Relapsing Remitting Multiple Sclerosis
Conditions
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.
Interventions
DRUGVitamin 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).
Sponsors
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
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects That Experience a Relapse | 2 years | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Relapses Requiring Treatment | 2 years | — |
| Number of New or Enlarging T2 Lesions | 2 years | — |
| Proportion of Participants With Sustained Disability Progression | 2 years | 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 | 2 years | 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 | 2 years | 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. |
| Annualized Relapse Rate | 2 years | Average relapses per year |
| Change in Brain Parenchymal Volume | 2 years | — |
| Change in Normalized Gray Matter Volume | 2 years | — |
| Change in Cortical Thickness | 2 years | Unable to analyze this outcome measure |
| Development of Hypercalcemia | 2 years | — |
| Development of Nephrolithiasis | 2 years | — |
| Change in Health-related Quality of Life | 2 years | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment took place from March 2012 through April 2019 at 16 neurology clinics in the United States.
Pre-assignment details
After successful screening, a thirty day run-in period was used to assess compliance with daily subcutaneous glatiramer acetate injections. Participants who missed more than 3 injections during the run-in period were ineligible to be randomized and were withdrawn from further study participation.
Participants by arm
| Arm | Count |
|---|---|
| Low-dose Vitamin D3 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). | 83 |
| High-dose Vitamin D3 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). | 89 |
| Total | 172 |
Baseline characteristics
| Characteristic | High-dose Vitamin D3 | Total | Low-dose Vitamin D3 |
|---|---|---|---|
| Age, Continuous | 34.5 years STANDARD_DEVIATION 7.1 | 34.4 years STANDARD_DEVIATION 7.4 | 34.2 years STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 30 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 71 Participants | 141 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Expanded Disability Status Scale (EDSS) score | 2.00 units on a scale | 2.00 units on a scale | 2.00 units on a scale |
| Health-related Quality of Life | 126 units on a scale STANDARD_DEVIATION 27 | 126 units on a scale STANDARD_DEVIATION 26 | 126 units on a scale STANDARD_DEVIATION 24 |
| Low-contrast acuity | 34 letters STANDARD_DEVIATION 10 | 35 letters STANDARD_DEVIATION 10 | 36 letters STANDARD_DEVIATION 10 |
| Multiple Sclerosis Functional Composite (MSFC) score | 0.6 Z-score STANDARD_DEVIATION 0.5 | 0.5 Z-score STANDARD_DEVIATION 0.4 | 0.5 Z-score STANDARD_DEVIATION 0.4 |
| Normalized Brain Parenchymal Volume | 1,496,147 microliters | 1,492,411 microliters | 1,488,270 microliters |
| Normalized Gray Matter Volume | 781,461 microliters | 774,469 microliters | 772,736 microliters |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 29 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) White | 71 Participants | 132 Participants | 61 Participants |
| Region of Enrollment United States | 89 Participants | 172 Participants | 83 Participants |
| Sex: Female, Male Female | 61 Participants | 131 Participants | 70 Participants |
| Sex: Female, Male Male | 28 Participants | 41 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 0 / 83 |
| other Total, other adverse events | 66 / 82 | 63 / 83 |
| serious Total, serious adverse events | 11 / 82 | 11 / 83 |
Outcome results
Primary
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).
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Vitamin D3 | Proportion of Subjects That Experience a Relapse | 0.32 proportion of participants |
| High-dose Vitamin D3 | Proportion of Subjects That Experience a Relapse | 0.34 proportion of participants |
p-value: 0.6Log Rank
p-value: 0.5795% CI: [0.67, 2.05]Regression, Cox
Secondary
Annualized Relapse Rate
Average relapses per year
Time frame: 2 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Annualized Relapse Rate | 0.20 relapses per participant per year |
| High-dose Vitamin D3 | Annualized Relapse Rate | 0.34 relapses per participant per year |
p-value: 0.07Andersen Gill model for recurrent events
Secondary
Change in Brain Parenchymal Volume
Time frame: 2 years
Population: Participants analyzed had \> 1 MRI during the study (baseline MRI and at least one follow-up MRI of sufficient quality).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Change in Brain Parenchymal Volume | -0.29 microliters |
| High-dose Vitamin D3 | Change in Brain Parenchymal Volume | -0.81 microliters |
p-value: 0.13Mixed Models Analysis
Secondary
Change in Cortical Thickness
Unable to analyze this outcome measure
Time frame: 2 years
Population: The quality of the clinical MRI scans acquired for this study prevented the analysis of cortical thickness.
Secondary
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.
Time frame: 2 years
Population: Participants analyzed completed a baseline FAMS questionnaire and at least 1 follow-up FAMS questionnaire.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Change in Health-related Quality of Life | -0.78 score on a scale |
| High-dose Vitamin D3 | Change in Health-related Quality of Life | -2.21 score on a scale |
Comparison: Rate of change in quality of life was analyzed using a linear mixed effects model with unstructured covariance structure and random intercepts. The p-value is a test of whether there is a difference in the rate of change in health-related quality of life between treatment arms.p-value: 0.21Mixed Models Analysis
Secondary
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.
Time frame: 2 years
Population: Participants analyzed did not have an MS relapse between screening and baseline visits and had at least one low-contrast acuity measure at a follow-up visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Change in Low-contrast Acuity | 0.82 letters |
| High-dose Vitamin D3 | Change in Low-contrast Acuity | 1.09 letters |
Comparison: Rate of change in 2.5% low-contrast acuity was analyzed using a linear mixed effects model with unstructured covariance structure and random intercepts. The p-value is a test of whether there is a difference in the rate of change in low-contrast acuity between treatment arms.p-value: 0.67Mixed Models Analysis
Secondary
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.
Time frame: 2 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Change in Multiple Sclerosis Functional Composite (MSFC) Score | 0.051 Z-score |
| High-dose Vitamin D3 | Change in Multiple Sclerosis Functional Composite (MSFC) Score | 0.025 Z-score |
Comparison: The average rate of change in MSFC Z-score over time was analyzed using a linear mixed-effects model with unstructured covariance structure and random intercepts. The p-value is a test of whether there is a difference in the rate of change in the MSFC Z-score between treatment arms.p-value: 0.2Mixed Models Analysis
Secondary
Change in Normalized Gray Matter Volume
Time frame: 2 years
Population: Participants analyzed had \> 1 MRI during the study (baseline MRI and at least one follow-up MRI of sufficient quality).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Change in Normalized Gray Matter Volume | -0.15 microliters |
| High-dose Vitamin D3 | Change in Normalized Gray Matter Volume | -0.87 microliters |
p-value: 0.08Mixed Models Analysis
Secondary
Development of Hypercalcemia
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low-dose Vitamin D3 | Development of Hypercalcemia | 0 Participants |
| High-dose Vitamin D3 | Development of Hypercalcemia | 0 Participants |
Secondary
Development of Nephrolithiasis
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low-dose Vitamin D3 | Development of Nephrolithiasis | 1 Participants |
| High-dose Vitamin D3 | Development of Nephrolithiasis | 2 Participants |
Secondary
Number of New or Enlarging T2 Lesions
Time frame: 2 years
Population: Participants analyzed had \> 1 MRI during the study (baseline and at least one follow-up MRI of sufficient quality).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Number of New or Enlarging T2 Lesions | 1.95 lesions |
| High-dose Vitamin D3 | Number of New or Enlarging T2 Lesions | 2.88 lesions |
p-value: 0.1495% CI: [0.88, 2.46]Negative Binomial Model
Secondary
Number of Relapses Requiring Treatment
Time frame: 2 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low-dose Vitamin D3 | Number of Relapses Requiring Treatment | 0.15 relapses |
| High-dose Vitamin D3 | Number of Relapses Requiring Treatment | 0.28 relapses |
p-value: 0.0795% CI: [0.94, 3.45]Negative Binomial Model
Secondary
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).
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Vitamin D3 | Proportion of Participants With Sustained Disability Progression | 0.05 proportion of participants |
| High-dose Vitamin D3 | Proportion of Participants With Sustained Disability Progression | 0.08 proportion of participants |
p-value: 0.6Log Rank