Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Apr 22;333(16):1413-1422.
doi: 10.1001/jama.2025.1604.

High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial

Eric Thouvenot  1   2 , David Laplaud  3 , Christine Lebrun-Frenay  4 , Nathalie Derache  5 , Emmanuelle Le Page  6 , Elisabeth Maillart  7 , Caroline Froment-Tilikete  8   9 , Giovanni Castelnovo  1 , Olivier Casez  10 , Marc Coustans  11 , Anne-Marie Guennoc  12 , Olivier Heinzlef  13 , Laurent Magy  14 , Chantal Nifle  15 , Xavier Ayrignac  16 , Agnès Fromont  17 , Nicolas Gaillard  18 , Nathalie Caucheteux  19 , Ivania Patry  20 , Jérôme De Sèze  21 , Romain Deschamps  22 , Pierre Clavelou  23 , Damien Biotti  24 , Gilles Edan  6 , William Camu  25 , Hanane Agherbi  1 , Dimitri Renard  1 , Christophe Demattei  26 , Pascale Fabbro-Peray  26 , Thibault Mura  26 , Manon Rival  1   2 ; D-Lay MS Investigators
Collaborators, Affiliations
Clinical Trial

High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial

Eric Thouvenot et al. JAMA. .

Abstract

Importance: Vitamin D deficiency is a risk factor for multiple sclerosis (MS) and is associated with the risk of disease activity, but data on the benefits of supplementation are conflicting.

Objective: To evaluate the efficacy of high-dose cholecalciferol as monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) typical for MS.

Design, setting, and participants: The D-Lay MS trial was a parallel, double-blind, randomized placebo-controlled clinical trial in 36 MS centers in France. Patients were enrolled from July 2013 to December 2020 (final follow-up on January 18, 2023). Untreated patients with CIS aged 18 to 55 years with CIS duration less than 90 days, serum vitamin D concentration less than 100 nmol/L, and diagnostic magnetic resonance imaging (MRI) meeting 2010 criteria for dissemination in space or 2 or more lesions and presence of oligoclonal bands were recruited.

Intervention: Patients were randomized 1:1 to receive oral cholecalciferol 100 000 IU (n = 163) or placebo (n = 153) every 2 weeks for 24 months.

Main outcomes and measures: The primary outcome measure was disease activity, defined as occurrence of a relapse and/or MRI activity (new and/or contrast-enhancing lesions) over 24 months of follow-up, also analyzed as separate secondary outcomes.

Results: Of the 316 participants enrolled and randomized (median [IQR] age, 34 [28-42] years; 70% women), the primary analysis included 303 patients (95.9%) who took at least 1 dose of the study drug and 288 (91.1%) ultimately completed the 24-month trial. Disease activity was observed in 94 patients (60.3%) in the vitamin D group and 109 patients (74.1%) in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; P = .004), and median time to disease activity was longer in the vitamin D group (432 vs 224 days; log-rank P = .003). All 3 secondary MRI outcomes reported significant differences favoring the vitamin D group vs the placebo group: MRI activity (89 patients [57.1%] vs 96 patients [65.3%]; HR, 0.71 [95% CI, 0.53-0.95]; P = .02), new lesions (72 patients [46.2%] vs 87 patients [59.2%]; HR, 0.61 [95% CI, 0.44-0.84]; P = .003), and contrast-enhancing lesions (29 patients [18.6%] vs 50 patients [34.0%]; HR, 0.47 [95% CI, 0.30-0.75]; P = .001). All 10 secondary clinical outcomes showed no significant difference, including relapse, which occurred in 28 patients (17.9%) in the vitamin D group vs 32 (21.8%) in the placebo group (HR, 0.69 [95% CI, 0.42-1.16]; P = .16). Results were similar in a subset of 247 patients meeting updated 2017 diagnostic criteria for relapsing-remitting MS at treatment initiation. Severe adverse events occurred in 17 patients in the vitamin D group and 13 in the placebo group, none of which were related to cholecalciferol.

Conclusions and relevance: Oral cholecalciferol 100 000 IU every 2 weeks significantly reduced disease activity in CIS and early relapsing-remitting MS. These results warrant further investigation, including the potential role of pulse high-dose vitamin D as add-on therapy.

Trial registration: ClinicalTrials.gov Identifier: NCT01817166.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Thouvenot reported receiving grants from Programme Hospitalier de Recherche Clinique (PHRC) (French Ministry of Health) and grants from Agence Nationale de la Recherche (French National Research Agency) during the conduct of the study and personal fees from Biogen, Merck, Novartis, Roche, and Sanofi and grants from Biogen, Novartis, France SEP (sclérose en plaques), and EDMUS Foundation outside the submitted work. Dr Laplaud reported receiving personal fees from Biogen, Novartis, Merck, Roche, and MSD outside the submitted work and grants from EDMUS Foundation and France SEP. Dr Derache reported receiving personal fees from Biogen, Janssen, Sanofi, Merck, and Novartis outside the submitted work. Dr Le Page reported receiving personal fees from Merck, Biogen Idec, Sanofi, Novartis, and Alexion outside the submitted work. Dr Maillart reported receiving personal fees from Biogen, Alexion, Janssen, Amgen, Novartis, Merck, Sandoz, Sanofi, and Roche and grants from Biogen outside the submitted work. Dr Casez reported receiving nonfinancial support from Biogen and personal fees from Merck, Novartis, Roche, and Janssen outside the submitted work. Dr Guennoc reported receiving personal fees from Merk Serono and grants from Biogen and ROCHE outside the submitted work. Dr Heinzlef reported receiving personal fees from Sanofi and Edimark and support for meeting organization from Merck, Biogen, Novartis outside the submitted work. Dr Magy reported receiving personal fees from Biogen, Novartis, Sanofi, and Merck outside the submitted work. Dr De Sèze reported receiving personal fees from Biogen, Roche, Novartis, Sanofi, Merck, Alexion, Amgen, and Sandoz outside the submitted work. Dr Camu reported receiving grants from French Ministry of Health during the conduct of the study. Dr Mura reported grants from PHRC during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Participants in the D-Lay MS Clinical Trial
MRI indicates magnetic resonance imaging. aEnrollment information was not collected. bOne patient before month 3, 3 before month 6, 1 before month 12, and 4 after month 12. cOne patient before month 6, 2 before month 12, and 3 after month 12. dNo disease activity with follow-up until month 24 or disease activity.
Figure 2.
Figure 2.. Disease Activity in the Treatment Groups During the 2 Years of Follow-Up
Vertical solid lines represent median time to disease activity for each group (14.2 [95% CI, 11.8-24.1] months for the vitamin D group and 7.3 [95% CI, 3.4-11.8] months for the placebo group). Median (IQR) observation time was 23.7 (23.4-24.2) months for the vitamin D group and 23.8 (23.6-24.0) months for the placebo group.
Figure 3.
Figure 3.. Interaction Between Covariates and Vitamin D
Squares represent hazard ratios (HRs) after adjustment on randomization strata (contrast-enhancing lesions) and centers. Bars represent 95% CIs. Missing data per group: fluid-attenuated inversion recovery (FLAIR): 4 in the vitamin D group and 5 in the placebo group; Expanded Disability Status Scale (EDSS) score: 1 in the placebo group; serum vitamin D level: 1 in the vitamin D group and 2 in the placebo group; body mass index: 3 in the vitamin D group and 3 in the placebo group; cerebrospinal fluid (CSF) oligoclonal bands: 35 in the vitamin D group and 28 in the placebo group. See Supplement 2 for details of the EDSS, which evaluates neurological disability associated with multiple sclerosis. IVMP indicates high-dose intravenous methylprednisolone pulse therapy.
See this image and copyright information in PMC

References

    1. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838. doi: 10.1001/jama.296.23.2832 - DOI - PubMed
    1. Tintore M, Rovira À, Río J, et al. Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain. 2015;138(Pt 7):1863-1874. doi: 10.1093/brain/awv105 - DOI - PubMed
    1. Kuhle J, Disanto G, Dobson R, et al. Conversion from clinically isolated syndrome to multiple sclerosis: a large multicentre study. Mult Scler. 2015;21(8):1013-1024. doi: 10.1177/1352458514568827 - DOI - PubMed
    1. Simpson S Jr, Taylor B, Blizzard L, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010;68(2):193-203. doi: 10.1002/ana.22043 - DOI - PubMed
    1. Mowry EM, Waubant E, McCulloch CE, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol. 2012;72(2):234-240. doi: 10.1002/ana.23591 - DOI - PMC - PubMed

Publication types

MeSH terms

Associated data