LONDON — A new randomized study of vitamin D supplementation in multiple sclerosis (MS) has shown some intriguing results. Although the primary endpoint of "no evidence of disease activity" was not improved with vitamin D, imaging results did suggest a benefit in the group given supplementation.
The double-blind placebo-controlled SOLAR study of high-dose oral cholecalciferol (vitamin D3) oil was presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016 by Raymond Hupperts, MD, Orbis Medical Center, Sittard, the Netherlands.
"I think the most important message of SOLAR is that the vitamin D status of an MS patient matters for the disease process," coauthor Joost Smolders, MD, Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands, told Medscape Medical News. The significant improvements we saw in the vitamin D group after supplementation on important MRI measures in our subjects, combined with a point estimate of annualized relapse rate reduction of 30% (albeit nonsignificant), show that vitamin D status is relevant for the disease process of MS."
He added: "This shows that findings in association studies thus far cannot be regarded as exclusive confounding or reverse causality. Of course, further trials are needed to confirm these findings on clinical endpoints, and several important issues, including dosing and eligible patients, also need to be resolved."
Small Sample, Largest Trial
Commenting on the study for Medscape Medical News, Alberto Ascherio, MD, professor of nutrition and epidemiology at the Harvard TH Chan School of Public Health, Boston, Massachusetts, said, "The results of SOLAR provide further evidence that vitamin D supplementation is a safe and effective add-on treatment in patients with MS treated with β-interferon.
"The lack of significance for clinical outcomes should be interpreted considering the short duration of the trial (48 weeks) and relatively small sample size (219 patients) — for comparisons, most randomized trials of new MS drugs recruited over 800 patients to be able to demonstrate a significant effect," he added.
Dr Smolders noted that although the SOLAR study was small, it was in fact the largest randomized study to date of vitamin D3 as add-on therapy in MS.
For the study, 229 patients with a 25-hydroxyvitamin D serum concentration below 150 nmol/L were randomly assigned to the cholecalciferol oil at an oral daily dose of 14,000 IU (350 μg) or placebo. All patients were already receiving subcutaneous interferon β1a.
The primary endpoint was the percentage of patients who were disease activity free at week 48. This was defined as the absence of relapses, disability progression, and new combined unique active lesions (Gd-enhancing T1 or new or enlarging T2 lesions).
This endpoint was not different between the two groups, with 37.2% of the vitamin D group achieving "no evidence of disease activity" vs 35.3% of those receiving placebo (P = .912).
However, there were some interesting observations in secondary endpoints, in particular the MRI data, with a significant 32% reduction in the number of new combined unique active lesions in the cholecalciferol group. And there was a trend toward more cholecalciferol recipients being free from new T1 hypointense lesions, which became significant in those aged 18 to 30 years.
Dr Smolders suggested that cholecalciferol supplementation might be more effective in early stages of disease, when intense inflammatory activity is likely.
Table. SOLAR: MRI Data
|Endpoint||Cholecalciferol (n = 113)||Placebo (n = 116)||P Value|
|No. of new combined unique active lesions (mean)||1.09||1.49||.0045|
|Free from new T1 hypointense lesions (%)|
|Aged 18 - 30 y||85.7||46.8||.0063|
|Change from baseline total volume of T2 lesions (mean) (%)||3.57||6.07||.0354|
Dr Ascherio explained that a role for vitamin D supplementation for the treatment of MS has previously been suggested by a smaller randomized trial in Finland in which patients receiving 20,000 IU of vitamin D3 per week had better MRI outcomes than those receiving placebo.
Other evidence has come from observational data showing that patients with higher circulating levels of vitamin D have significantly better MRI and clinical outcomes than those with low levels. "The positive results on MRI outcomes in SOLAR are an important confirmation of the beneficial effects of vitamin D," he said.
He pointed out that SOLAR used "an exceedingly high dose" of vitamin D supplementation (14,000 IU/day), which is expected to elevate circulating levels of 25-hydroxyvitamin D to a supraphysiologic level.
"Considering that previous trials and observational studies support similar benefit from much lower levels of vitamin D supplementation (equivalent to about 3000 to 4000 IU/day, which is around a third of the dose given in SOLAR), there is no convincing rationale to give patients such a high dose," he said. Although no significant increase in adverse effects was reported in SOLAR, the size of the trial and its short duration limit the evidence in favor of safety of this mega-dose, and a dose of 3000 to 4000 IU of vitamin D per day remains the preferred treatment.
"It seems reasonable to expect that similar benefit will be observed in patients treated with immunomodulatory drugs other than interferon, but data on this are extremely sparse," Dr Ascherio added. "It should also be noted that virtually all studies included only white patients, so it remains uncertain whether similar benefits of vitamin D apply to African-Americans and other ethnic minorities."
The SOLAR study was supported by Merck KGaA, Darmstadt, Germany. Professor Hupperts and Dr Smolders have disclosed no relevant financial relationships, but one coauthor is an employee of Merck KGaA and another coauthor has received patent royalties for an infant vitamin D supplement.
Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Abstract 166. Presented September 16, 2016.
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Cite this: SOLAR: Vitamin D in MS Misses Endpoint but Hints of Benefit - Medscape - Sep 27, 2016.