High-Dose Vitamin D in Multiple Sclerosis Spectrum: Insights from the D-Lay MS Trial
Lusi Zhang, PharmD, MHI, Geritom Medical, Inc.
Background: Clinically isolated syndrome (CIS) refers to an initial neurological episode suggestive of multiple sclerosis (MS), though not all cases progress to definitive MS. Vitamin D deficiency is a well-established risk factor for MS and has been associated with greater disease activity. While prior studies have explored vitamin D supplementation in MS, results have been mixed, largely based on small pilot trials or concurrent use with disease-modifying therapies. Given vitamin D’s potential immunomodulatory effects, including regulation of T and B cells and reduction of Central Nervous System (CNS) inflammation, its role as a monotherapy in delaying MS progression remains an open question. These uncertainties highlight the need for larger, randomized clinical trials to evaluate vitamin D’s efficacy in early MS management.
Objective: To determine if high-dose vitamin D (cholecalciferol) monotherapy effectively reduces disease activity in patients experiencing CIS suggestive of MS.
Study Design: The D-Lay MS trial was a multicenter, randomized, double-blind, phase 3 placebo-controlled study conducted at 36 MS centers across France. Enrollment occurred between July 2013 and December 2020, with final follow-up in January 2023. The trial included 316 adults between the ages of 18 to 55 years who experienced a recent CIS episode (within 90 days), had serum vitamin D levels below 100 nmol/L, and met diagnostic criteria suggestive of MS based on magnetic resonance imaging (MRI) findings and the presence of cerebrospinal fluid oligoclonal bands. Participants were randomized in a 1:1 ratio to receive either 100,000 IU of oral cholecalciferol or a matching placebo every two weeks for 24 months. The primary outcome was disease activity, defined as either clinical relapse or the presence of new or enlarging brain or spinal cord MRI lesions during the study period. Secondary outcomes included more detailed assessments of disease activity characteristics as well as clinical disability measures with the Expanded Disability Status Scale (EDSS) and other clinical rating scales. Time to disease activity was evaluated using Kaplan-Meier survival analysis and compared between groups with the log-rank test; a random-effects Cox model was used to estimate the effect of treatment while adjusting for key baseline covariates.
Results: Of the 316 patients enrolled, 303 participants who took at least 1 dose of vitamin D (cholecalciferol) or placebo were included in the primary analysis, and 288 completed the full 24-month follow-up. The median age of participants was 34 years, and 70% were women. There was no significant difference in baseline demographic and clinical characteristics between the two treatment groups. The primary outcome, disease activity, was observed in 60.3% of patients receiving high-dose vitamin D compared to 74.1% in the placebo group. This corresponded to a statistically significant 34% reduction in the risk of disease activity (hazard ratio-HR 0.66; 95% CI, 0.50 to 0.87; P=0.004), with a longer median time to disease activity in the vitamin D group (432 vs. 224 days; P=0.003). MRI-based secondary outcomes also favored vitamin D: fewer patients experienced new or enlarging lesions (46.2% vs. 59.2%; HR 0.61; 95% CI, 0.44 to 0.84; P=0.003), contrast-enhancing lesions (18.6% vs. 34.0%; HR 0.47; 95%CI, 0.30 to 0.75; P=0.001), and overall MRI activity (57.1% vs. 65.3%; HR 0.71; 95%CI, 0.53-0.95; P=0.02). No significant differences were found in clinical outcomes such as relapse rates or clinical measures of psychological and functional disability. Results were consistent in a subgroup meeting updated 2017 diagnostic criteria for relapsing-remitting MS. Adverse events were similar between groups, with no serious events attributed to vitamin D.
Conclusions: High-dose vitamin D supplementation every two weeks significantly reduced MRI-detected disease activity in patients with CIS and early relapsing-remitting MS. The safety profile was favorable, with no treatment-related severe adverse events reported. The results support further investigation into high-dose vitamin D as a potential adjunct therapy early in the MS treatment pathway.
Key Point: High-dose vitamin D supplementation effectively delays MRI-defined disease progression in early MS, representing a promising therapeutic option for patients with CIS.
Published July 15, 2025
References:
1. Thouvenot E, Laplaud D, Lebrun-Frenay C, et al. High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial. JAMA. 2025;333(16):1413-1422. doi:10.1001/jama.2025.1604