Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) in western countries [1]. Based on autoimmune mediated damage to both glial and neuroaxonal structures, the disease is not yet curable and therapeutic options mainly focus on the control of the autoimmune reaction. The approved therapies include immunomodulatory (interferon-β, glatiramer acetate), (selective) immunosuppressive (fingolimod, azathioprine, mitoxantrone) or antibody-mediated (natalizumab) approaches. Additionally, new drugs are currently under investigation at different clinical stages. Although efficacy of all these drugs has been proven in large-scale clinical trials, some major issues still remain unsolved including partial efficacy, inconvenience of parenteral application, safety and tolerability aspects, insufficient neuroprotective capacity, and last but not least considerable treatment costs [2, 3]. Against this background the need for an improvement of therapeutic options in MS remains.

Numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D which is the biologically inactive storage form of vitamin D (extensively reviewed in [4]): it is long known that the geographic distribution of MS prevalence depends on latitude which is associated with both sunlight intensity and vitamin D serum levels [5‐8]. Particularly, increased sun exposure during childhood has been consistently shown to decrease the risk of MS [9‐11]. Several epidemiological studies provide a direct correlation between vitamin D intake and vitamin D serum levels with both the risk for new disease development and the course of already established MS [12‐15]. Further evidence for a beneficial role of vitamin D derives from the experimental autoimmune encephalomyelitis (EAE), which is the best established animal model for MS: it has been demonstrated that treatment with 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, prevents the development of murine EAE (preventive approach) [16, 17] and, commenced at onset of symptoms, reversibly blocks the progression of disease (therapeutic approach) [17]. Importantly, a recent EAE study provided evidence for a synergistic effect of a vitamin D analogue and interferon-β [18]. Less clear are the mechanisms of action by which vitamin D exerts its beneficial effects in autoimmune CNS disease. Modulatory effects on cellular and soluble components of the underlying immune reaction are probably most important [4, 19]. Additionally, prevention of demyelination has also been demonstrated recently in a model of toxic demyelination [20]. Compared to the large body of existing preclinical data, data on treatment effects derived from well-designed clinical trials are scarce, and most clinical trials so far focused rather on safety and tolerability aspects. Weekly peak doses of up to 280.000 IU 25-hydroxyvitamin D and long term treatment with a mean weekly dose of at least 70.000 IU for 36 weeks have been well-tolerated. In particular, there was no evidence for treatment-related hypercalcaemia [21, 22]. According to a review on the safety of high-dose vitamin D supplementation, daily doses of at least 10.000 IU can be considered safe in individuals with normal renal function [23]. Less clear is the optimal serum level for immunomodulatory treatment effects and hence the optimal daily dose [24]. A trend for a reduction of the annualized relapse rate was observed in clinical trials with daily doses of 5.000 to 10.000 IU, although these studies were not powered to detect a treatment effect on clinical parameters [22, 25]. The effect on MRI parameters is even more obscure. Accordingly, a recent Cochrane review concluded that "multi-centered RCTs (randomized controlled trials) with a focus on clinical as well as immunological and MRI outcomes (...) are still required" [26].

Against this background, we here present the study protocol for a randomized controlled clinical phase II pilot study on the effect of vitamin D supplementation on MRI in patients with relapsing-remitting MS or clinically isolated syndrome (CIS). We hypothesize, that high-dose supplementation is superior to low-dose supplementation with respect to imaging parameters including MRI and optical coherence tomography (OCT) as well as clinical parameters.

In light of the discrepancy between existing epidemiological and preclinical data on the one hand and available clinical data on the other the study design presented here has the potential to substantially contribute to the evaluation of the efficacy of vitamin D supplementation in MS and CIS patients. The randomized, controlled, double-blinded study design and the implementation of independent evaluation of outcome parameters fulfill the criteria for a high-quality clinical phase II trial in MS [34]. Some aspects of the study design however may deserve a closer discussion: Why was an active treatment regimen instead of a placebo treatment chosen for the control arm, i.e. low-dose vitamin D? In fact, this question was heavily debated. Although we do not know whether this represents rather a causal factor or a consequence, serum levels of 25-hydroxyvitamin D are often quite low in MS patients [13, 35]. Thus, we expect that low serum levels or even vitamin D deficiency will be detected in a substantial number of screened study candidates. From an ethical point of view and bearing in mind the importance of vitamin D for bone metabolism it would be difficult not to supplement these patients with vitamin D. On the other hand, the daily dose provided in the control arm may not be immunologically active itself as this would prevent the detection of any difference between both groups. Thus, the daily dose recommended by the German Nutrition Society for this group of age which corresponds to 5 μg or 200 IU and which most probably has no immunomodulatory potential represents a compromise between ethical concerns and efficacy aspects. Another important question relates to the dose used in the high-dose arm. In fact, we do not know, at which minimum doses or serum levels vitamin D starts to have immunomodulatory effects. To prevent failure of the trial because of an insufficient treatment dose, we choose the maximum dose for which sufficient safety data are available, which currently corresponds to 10.000 IU per day [23]. It might well be that already smaller doses would be sufficient, but on the other hand it is rather unlikely, that if this dose does not demonstrate any treatment effect, even higher daily doses would do. A further question might be why an add-on regimen to an established immunomodulatory treatment with interferon-β was chosen? In fact, from a methodological point of view, a monotherapeutic design would be preferable. However, since disease-modifying drugs are established and approved for the treatment of MS it would again be unethical to withhold these treatment options in favor of an experimental approach. The restriction to interferon-β as immunomodulatory treatment is explained by the need for maximum homogeneity in the trial cohort on the one hand and the reported synergistic effects of interferon-β and the vitamin D system on the other [18]. Finally, one might suspect that in view of the rather small sample size of 80 participants the study might be underpowered to detect a significant difference between both groups. However, the study will be able to detect a difference in mean new T2-hyperintense lesions per year of 1.5 with a power of more than 0.8. In the pivotal interferon-β1b trial, verum treatment resulted in a reduction of 2.0 lesions per year as compared to a placebo arm [36]. Thus, if high-dose supplementation with vitamin D is indeed effective, a reduction of 1.5 lesions per year would not be unrealistic.

In conclusion, vitamin D has the potential for a safe, orally available and cheap treatment option in MS and the EVIDIMS trial may help to close the existing gap between available promising preclinical and the lacking clinical data on the immunomodulatory efficacy of vitamin D in MS.