Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome

Abstract

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Keywords: clinical trial; multiple sclerosis; vitamin D.

Figure 1

PREVANZ study, flow chart of participants. AE = adverse event; IMP = Investigational Medicinal Product; ITT = intention to treat; IU = international units.

Figure 2

Baseline and within study achieved serum 25(OH)D levels. (A) Distribution of baseline serum 25(OH)D₃ levels (nmol/l). (B) Mean serum 25(OH)D₃ (nmol/l) levels by treatment group/dose and week (with 95% confidence intervals, CIs). (C) Mean serum 25(OH)D₃ concentrations over the 48-week study period post baseline for all trial arms.

Figure 3

Outcomes for all participants by assigned treatment. MRI conversions plotted above clinical conversions and right-censored (non-converted) participants, and then plotted in order of failure time. Grey lines show time on study without conversion. Short light grey lines ending in a black dot show clinical conversions. Dark grey lines show intervals between MRI scans during which radiological conversion took place. IU = international units.

Figure 4

Centre-specific risk of conversion per day on study. Centre-specific risk of conversion per day on study, limited to those centres with more than four participants recruited. The symbol sizes (areas) are proportional to the number of participants accrued.