composite (MSFC) Score
timeFrame: 2 years
measure: Change in Low-contrast Acuity
timeFrame: 2 years
measure: Change in Health-related Quality of Life
timeFrame: 2 years
measure: Change in Brain Parenchymal Volume
timeFrame: 2 years
measure: Change in Normalized Gray Matter Volume
timeFrame: 2 years
measure: Change in Cortical Thickness
timeFrame: 2 years
measure: Development of Hypercalcemia
timeFrame: 2 years
measure: Development of Nephrolithiasis
timeFrame: 2 years
Other outcomes:
Locations:
city: Carmichael
country: United States
facility: Dignity Health Medical Foundation
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Annapolis
country: United States
facility: Anne Arundel Health System Research Institute
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Worcester
country: United States
facility: University of Massachusetts
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University St. Louis
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
Study officials:
affiliation: Johns Hopkins University
name: Ellen M Mowry, MD, MCR
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.