High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis The D-Lay MS Randomized Clinical Trial
2 IGF - Institut de Génomique Fonctionnelle
3 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
4 CIC Plurithématique de Nantes
5 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
6 CHU Nice - Centre Hospitalier Universitaire de Nice
7 UR2CA URRIS - UR2CA - URRIS - Unité de Recherche sur le syndrome Radiologique ISolé et maladies apparentées
8 CHU Caen Normandie - CHU Caen Normandie – Centre Hospitalier Universitaire de Caen Normandie
9 CRC-SEP Normandie - Centre de Ressources et de Compétences sur la Sclérose en Plaques (CRC-SEP) [Caen]
10 CIC - Centre d'Investigation Clinique [Rennes]
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
12 CHU Charles Foix [AP-HP]
13 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
14 HCL - Hospices Civils de Lyon
15 CHUGA - CHU de Grenoble-Alpes - Centre Hospitalier Universitaire CHU Grenoble
16 CHIC - Centre Hospitalier Intercommunal de Cornouaille
17 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
18 CHI Poissy-Saint-Germain
19 CHU Limoges
20 CHU Limoges - Centre Hospitalier Universitaire Dupuytren 1 et 2
21 CHV - Centre Hospitalier de Versailles André Mignot
22 Département de Neurologie [Hôpital Gui de Chauliac - CHU Montpellier]
23 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
24 CH Perpignan - Centre Hospitalier Saint Jean de Perpignan
25 CHU Reims - Hôpital universitaire Robert Debré [Reims]
26 CHSF - Centre Hospitalier Sud Francilien - Centre Hospitalier d'Evry
27 Service de Neurologie [Strasbourg]
28 Service de neurologie [Hôpital Fondation Adolphe de Rothschild]
29 CHU Gabriel Montpied [Clermont-Ferrand]
30 Département Neurologie [CHU Toulouse]
31 INM - Institut des Neurosciences de Montpellier
32 BESPIM - Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie [CHU Nîmes]
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Résumé
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