Multiple Sclerosis relapses cut in half by 100,000 IU of Vitamin D every 2 weeks– RCT 2019

Effect of vitamin D supplements on MS activity MS Trust UK 08 January 2020

People with MS are often advised to take high doses of vitamin D, but there’s been very little research to assess what effect this might have. Two recent clinical trials (CHOLINE and SOLAR) investigated the effect of vitamin D supplements in people with relapsing remitting MS already taking a disease modifying drug.

CHOLINE: 129 participants already taking Rebif (beta interferon 1a) and with low blood levels of vitamin D were recruited at 27 MS clinics in France. They were randomly assigned to take either 100,000 IU vitamin D3 (equivalent to about 7,000 IU/day) or placebo, once a fortnight for just under two years. The main measure of the study was a change in the number of relapses.

SOLAR: 229 participants already taking Rebif were recruited from 40 MS clinics in Europe and assigned to take either 14,000 IU vitamin D or placebo each day for just under one year. The main measure was the proportion of people at week 48 with no evidence of disease activity (NEDA), a measure which combines no relapses, no increase in disability and no new lesions seen on MRI scans.

Neither study was able to show a clear benefit from taking vitamin D as an add-on to disease modifying drugs but did show some improvements in MRI measures, indicating there may be some improvements in MS activity.

The researchers from these two studies teamed up to consider their results. They conclude that the effect of vitamin D supplementation is uncertain and less pronounced than might be expected from correcting low blood levels of vitamin D observed during relapses and MS progression. There could be a number of reasons for this discrepancy; for example, low vitamin D levels and more active MS are in fact unrelated and independently caused by a third, unknown factor.

The researchers conclude that doses of 1000-2000 IU/day would be sufficient to ensure bone health, an important role of vitamin D. They also suggest that a dose of 4000 IU/day would be reasonable advice for people with MS in northern parts of Europe to maintain ideal blood levels of vitamin D.

The studies in more detail

Background
Low levels of vitamin D have been linked with an increased risk of getting MS, but also with more frequent relapses and increased disability in those with established MS. As a result, people with MS are often advised to take high doses of vitamin D. But there’s been very little research to assess whether high dose vitamin D supplements affect MS activity. Two clinical trials (CHOLINE and SOLAR), which have just been published, investigated the effect of high doses of vitamin D in people with relapsing remitting MS already taking a disease modifying drug.

How these studies were carried out
CHOLINE: 129 participants already taking Rebif (beta interferon 1a) and with low blood levels of vitamin D were recruited at 27 MS clinics in France. They were randomly assigned to take either 100,000 IU vitamin D3 (equivalent to about 7,000 IU/day) or placebo, once a fortnight for just under two years. The main measure of the study was a change in the number of relapses.

SOLAR: 229 participants already taking Rebif were recruited from 40 MS clinics in Europe and assigned to take either 14,000 IU vitamin D or placebo each day for just under one year. The main measure was the proportion of people at week 48 with no evidence of disease activity (NEDA), a measure which combines no relapses, no increase in disability and no new lesions seen on MRI scans.

What was found?
CHOLINE: Taking all those who started treatment, there was no significant difference in the number of relapses between the two groups. However, analysing data for just those who completed the study, in the vitamin D group there were fewer relapses, improvement in some MRI measures, and lower disability progression.

SOLAR: There was no difference in the number of people with a NEDA status between the two groups. Analysing the data in more detail, the vitamin D group showed improvements in some MRI measures.

What does it mean?
Disappointingly, these studies have not helped to establish appropriate doses of vitamin D, who is most likely to benefit and when treatment would be most effective. Neither study was able to show a clear benefit from taking vitamin D as an add-on to disease modifying drugs but did show some improvements in MRI measures, indicating there may be some improvements in MS activity.

A large number of participants, approximately 20% in each study, dropped out. Both studies coincided with the introduction of oral disease modifying drugs, which made it difficult to recruit and hold on to participants; in both studies, people mostly dropped out because they had a relapse or wanted to switch from self-injecting to taking a pill. This high rate of drop-outs makes it difficult to draw firm conclusions; analysing data for just those who completed the studies could introduce bias into the results.

Researchers from these two studies collaborated to reflect on their findings and the results from other studies. They conclude that the effect of vitamin D supplementation is uncertain and less pronounced than might be expected from correcting low blood levels of vitamin D observed during relapses and MS progression. If vitamin D levels are directly linked to MS activity, you might expect there to be a huge treatment effect from increasing blood levels of vitamin D, but this doesn't seem to be the case. There could be a number of reasons for this discrepancy; for example, vitamin D levels and more active MS are in fact unrelated and independently caused by a third, unknown factor.

The researchers suggest that doses of 1000-2000 IU/day would be sufficient to ensure bone health, an important role of vitamin D. They also suggest that a dose of 4000 IU/day would be reasonable advice for people with MS in northern parts of Europe to maintain ideal blood levels of vitamin D.

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Hupperts R, et al.
Randomized trial of daily high-dose vitamin D(3) in patients with RRMS receiving subcutaneous interferon β-1a.
Neurology. 2019 Nov 12;93(20):e1906-e1916.
Summary(link is external), Read the full article(link is external)

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Camu W, et al.
Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE).
Neurol Neuroimmunol Neuroinflamm. 2019 Aug 6;6(5). pii: e597.
 Download the PDF from VitaminDWiki
Post hoc analysis – from PDF
There were 39 dropouts, almost 3 times higher than initially estimated. Drug-related dropouts were the most frequent cause. The corrected ARRc, used to avoid the potential bias of early dropout on ARR estimate, was significantly lower in the cholecalciferol group both in the ITT (rR = 0.502, 95% CI 0.326–0.764; p = 0.001) and in the completers’ population (rR = 0.395, 95% CI 0.186–0.801; p = 0.01).

• When dropouts were considered as relapse, the observed effect of the cholecalciferol treatment was significant (HR = 0.508, 95% CI 0.286–0.901; p = 0.02).
• When considering drug-related dropout as a failure, 66% fewer relapses were found in the cholecalciferol group compared with placebo (HR = 0.333, 95% CI 0.164–0.675;

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Smolders J, et al.
An update on vitamin D and disease activity in multiple sclerosis.
CNS Drugs. 2019 Dec;33(12):1187-1199.
Summary(link is external)
Read the full article(link is external)