A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis

Neurology

Jun 2010

DOI: 10.1212/WNL.0b013e3181e1cec2

Citations:349

Influential Citations:22

Interventional (Human) Studies

Enhanced Details

Methods

Open-label randomized prospective controlled 52-week trial in adults with multiple sclerosis; 49 participants (25 treatment, 24 control); mean age 40.5 years; 40 women and 9 men; 45 relapsing-remitting MS and 4 secondary progressive MS; disease-modifying therapy allowed; randomization by blinded drawing; groups matched for age, disease duration, EDSS, and disease-modifying drug use.

Intervention

Vitamin D3 with calcium: vitamin D3 dose escalated to 40,000 IU/day over 28 weeks, then 10,000 IU/day for 12 weeks, followed by down-titration to 0; calcium 1,200 mg/day throughout; vitamin D3 taken orally as hyperconcentrated solutions with dose adjustments (1–4 mL/week) to achieve target dose; calcium provided as powder (tricalcium phosphate) to deliver 1,200 mg/day.

Results

High-dose vitamin D3 with calcium for 52 weeks is safe in MS: serum calcium remained within the reference range with no significant adverse events; peak 25(OH)D reached about 413 nmol/L; urinary calcium/creatinine rose at the highest doses but stayed below 1.0; PTH stayed in normal range; no renal or hepatic dysfunction observed. Immunologic measures showed reduced T-cell proliferative responses in the vitamin D group (TCS decreased; p=0.002); greater reductions in TCS seen in those with 25(OH)D ≥100 nmol/L at 52 weeks (p=0.032). Clinically, relapse rate declined in the treatment group (ARR 0.26) vs control (ARR 0.45) but not statistically significant (p=0.09); EDSS changes were small. Overall, the regimen appears safe and immunomodulatory, but clinical outcomes were underpowered; evidence for safety is Class II, for clinical outcomes Class IV; a multicenter, blinded Phase II trial is planned to better define MRI and clinical benefits.

Limitations

Open-label design; small sample size (n=49); not powered for clinical outcomes; matching design limited enrollment; potential biases due to nonblinding and differential monitoring; control group allowed some vitamin D intake; results require replication in larger, blinded trials.

Abstract

Objective: Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively. Methods: An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score. Results: Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls. Conclusions: High-dose vitamin D (∼10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects. Classification of evidence: This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes. show less