Contemporary Clinical Trials 39 (2014) 288–293

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The Vitamin D to Ameliorate Multiple Sclerosis (VIDAMS) trial: Study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis Pavan Bhargava a, Sandra Cassard a, Sonya U. Steele a, Christina Azevedo b, Daniel Pelletier b, Elizabeth A. Sugar c, Emmanuelle Waubant d, Ellen M. Mowry a,⁎ a

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Yale Multiple Sclerosis Center Department of Neurology, Yale University, CT, USA c Department of Biostatistics, Johns Hopkins School of Public Health, Baltimore, MD, USA d Department of Neurology, University of California San Francisco, San Francisco, CA, USA b

a r t i c l e

i n f o

Article history: Received 23 July 2014 Received in revised form 30 September 2014 Accepted 4 October 2014 Available online 12 October 2014 Keywords: Vitamin D Multiple sclerosis Clinical trial Randomized Double-blind

a b s t r a c t Background: Lower levels of vitamin D are associated with increased MS risk and with greater clinical and brain MRI activity in established relapsing MS. Objective: The VIDAMS trial (NCT01490502) is evaluating whether high-dose vitamin D supplementation reduces the risk of MS activity. Design/methods: Eligibility criteria include diagnosis of RRMS, age 18 to 50 years, and Expanded Disability Status Scale ≤4.0. Disease duration and activity requirements depend on whether 2005 or 2010 criteria are used for diagnosis. Enrollment is restricted based on prior MS therapy exposure and recent vitamin D use. After completing a one-month run-in of glatiramer acetate, 172 patients will be randomized 1:1 to oral vitamin D3 5000 IU versus 600 IU daily. Clinical visits occur every 12 weeks for 96 weeks. Results: Sixteen sites throughout the United States are participating in the trial. Complete enrollment is expected by late 2014, with follow-up through 2016. No interim analyses are planned. The primary outcome for the trial is the proportion of patients experiencing a relapse in each group. Other clinical, patient-reported, and MRI outcomes will be evaluated. Conclusions: The VIDAMS trial will provide critical information about the safety and efficacy of vitamin D therapy in RRMS, with implications for MS patients worldwide. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Multiple sclerosis (MS) is a chronic demyelinating disorder involving the central nervous system that is characterized by both inflammatory and neurodegenerative processes [1]. Despite advances in understanding its pathogenesis and treatment, MS remains a major cause of neurological disability

⁎ Corresponding author at: Department of Neurology, Johns Hopkins University, 600 N. Wolfe Street, Pathology 627, Baltimore, MD 21287, USA. Tel.: +1 410 614 1522; fax: +1 410 502 6736. E-mail address: [email protected] (E.M. Mowry).

http://dx.doi.org/10.1016/j.cct.2014.10.004 1551-7144/© 2014 Elsevier Inc. All rights reserved.

among young adults. While its etiology remains unknown, it is fairly well established that both genetic and environmental factors play a role in MS susceptibility [1]. The prevalence of MS increases with higher latitude and less exposure to ultraviolet light (the main source of vitamin D) [2,3], and in a nested case–control study, higher vitamin D levels were associated with lower subsequent risk of MS [4]. Data from epidemiologic studies suggest that vitamin D levels may influence the course of established MS. A longitudinal study in pediatric MS showed a 34% lower risk of relapse for every 10 ng/ml higher 25-hydroxyvitamin D level [5]. A similar magnitude of reduced relapse risk was later reported in an

P. Bhargava et al. / Contemporary Clinical Trials 39 (2014) 288–293

adult MS cohort [6]. Higher vitamin D levels have also been shown to be associated with less subsequent inflammatory MS activity on brain magnetic resonance imaging (MRI) [7]. Finally, studies have demonstrated that patients have lower vitamin D levels during MS relapses [8]. Previous interventional studies of vitamin D supplementation in MS have been inconclusive. Initial studies aimed to establish the safety of vitamin D supplementation in MS and were generally small or not randomized [9–12]. These studies utilized short-term doses of up to 40,000 IU/day of vitamin D, resulting in supra-physiological levels of 25-hydroxyvitamin D although notably these dose levels were without significant adverse effects [9,12]. A phase 1/2 trial randomized 49 MS patients to very high-dose (dose escalation up to 40,000 IU/day, followed by a de-escalation to 0 IU/day) versus discretionary vitamin D3 (up to 4,000 IU/day) for one year and found some evidence for better outcomes in the intervention group, although they were not statistically significant [9]. The limitations of this study include the fact that participants had different follow-up schedules depending on treatment assignment and that follow-up vitamin D levels were not available for those assigned to the discretionary arm. A randomized double-blind trial of vitamin D3 20,000 IU/week versus placebo in 66 MS patients demonstrated a reduction in gadolinium-enhancing lesions [13]. On the other hand, a preliminary phase 2 trial of calcitriol in 50 MS patients failed to demonstrate a beneficial effect on Expanded Disability Status Scale (EDSS) or relapse rate [14]. A Cochrane review suggested that current evidence for vitamin D supplementation in MS was insufficient to allow for confident decision making and stressed the need for further multicenter, randomized controlled trials (RCTs) [15]. Despite the lack of evidence, vitamin D supplementation for MS patients is already becoming part of clinical practice [16]. Of further concern, vitamin supplements that initially seemed beneficial for other diseases in observational studies had null or negative impacts in randomized trials [17], highlighting the fact that observational data, even when quite strong, are not always confirmed in the gold standard setting of a RCT. From a mechanistic standpoint, there are several ways in which vitamin D supplementation may help patients with MS. Vitamin D is a potent immunomodulator and plays a role in several different immune processes in both the innate and adaptive immune systems [18]. 1,25-Dihydroxyvitamin D3 promotes the production of tolerogenic dendritic cells [19], prevents the proliferation and enhances apoptosis of activated B cells [20]. It also has direct effects (inhibiting proinflammatory TH1 cells and promoting the production of CD4+CD25+FOXP3+ Treg cells) and indirect effects (reducing antigen presentation via B-cells, monocytes and dendritic cells) on T cells [21–23]. There is also evidence from human pathological studies that suggests a role for vitamin D metabolism in modulation of inflammatory activity in MS lesions [24]. In addition, studies have shown a reduced CSF:serum ratio of 25-hydroxyvitamin D levels in MS compared to other inflammatory and non-inflammatory neurological disease subjects [25]. The need for appropriately powered, well-designed RCTs of vitamin D supplementation in MS is clear. We describe herein the design of our multicenter, randomized, doubleblind, controlled trial of high- versus low-dose vitamin D3

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supplementation as add-on therapy among patients with RRMS. The primary objective of this trial is to determine if high-dose vitamin D3 supplementation is associated with a decrease in the proportion of RRMS patients experiencing a relapse. 2. Methods/design 2.1. Trial design and participants The Vitamin D to Ameliorate Multiple Sclerosis (VIDAMS) trial is a prospective, randomized, double-blind, multicenter trial of high- versus low-dose vitamin D3 as add-on therapy to glatiramer acetate, a standard therapy for RRMS. The trial began enrolling participants in April 2012. Subjects are randomized in according to a 1:1 allocation ratio to identical'appearing tablets of 600 IU or 5000 IU of oral vitamin D3 (Continental Vitamin Company, Los Angeles, CA) daily for two years. Recruitment is expected to be complete by late 2014. The final study population will consist of 172 subjects with a diagnosis of RRMS who satisfy the inclusion and exclusion criteria noted in Table 1. Institutional Review Boards have approved the study at all participating institutions. All participants provide written informed consent. 2.2. Enrollment & randomization Subjects initiate therapy with daily glatiramer acetate for a one month run-in period prior to randomization. The run-in was chosen to reduce the risk of randomizing nonadherent individuals. Those who successfully complete the run-in period and remain adherent to glatiramer acetate (defined by no more than three missed doses in the run-in period) are then randomized in a 1:1 fashion to receive either 5000 IU daily or 600 IU daily of oral vitamin D3. The study statistician generated the randomization schedule, which is stratified by site (to account for differences in ultraviolet light as well as other site-specific factors that may influence outcomes) and is based on randomly permuted blocks of varying sizes to ensure proper balance and masking of treatment assignments within each center. Vitamin D is provided in bottles that are identified by a unique ID number and do not list the treatment dosage. In order to prevent unblinding, each participant's primary care physician and regular neurologist are informed that the subject is in the trial and are asked not to check vitamin D levels during the trial. 2.3. Interventions Subjects are randomized to receive oral vitamin D3 5000 IU or 600 IU once daily. All patients are treated with subcutaneous glatiramer acetate 20 mg daily throughout the course of the study. Subjects are encouraged to take glatiramer acetate and the study drug together at the same time each day to minimize the chance that they will be forgotten. They are also instructed to take the medication within an hour of a meal, since oral vitamin D is fat-absorbed. Subjects who experience two or more relapses or excessive MRI activity (more than 3 new T2 lesions on the year 1 brain MRI) or one relapse plus more than 2 new T2 lesions on the year 1 MRI, may be offered a switch from glatiramer acetate to

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Table 1 Inclusion and exclusion criteria. Inclusion criteria 1. 2. 3. 4.

5.

6. 7. 8.

Must meet the 2005 or 2010 revised McDonald criteria for RRMS. Aged 18 to 50 years. Baseline EDSS between 0.0 and 4.0. If meeting the 2005 McDonald criteria for RRMS, must have disease duration of ≤10 years, and must have had either one clinical attack in the past two years and at least one new silent T2 or gadoliniumenhancing lesion on brain MRI within the past year or have had two clinical attacks in past two years, one of which occurred in the past year. If meeting criteria for CIS using the 2005 McDonald criteria but now satisfying the 2010 McDonald criteria for MS, disease onset must have occurred within the year prior to screening. 25-Hydroxyvitamin D level ≥15 ng/mL within 30 days of screening. If a female of childbearing potential, must be willing to use at least one form of pregnancy prevention throughout the study. Willing to stop taking additional supplemental vitamin D, except as part of a multivitamin (can contain up to 600 IU), and must be willing to avoid the use of cod liver oil.

Exclusion criteria 1. Pregnant or nursing. 2. Ongoing liver or renal disease. 3. Known history of nephrolithiasis, non-spurious hypercalcemia, sarcoidosis, active tuberculosis or leprosy, HIV, cancer (other than basal cell or squamous cell carcinomas of the skin), clinically relevant cardiac disease, ongoing hyperthyroidism, malabsorptive gastrointestinal disease or other serious medical disorders. 4. History of self-reported alcohol or substance abuse in the past six months. 5. Contraindications to completing MRI procedures. 6. Active suicidal ideation in the past 6 months, passive suicidal ideation in the past 2 months, or suicidal attempts or preparatory attempts in the past 5 years. 7. Serum calcium N0.2 mg/dL above the upper limit of normal. 8. Currently using thiazide diuretics, digoxin, diltiazem, verapamil, cimetidine, heparin, low-molecular weight heparin, carbamazepine, phenytoin, phenobarbital, routine systemic corticosteroids, rifampin, cholestyramine, or medications that may cause malabsorption. 9. History of treatment with rituximab, any chemotherapeutic agent, an investigational therapy for MS, or total lymphoid irradiation, or treatment in the past six months with natalizumab, fingolimod, or dimethyl fumarate, or treatment in the past month with interferon beta or steroids. 10. Must not have received glatiramer acetate for more than three months, and the most recent treatment must have been administered greater than one month ago. 11. Use of more than an average of 1000 IU/day of vitamin D in the three months prior to screening.

another disease-modifying therapy for MS at the discretion of the treating physician but will remain in the study and continue with the assigned vitamin D dosage. 2.4. Study visits Study visits include screening and run-in visits prior to randomization at the baseline visit. Subsequent follow-up visits occur every 12 weeks; unscheduled relapse visits and premature study withdrawal visits occur when necessary. All study visits are expected to occur within 10 days of the target visit date. Between study visits, the study coordinator contacts all subjects to inquire about new symptoms and assess adherence.

2.5. Study assessments Assessments for measures of efficacy include clinical relapse assessments, EDSS evaluations, MS functional composite (MSFC), MRI brain with and without gadolinium, low-contrast visual acuity (2.5% Sloan chart, measured binocularly) and health-related quality of life (Functional Assessment in MS version 4.0) (Table 2). Relapses are defined as new or recurring symptoms referable to the central nervous system lasting for at least 24 h after a remission of 30 days or more since the prior event. Pseudo-exacerbations (worsening in the context of a fever/infection) are excluded. Relapses must be accompanied by worsening of the EDSS (≥ 0.5 points) or in the Functional Systems (FS) scales (2 points on at least one FS scale or 1 point ≥ 2 FS scales), as determined by the blinded examining neurologist [26]. Possible relapses meet the same historical criteria but are not required to satisfy the same EDSS/FS scale criteria. Brain MRI scans are performed at 3 T and processed at baseline and at weeks 48 and 96. The standardized protocol includes a 3D isotropic volumetric T1-weighted gradient echo sequence (MPRAGE/SPGR, 1 mm × 1 mm × 1 mm voxel size), a 2D multislice dual echo sequence (proton density and T2weighted, 1 mm × 1 mm × 3 mm voxel size and no gaps), and pre- and post-contrast T1-weighted spin echo sequence (1 mm × 1 mm × 3 mm voxel size and no gaps). Sites are required to submit dummy scans for approval to ensure adherence to this standardized protocol, and each scan is quality checked by the central reading site (Advanced imaging in MS laboratory). De-identified MRIs will undergo post-processing and analysis by an experienced neurologist/MRI reader who is blinded to treatment group and disease course. Brain lesions will be identified on simultaneously viewed, T1-weighted gradient echo (MPRAGE), T2-weighted, and proton density images. Both T1- and T2-visible white matter lesions will be manually segmented using commercially available Osirix software. T1- and T2-lesion masks and volumes will be created as described previously [27]. Intra- and interobserver variability analyses will be performed to ensure accuracy. Normalized brain parenchymal, grey matter and white matter volumes will be calculated from MPRAGE images using SIENAX (Oxford, UK), which is part of FSL [28]. Whole brain volume change will be calculated from highresolution 3D T1-weighted images by SIENA [29]. Output will be converted into percentage brain volume change per year. Novel measures, such as cortical thickness, will also be assessed using FreeSurfer [30]. Adherence to vitamin D is assessed at each follow-up visit by pill count; adherence to glatiramer acetate is assessed simultaneously by self-reported number of remaining injections. Blood samples will be collected to measure 25-hydroxyvitamin D levels at baseline and at weeks 12, 24, 48, 72 and 96. These levels will be determined in a single batch at the end of the study to ensure the best possible reproducibility and to ensure that no unblinding occurs. In terms of safety assessments, participants will have screening laboratory tests (blood urea nitrogen, creatinine, calcium, aspartate aminotransferase, alanine aminotransferase, and urine pregnancy). Calcium and, in women of childbearing

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Table 2 Assessments at each study visit.

Informed consent Medical history and medication check Clinical exam Vital signs EDSS MSFC MRI Suicidality assessment Low-contrast acuity FAMS Sun exposure survey Skin tone card Fitzpatrick skin tone survey Sodium screener Screening labse Urine pregnancy test Calcium Vitamin D level Blood storage Dispensing study drug Compliance check Adverse events evaluation Relapse verification Evaluation of blind a b c d e

Screen (−6 weeks)

Run-in (−4 weeks)

Baseline Week 0

Week 12, 36, 60, 84

Week 24, 48, 72

Week 96

Relapse visit

X X X

X

X

X

X X Xc X Xc X X X X

X X X X X X X X X X

X Xd Xd X

Xc

X X

X X

X

X

X

X X X X X X X X X X

c

X

X

X

X X

X

X X X X X X

X Xa Xb X X X X

X X X Xc X X X X

X X X X X X X

X X

Weeks 12 and 36 only. Week 12 only. Week 48 only. If clinically indicated. Screening labs include BUN, creatinine, calcium, AST, ALT, vitamin D level and urine pregnancy and are processed locally.

potential, pregnancy tests, occur during the study as detailed in Table 1. Suicidality assessments are conducted at each study visit, per the United States (US) Food and Drug Administration (FDA) requirements. 2.6. Criteria for discontinuing study drug The study drug will be discontinued if the participant becomes pregnant or develops nephrolithiasis or persistently elevated serum calcium levels, if it is in the participant's best interest (as determined by the treating physician), if the participant experiences an adverse event grade 3 or higher (National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0) that is at least possibly related to the study drug, or if the subject cannot tolerate the study drug or wants to discontinue treatment. An independent data and safety monitoring board (DSMB), which consists of two neurologists and one statistician, meets two times per year and is notified and weighs in any time a serious adverse event occurs. 2.7. Study outcomes The primary outcome is the proportion of subjects in each group who have had a relapse at two years. Secondary end points will include the annualized relapse rate, the occurrence of sustained clinical disease progression on EDSS (increase in EDSS score at month 12 by at least 1.0 point that is confirmed on the final examination one year later), the number of new or enlarging T2-weighted hyperintense MRI lesions, and the

change in T2 lesion volume and normalized brain parenchymal volume and normalized gray matter volume and cortical thickness. Additional tertiary endpoints include the number of relapses requiring treatment with high-dose steroids, the time to first on-study relapse, the proportion with probable relapse, the annualized probable relapse rate, the change in MSFC score, the change in low-contrast letter acuity over two years, and the change in Functional Assessment in MS score over two years, the percentage of patients with a new T2 lesion on brain MRI and the percentage of patients with gadolinium enhancing lesions on brain MRI. 2.8. Sample size In a phase-1/2 trial comparing approximately 10,000 IU/day vs b4,000 IU/day [9], the proportion experiencing a relapse was 37% in the low-dose vitamin D group versus 16% in the high-dose vitamin D group. A sample size of 172 patients provides 80% power to detect a 57% decrease (from 37% to 16%) in the proportion of subjects with relapses for participants receiving high- versus low-dose vitamin D assuming a drop-out rate of 10% and a two-sided type I error rate of 0.05. 3. Discussion While it is clear that vitamin D insufficiency is associated with increased MS risk and may also be related to increased clinical and radiological disease activity, there still exists a lack of evidence for a beneficial effect of vitamin D supplementation on disease activity in established MS. This gap can only be bridged

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by high quality, randomized trials of vitamin D supplementation in MS [31]. The VIDAMS trial is a step towards understanding the effect of vitamin D supplementation in patients with RRMS. While there are other vitamin D trials ongoing in Europe [32,33], the VIDAMS trial is unique in several ways. First, the dose of vitamin D3 utilized in this trial is different. Unlike other ongoing trials, which are utilizing an intervention dose of 10,000 IU daily [32,33], we chose an intervention dose of 5000 IU daily. The ideal serum level of 25-hydroxyvitamin D for patients with MS is still debated. Several experts have suggested that 30 ng/mL (75 nmol/L; conversion factor from ng/mL to nmol/L is 2.496) is the minimum desired 25hydroxyvitamin D level for the general population [34]; however, levels above 40 ng/mL were protective against MS [4]. Further, in the pediatric-onset MS study, there was no evidence of a threshold above which vitamin D was not important (up to approximately 60 ng/mL, the highest level measured) [5]; no threshold was determined in the adult MS cohort in the Australian study either [6]. However, since patients in these studies didn't have higher levels of vitamin D, it is unclear if the apparent linear relationship persists above 60 ng/mL. Some experts believe the tolerable upper limit dose to be 10,000 IU/day [34]. It is important to consider that all the studies regarding safety of vitamin D have been fairly short and, although no significant adverse events emerged with levels of 25-hydroxyvitamin D up to 192 ng/mL, the longterm effects of such supraphysiological levels are unknown. It thus seems likely that the appropriate target level is between 40 ng/mL and 60 ng/mL. In a vitamin D3 pharmacokinetic study [35], healthy subjects with a mean baseline level of 28 ng/mL were treated with vitamin D3 5,000 IU daily for 20 weeks and had a final 25-hydroxyvitamin D level that approached 60 ng/mL. As such, we rationalized that 5000 IU daily is a justifiable dose for achieving the target 25-hydroxyvitamin D level of 40–60 ng/mL. Another feature differentiating our trial from most other trials is the provision of some vitamin D supplementation to subjects in the control arm. The control dose of vitamin D3 600 IU was chosen for equipoise, as it is the current recommended daily allowance by the US Food and Nutrition Board [36]. This dose, however, is not expected to raise the serum 25-hydroxy vitamin D level substantially based on previous pharmacokinetic studies [35]. Another feature distinguishing the VIDAMS trial is the incorporation of a run-in period. We expect that this will help us minimize drop-out by pre-identifying participants at risk of non-adherence. However, it does limit the generalizability to individuals who are more adherent to medication, which may represent a subset of the general MS population. We felt that this was a reasonable trade-off since our main focus is on proving the efficacy, as opposed to effectiveness, of the medication. The duration of this trial is longer than most other previous pilot studies and currently ongoing RCTs, which will increase the chance of observing a significant change in disease activity with high-dose vitamin D supplementation and will also provide a longer duration of monitoring for significant adverse events. There is mounting evidence that vitamin D has an effect on MS disease activity as well as progression [37]. Besides assessing endpoints that measure inflammatory disease activity, the VIDAMS trial also includes surrogate endpoints for

disease progression such as change in brain volume. This will enable us to assess the direct effects of vitamin D supplementation on brain atrophy. Finally, the use of glatiramer acetate as the diseasemodifying therapy for subjects is unique to this trial. Other currently-enrolling phase 2/3 trials of vitamin D are utilizing interferon beta as the disease-modifying therapy for participants [32,33]. Glatiramer acetate was chosen due to low incidence of serious adverse events and ease of monitoring. While the choice of a single DMT may limit the generalizability of the results of this trial to MS patients treated with other DMTs, demonstrating a benefit with vitamin D as an add-on to glatiramer acetate will help increase the overall generalizability of results obtained from the collective group of trials of vitamin D supplementation. In conclusion, the VIDAMS trial will help to bridge the gap in knowledge regarding the effect of vitamin D supplementation on MS disease activity and will thus have consequences for the treatment of MS patients worldwide. Acknowledgments We would like to acknowledge funding support from the National Multiple Sclerosis Society through RG-4407A2/1 to E.M.M and FP-1787A1 to P.B. We would also like to acknowledge the principal investigators at the various sites of the VIDAMS trial. References [1] Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–17. [2] Simpson S, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a metaanalysis. J Neurol Neurosurg Psychiatry 2011;82:1132–41. [3] Ramagopalan SV, Handel AE, Giovannoni G, Rutherford Siegel S, Ebers GC, Chaplin G. Relationship of UV exposure to prevalence of multiple sclerosis in England. Neurology 2011;76:1410–4. [4] Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296: 2832–8. [5] Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010;67:618–24. [6] Simpson S, Taylor B, Blizzard L, Ponsonby A-L, Pittas F, Tremlett H, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010;68:193–203. [7] Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista A a, Lincoln RR, et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012;72:234–40. [8] Soilu-Hänninen M, Laaksonen M, Laitinen I, Erälinna J-P, Lilius E-M, Mononen I. A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J Neurol Neurosurg Psychiatry 2008;79:152–7. [9] Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch H-M, Cheung R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010;74:1852–9. [10] Wingerchuk DM, Lesaux J, Rice GP a, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2005;76:1294–6. [11] Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses 1986;21:193–200. [12] Kimball SM, Ursell MR, O'Connor P, Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr 2007;86:645–51. [13] Soilu-Hänninen M, Aivo J, Lindström B-M, Elovaara I, Sumelahti M-L, Färkkilä M, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2012;83:565–71.

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