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Vitamin D Supplementation in Multiple Sclerosis

Primary Purpose

Relapsing Remitting Multiple Sclerosis

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Vitamin D3
Sponsored by
Johns Hopkins University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsing Remitting Multiple Sclerosis

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Dignity Health Medical Foundation
  • University of California, San Francisco
  • Stanford University
  • Yale University
  • Anne Arundel Health System Research Institute
  • Johns Hopkins University School of Medicine
  • University of Massachusetts
  • Washington University St. Louis
  • Columbia University
  • Mount Sinai School of Medicine
  • University of Rochester
  • Cleveland Clinic
  • Oregon Health Sciences University
  • University of Pennsylvania
  • University of Virginia
  • Swedish Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Low-dose vitamin D3

High-dose vitamin D3

Arm Description

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Annualized Relapse Rate
Average relapses per year
Number of Relapses Requiring Treatment
Number of New or Enlarging T2 Lesions
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).
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.
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.
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.
Change in Brain Parenchymal Volume
Change in Normalized Gray Matter Volume
Change in Cortical Thickness
Unable to analyze this outcome measure
Development of Hypercalcemia
Development of Nephrolithiasis

Full Information

First Posted
December 6, 2011
Last Updated
September 12, 2022
Sponsor
Johns Hopkins University
Collaborators
Oregon Health and Science University, University of California, San Francisco, Washington University School of Medicine, Icahn School of Medicine at Mount Sinai, 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, Columbia University, University of Massachusetts, Worcester, Dignity Health
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1. Study Identification

Unique Protocol Identification Number
NCT01490502
Brief Title
Vitamin D Supplementation in Multiple Sclerosis
Official Title
A Randomized Controlled Trial of Vitamin D Supplementation in Multiple Sclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
March 2012 (Actual)
Primary Completion Date
May 15, 2021 (Actual)
Study Completion Date
May 15, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University
Collaborators
Oregon Health and Science University, University of California, San Francisco, Washington University School of Medicine, Icahn School of Medicine at Mount Sinai, 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, Columbia University, University of Massachusetts, Worcester, Dignity Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing Remitting Multiple Sclerosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
172 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Low-dose vitamin D3
Arm Type
Active Comparator
Arm Title
High-dose vitamin D3
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Vitamin D3
Intervention Description
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).
Primary Outcome Measure Information:
Title
Proportion of Subjects That Experience a Relapse
Description
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).
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Annualized Relapse Rate
Description
Average relapses per year
Time Frame
2 years
Title
Number of Relapses Requiring Treatment
Time Frame
2 years
Title
Number of New or Enlarging T2 Lesions
Time Frame
2 years
Title
Proportion of Participants With Sustained Disability Progression
Description
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).
Time Frame
2 years
Title
Change in Multiple Sclerosis Functional Composite (MSFC) Score
Description
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.
Time Frame
2 years
Title
Change in Low-contrast Acuity
Description
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.
Time Frame
2 years
Title
Change in Health-related Quality of Life
Description
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.
Time Frame
2 years
Title
Change in Brain Parenchymal Volume
Time Frame
2 years
Title
Change in Normalized Gray Matter Volume
Time Frame
2 years
Title
Change in Cortical Thickness
Description
Unable to analyze this outcome measure
Time Frame
2 years
Title
Development of Hypercalcemia
Time Frame
2 years
Title
Development of Nephrolithiasis
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ellen M Mowry, MD, MCR
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dignity Health Medical Foundation
City
Carmichael
State/Province
California
Country
United States
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
Country
United States
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
Country
United States
Facility Name
Anne Arundel Health System Research Institute
City
Annapolis
State/Province
Maryland
Country
United States
Facility Name
Johns Hopkins University School of Medicine
City
Baltimore
State/Province
Maryland
Country
United States
Facility Name
University of Massachusetts
City
Worcester
State/Province
Massachusetts
Country
United States
Facility Name
Washington University St. Louis
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Mount Sinai School of Medicine
City
New York
State/Province
New York
Country
United States
Facility Name
University of Rochester
City
Rochester
State/Province
New York
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
Country
United States
Facility Name
Oregon Health Sciences University
City
Portland
State/Province
Oregon
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
Country
United States
Facility Name
University of Virginia
City
Charlottesville
State/Province
Virginia
Country
United States
Facility Name
Swedish Medical Center
City
Seattle
State/Province
Washington
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
25311447
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.
Results Reference
derived

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Vitamin D Supplementation in Multiple Sclerosis

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