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D-Lay MS

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

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Year of Publication: 2025

Authors: Eric Thouvenot, David Laplaud, Christine Lebrun-Frenay, ..., Manon Rival; for the D-Lay MS Investigators

Journal: JAMA

Citation: JAMA. 2025;333(16):1413-1422

Link: https://doi.org/10.1001/jama.2025.1604

Clinical Question

Does high-dose vitamin D monotherapy reduce disease activity in patients with clinically isolated syndrome typical for multiple sclerosis?

Bottom Line

Oral cholecalciferol 100,000 IU every 2 weeks significantly reduced disease activity (combined relapse and MRI activity) by 34% compared to placebo (HR 0.66, p=0.004) over 24 months in patients with CIS. The benefit was primarily driven by reduced MRI activity (new lesions and contrast-enhancing lesions), while relapse rates alone did not reach statistical significance. Treatment was safe with no hypercalcemia or drug-related serious adverse events. These results support high-dose vitamin D as a potential monotherapy or add-on therapy option for early MS.

Major Points

  • First large phase 3 RCT demonstrating efficacy of vitamin D monotherapy in reducing disease activity in CIS/early RRMS
  • Disease activity occurred in 60.3% of vitamin D group vs 74.1% of placebo group over 24 months (HR 0.66, p=0.004)
  • Number needed to treat to prevent one case of disease activity was 7.2 (95% CI 4.1-29.0)
  • MRI outcomes all significantly favored vitamin D: MRI activity (HR 0.71, p=0.02), new lesions (HR 0.61, p=0.003), contrast-enhancing lesions (HR 0.47, p=0.001)
  • Relapse rate was numerically lower but not statistically significant (17.9% vs 21.8%, HR 0.69, p=0.16)
  • Similar efficacy observed in subgroup of 247 patients meeting 2017 McDonald criteria for RRMS at baseline
  • Subgroup analysis showed greatest benefit in patients with severe vitamin D deficiency (<30 nmol/L), no spinal cord lesions, and normal BMI
  • No hypercalcemia or serious adverse events related to vitamin D supplementation
  • Median time to disease activity was doubled in vitamin D group (432 vs 224 days)
  • Efficacy (HR 0.66) was comparable to teriflunomide in TOPIC trial (HR 0.65) and slightly less than interferon beta in REFLEX/BENEFIT trials

Design

Study Type: Multicenter, double-blind, parallel, 1:1 randomized, phase 3, placebo-controlled clinical trial

Randomization: 1

Blinding: Double-blind. Site investigators, patients, and outcome assessors were blinded to treatment assignments. Randomization was performed by an independent statistician in blocks of 4, stratified by center and presence of contrast-enhancing lesions on diagnostic MRI. Active and placebo treatments were produced by Nexpharma.

Enrollment Period: July 15, 2013 to December 23, 2020

Follow-up Duration: 24 months (last patient visit January 18, 2023)

Centers: 36

Countries: France

Sample Size: 303

Analysis: Intention-to-treat (full analysis set: patients who took at least 1 dose). Random-effects Cox model adjusted for center and contrast-enhancing lesions on diagnostic MRI (partial adjustment). Fully adjusted model included age, sex, number of T2/FLAIR lesions, baseline EDSS score, serum vitamin D levels, high-dose IV methylprednisolone, and time from CIS onset. Linear mixed models for quantitative secondary endpoints. Multiple imputation for missing data. Two-tailed α level of 0.05.

Inclusion Criteria

  • Age 18 to 55 years
  • Clinically isolated syndrome (CIS) within the past 90 days
  • Diagnostic brain MRI with T2/FLAIR and T1-weighted gadolinium imaging
  • MRI showing dissemination in space according to 2010 revised McDonald criteria OR presence of at least 2 MRI lesions consistent with MS and positive cerebrospinal fluid (≥2 unique oligoclonal bands)
  • Serum vitamin D level <100 nmol/L

Exclusion Criteria

  • Already receiving disease-modifying therapy
  • Serum vitamin D levels >100 nmol/L
  • History of hypercalcemia
  • History of sarcoidosis
  • History of tuberculosis

Arms

FieldControlVitamin D (Cholecalciferol)
InterventionOral placebo vial every 2 weeks for 24 months or until occurrence of disease activityOral cholecalciferol 100,000 IU vial every 2 weeks for 24 months or until occurrence of disease activity
Duration24 months24 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Disease activity, defined as first occurrence of relapse OR MRI activity (new and/or unequivocally enlarging brain FLAIR or spinal cord T2 lesions or contrast-enhancing T1 lesions on follow-up MRI) over 24 months of follow-upPrimary109/147 (74.1%)94/156 (60.3%)0.660.004
RelapseSecondary32/147 (21.8%)28/156 (17.9%)0.690.16
MRI activitySecondary96/147 (65.3%)89/156 (57.1%)0.710.02
Contrast-enhancing lesionsSecondary50/147 (34.0%)29/156 (18.6%)0.470.001
New or enlarging lesionsSecondary87/147 (59.2%)72/156 (46.2%)0.610.003
EDSS annual changeSecondary-0.14 (SE 0.06)-0.17 (SE 0.05)0.67
PASAT annual changeSecondary3.15 (SE 0.62)3.29 (SE 0.49)0.86
EQ-5D-5L annual changeSecondary0.02 (SE 0.01)0.03 (SE 0.01)0.40
SF-36 physical annual changeSecondary1.10 (SE 0.52)1.41 (SE 0.41)0.64
SF-36 mental annual changeSecondary2.97 (SE 0.75)2.38 (SE 0.59)0.54
FSMC (fatigue) annual changeSecondary0.97 (SE 1.03)-0.77 (SE 0.82)0.19
HADS total annual changeSecondary-0.62 (SE 0.39)-0.54 (SE 0.30)0.86
Serious adverse events (patients)Adverse13 (8.8%)17 (10.9%)0.55
Hypercalcemia (mild, 2.6-2.88 mmol/L)Adverse2 patients0 patients
Moderate/severe hypercalcemia (>2.88 mmol/L)Adverse00
Kidney failureAdverse00
Drug-related serious adverse eventsAdverse00

Subgroup Analysis

Interaction analyses revealed patients who benefited most from vitamin D were: (1) those without spinal cord lesions at diagnosis (HR 0.23 vs 0.85; P for interaction=0.01), (2) those with severe vitamin D deficiency <30 nmol/L (HR 0.33 vs 0.78; P for interaction=0.03), and (3) those with normal BMI <25 at baseline (HR 0.53 vs 0.95; P for interaction=0.048). Age, sex, CIS phenotype (optic neuritis vs other), high-dose IV methylprednisolone, number of brain T2/FLAIR lesions, presence of contrast-enhancing lesions, EDSS score, and CSF oligoclonal bands did not significantly modify the treatment effect. In the subgroup of 247 patients meeting 2017 McDonald criteria for RRMS at baseline, results were similar: disease activity HR 0.66 (95% CI 0.49-0.89, p=0.007), MRI activity HR 0.71 (p=0.03), new/enlarging lesions HR 0.59 (p=0.003), contrast-enhancing lesions HR 0.49 (p=0.006).

Criticisms

  • MRI scans performed only at fixed intervals (3, 12, and 24 months), not necessarily capturing the precise timing of lesion development
  • Median times to disease activity reflect visit times rather than actual event times
  • EDSS not measured frequently enough to assess 3- or 6-month confirmed disability accumulation or NEDA-3
  • Unable to assess relapse-associated worsening or progression independent of relapse activity
  • Relapses and MRI activity were not diagnosed by central adjudication
  • Multiple secondary endpoint comparisons and subgroup analyses increase risk of type I error
  • Long enrollment period (2013-2020) with revision of McDonald criteria in 2017
  • Race and ethnicity data not collected per French law, limiting generalizability assessment
  • Low relapse rate may have limited ability to detect significant difference in relapse risk
  • Treatment discontinued upon disease activity, preventing assessment of longer-term outcomes

Funding

Programme Hospitalier de Recherche Clinique (PHRC) n°12-015-0425, French Ministry of Health

Based on: D-Lay MS (JAMA, 2025)

Authors: Eric Thouvenot, David Laplaud, Christine Lebrun-Frenay, ..., Manon Rival; for the D-Lay MS Investigators

Citation: JAMA. 2025;333(16):1413-1422

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