ARTICLE OPEN ACCESS CLASS OF EVIDENCE Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE) Correspondence William Camu, MD, PhD, Philippe Lehert, PhD, Charles Pierrot-Deseilligny, MD, Patrick Hautecoeur, MD, Dr. Camu Anne Besserve, MD, Anne-Sophie Jean Deleglise, MD, Marianne Payet, MD, Eric Thouvenot, MD, PhD, and firstname.lastname@example.org Jean Claude Souberbielle, MD Neurol Neuroimmunol Neuroinﬂamm 2019;6:e597. doi:10.1212/NXI.0000000000000597 Abstract MORE ONLINE Class of Evidence Objective Criteria for rating To evaluate the safety and eﬃcacy of cholecalciferol in patients with relapsing-remitting MS therapeutic and diagnostic (RRMS). studies NPub.org/coe Methods In this double-blind, placebo-controlled parallel-group, 2-year study, 181 patients with RRMS were randomized 1:1. Key inclusion criteria were a low serum 25-hydroxy vitamin D (25OHD) concentration (<75 nmol/L), a treatment with interferon beta-1a 44 μg (SC 3 times per week) 4 months ± 2 months before randomization, and at least one documented relapse during the previous 2 years. Patients received high-dose oral cholecalciferol 100,000 IU or placebo every other week for 96 weeks. Primary outcome measure was the change in the annualized relapse rate (ARR) at 96 weeks. Secondary objectives included safety and tolerability of cholecalciferol and eﬃcacy assessments (ARR, MRI parameters, and Expanded Disability Status Scale [EDSS]). Results The primary end point was not met. In patients who completed the 2-year follow-up (45 with cholecalciferol and 45 with placebo), all eﬃcacy parameters favored cholecalciferol with an ARR reduction (p = 0.012), less new hypointense T1-weighted lesions (p = 0.025), a lower volume of hypointense T1-weighted lesions (p = 0.031), and a lower progression of EDSS (p = 0.026). The overall rate of adverse events was well balanced between groups. Conclusions Although the primary end point was not met, these data suggest a potential treatment eﬀect of cholecalciferol in patients with RRMS already treated with interferon beta-1a and low serum 25OHD concentration. Together with the good safety proﬁle, these data support the explo- ration of cholecalciferol treatment in such patients with RRMS. Clinicaltrials.gov identifier NCT01198132. Classification of evidence This study provides Class II evidence that for patients with RRMS and low serum 25OHD, cholecalciferol did not signiﬁcantly aﬀect ARRs. ´ ´ From CHU Gui de Chauliac (W.C.) and Institut de Genomique Fonctionnelle (E.T.), Universite de Montpellier, France; Faculty of Economics (P.L.), UCL Mons, Louvain, Belgium; Faculty of ´ ˆ ` Medicine (P.L.), the University of Melbourne, Australia; CHU Pitie Salpetriere (C.P.-D.), Paris; GHICL St Vincent de Paul (P.H.), Lille; Merck (A.B., A.-S.J.-D., M.P.), Lyon; CHU Caremeau (E.T.), Nımes; and CHU Necker (J.C.S.), Paris, France. Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by Merck. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary 25OHD = 25-hydroxy vitamin D; ARR = annualized relapse rate; BOCF = Baseline Observed Carried Forward; DRAE = disease-related adverse event; EDSS = Expanded Disability Status Scale; HR = hazard ratio; ITT = intention to treat; NEDA = No Evidence of Disease Activity; PASAT = Paced Auditory Serial Addition Task; RRMS = relapsing-remitting MS; SCTIW = subcutaneously 3 times per week; SDRAE = serious DRAE; TEAE = treatment emergent adverse event; VD = vitamin D; VDCM = mean of VDC. Optimizing treatment in relapsing-remitting MS (RRMS) is Patients an unmet need. Immunomodulators or immunosuppressants Eligible patients were aged between 18 and 65 years, with are eﬃcient to lower relapse rate, but they are not deprived of a diagnosis of RRMS based on the 2005 revised McDonald adverse eﬀects, and poor response to treatment is still criteria, low serum 25OHD concentration (VDC, < 75 1,2 a concern. nmol/L), a treatment with interferon beta-1a 44 μg(or 22 μg in case of intolerance to 44 μg) SCTIW for 4 months Vitamin D (VD) is a biological regulator of the immune ± 2 months at the randomization visit, and an Expanded system. VD deﬁciency is a risk factor for MS, and the risk of Disability Status Scale (EDSS) score from 0 to 5.0, with at relapse and the risk of having new MRI lesions are inversely least one documented relapse during the previous 2 years correlated with 25-hydroxy vitamin D (25OHD) blood levels, and stable disease (no episode) over the last 30 days. Main 4–8 both in adults and children. VD is safe even at very high exclusion criteria were use of drugs aﬀecting VD metabo- doses in RRMS. Double-blind, placebo-controlled trials gave lism other than corticosteroids; previous or ongoing hy- controversial results and were characterized by a methodo- percalcemia; and abnormal renal function deﬁned by 10,11 logical heterogeneity. All studies with cholecalciferol, but eGFR < 60 mL/min. Eligible patients were identiﬁed in the one, gave positive results on biological parameters of in- clinic at each study site and recruited according to the ﬂammation, on MRI parameters of MS activity, or on quality protocol. 12–15 of life. However, none of these studies showed a clinical beneﬁt with VD treatment. The present study assessed the Study design and treatment safety and eﬃcacy of cholecalciferol in patients with RRMS, After enrollment, randomization was performed within an already treated with interferon beta-1a 44 μg subcutaneously 3 8-week period, and patients were randomly assigned (1:1) to times per week (SCTIW), using 2 original parameters at in- receive cholecalciferol or placebo at the second study visit. clusion, clinically active RRMS and VD insuﬃciency, com- The composition, appearance, and packaging of placebo bined with a 2-year duration. treatment were identical to those of active treatment. When starting medication, each subject was assigned a randomiza- tion number according to a chronological sequential order per Methods site. A unique randomization number was assigned to each subject at the initial visit. This number was retained by the Primary research question subject until the completion of the study. Treatment kits were This phase 2, multicenter, randomized, double-blind, labeled with batch number, expiry date, randomization placebo-controlled parallel-group study was designed number, storage/administration conditions, and a kit identi- to evaluate the eﬃcacy of cholecalciferol (Crinex labora- ﬁcation number. tories, Montrouge, France) in patients with RRMS that was conducted from January 2010 to June 2013 at 27 sites Randomized patients were treated for 96 weeks. Treatment in France. Class II evidence is provided here as more was an oral solution packaged in 2 mL yellow glass (type III) than 20% of randomized patients did not complete the ampoules with 2 self-breakable tips, containing 2.5 mg of study. cholecalciferol corresponding to 100,000 IU or placebo. Standard protocol approvals, registrations, Concomitant medications included medications that had and participant consents started before the ﬁrst dose of cholecalciferol or placebo and Before initiating the study, the study protocol was approved continued after the ﬁrst dose of blinded treatment. Study visits by a national review board, the CPP Sud-Mediterran ´ ee ´ IV were V1 (screening, week W-8), V2 (baseline, W0), V3 ethics committee. Written informed consent was obtained (W24), V4 (W48), V5 (W72), and V6 (W96). At each visit from all the study participants before any study-related pro- from V2 to V5, patients received a kit to self-administering cedures were performed (ClinicalTrials.gov identiﬁer orally an ampoule every other week (equivalent to a daily dose NCT01198132). The study was conducted in accordance of 7,143 IU of cholecalciferol) during the 96-week treatment with the International Conference on Harmonization period. Clinical (EDSS and Paced Auditory Serial Addition Guidelines for Good Clinical Practice and the Declaration of Task 3, second version [PASAT-3]) and quality of life (EQ- Helsinki. 5D-3L) assessments were performed at all study visits since 2 Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 5 | September 2019 Neurology.org/NN baseline. MRI scans were performed at baseline and V6 and Missing ARR data on the number of relapses after premature were analyzed at a central MRI center by trained staﬀ masked interruption were imputed by baseline ARR values. to study group assignment. Screening and baseline routine laboratory tests including blood 25OHD, renal function, and Time to ﬁrst relapse was compared using Cox regression calcium levels were performed to comply with inclusion and adjusted on baseline ARR. Any dropout was considered as exclusion criteria and repeated each month during the ﬁrst 6 failure at trial interruption time. For sensitivity purposes, months and then quarterly to ensure safety. a supportive analysis was based in diﬀerentiating on drug- related dropout considered as failure, with drug-unrelated dropout considered as censored at dropout date, the diﬀer- Outcomes entiation established by an adjudication committee blind to The primary objective was the reduction of the annualized treatment. relapse rate (ARR), deﬁned as the ratio of the number of relapses under treatment by the exposure duration, in years. MRI values at V6, for the completers’ population, were Key secondary objectives were time to ﬁrst relapse; EDSS compared between treatment groups in adjusting for baseline, progression; MRI parameters (number of new or enlarged sex, and age. Log transformation was used for the number of T1-and T2-weighted lesions, T2-weighted MRI lesion load, new or enlarged T1- and T2-weighted lesions and the number number of T1-weighted Gd-enhancing lesions, volume of T1-weighted Gd lesions, and the ratio Final/Baseline was change of hypointense T1-weighted MRI lesions, total brain reported. Disability progression was deﬁned as increase of at volume, and brain gray and white matter volume); change in least 1 unit from baseline EDSS. EDSS at last visit was com- cognitive abilities; and change in quality of life and treatment pared between the 2 groups by a linear model adjusting for safety. baseline. Safety monitoring Supportive analyses were as follows: (1) for early drug-related Safety was assessed from reports of adverse events, serious dropouts (either for poor eﬃcacy or safety), the short expo- adverse events, disease-related adverse events (DRAEs), sure duration inducing relapse-free proﬁle (ARR = 0) may routine laboratory tests, and vital signs. DRAEs were coded falsely conclude into therapy success: we corrected this bias in according to the Medical Dictionary for Regulatory Activities evaluating a corrected ARR in assuming post-dropout period coding system. Values for clinical laboratory assessments were ARR by baseline ARR following the Baseline Observed Car- compared with both the appropriate normal ranges and ried Forward (BOCF) principle; and (2) ﬁnal EDSS, for drug- ranges of potential clinical concern. Any abnormal test result related dropouts, was also assimilated to BOCF. Although or other safety assessment judged by the investigator to be ARR was the main end point of this study, progression of the clinically signiﬁcant was recorded as an adverse event or disease now constitutes a primary concern for regulatory a serious adverse event. authorities. Therapy success may thus be considered on both Population and statistical analysis end points: a patient characterized by relapse-free follow-up The Full Analysis Set was constituted by all the randomized and without EDSS progression (EDSS ≥ EDSS ). Response b F patients (intention to treat [ITT] population). Supportive and rate was compared between the 2 treatment groups in post hoc analyses were conducted on the ITT set, after ex- adjusting for baseline EDSS and ARR . A response based on clusion of subjects with major deviations, and a completers’ MRI was also deﬁned in considering therapy success when population, which corresponded to the group of patients who radiologic disease-free status was observed (i.e., no Gd- completed the 96-week trial, as only those patients underwent enhancing lesions and no new or enlarging T2-weighted EDSS and MRI examination at the ﬁnal visit after 2 years (V6). lesions on brain MRI). A last alternative combining the 2 ﬁrst response deﬁnitions is the recently proposed No Evidence of The primary eﬃcacy analysis compared the cholecalciferol Disease Activity (NEDA-3) binary end point deﬁned as no group with placebo using a generalized linear model fea- relapses + no sustained disability progression + radiologic turing a Poisson regression adjusted for baseline values of disease-free status. annualized relapse rate (ARR ), sex, age, EDSS, controlled for overdispersion, and using the log-transformed exposure The eﬀect of serum 25OHD concentration (VDC), measured time as an oﬀset variable. ARR values were descriptively at each visit, was also assessed. The summary mean of VDC reported by geometric means due to the positive skewness (VDCM) was calculated during the follow-up period (V3 to of the distribution. V6). Poisson regression and linear model tested the VDCM eﬀect on relapse count and EDSS, in adjusting for baseline The trial was powered according an assumed rate ratio (rR) values. The PASAT-3 and the EQ-5D-3L scores were com- between cholecalciferol and placebo of 0.75, a mean number pared between treatment groups using analysis of covariance of 1 relapse per year, and a correlation R(ARR , ARR) of 0.7. adjusting for baseline value. Under these conditions, a sample size of 106 patients/group was needed for a power of at least 0.75 at a 95% 2-sided The safety analysis was performed on all randomized signiﬁcance level. patients who received at least 1 dose of study drug during Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 5 | September 2019 3 the study. The number of treatment emergent adverse or to patient willing or physician deciding to switch to another events (TEAEs) of any type and the total number of sub- disease-modifying drug. A total of 90 patients (45 in each jects with at least one TEAE were compared between treated group) completed the trial, constituting the com- treatment groups. The same analysis was performed in pleters’ population. comparing suspected DRAEs, serious DRAEs (SDRAEs), and deaths. Efficacy A total of 85 patients (65.8%) were relapse-free, and the The study was analyzed in compliance with standard Good highest value of ARR = 1.5 was observed for 2 patients. Clinical Practice regulations, database, and statistical analysis Mean ARR in the cholecalciferol group was 0.094 compared plan locked before unblinding. Software package SAS, version with 0.110 for placebo; this diﬀerence was not statistically 9.4 (SAS Institute Inc) and R version 3.3.2 were used for signiﬁcant (ITT sample: rR = 0.799, 95% CI 0.481–1.32, p = analysis. 0.38, Poisson regression). Conversely, ARR was signiﬁ- cantly lower on the completers’ population: rR = 0.395, Data availability 95% CI 0.186–0.012, p = 0.01. A total of 19 relapses oc- We provide qualiﬁed researchers access to individual patient- curred in the cholecalciferol group compared with 25 with level data through the Merck KGaA’s data-sharing portal: placebo. Time to ﬁrst relapse was not signiﬁcantly diﬀerent merckgroup.com/en/research/our-approach-to-research- between the 2 groups (hazard ratio [HR] = 0.801; 95% CI and-development/healthcare/clinical-trials/commitment-re- 0.403–1.454; p = 0.43). sponsible-data-sharing.html. For completers, at baseline, MRI measurements were in accordance with the protocol for 49 patients in the chole- Results calciferol group and for 47 patients in the placebo group, Study population and ﬁnal values at last visit were available for 44 and 41 of Between January 2010 and June 2013, a total of 181 patients them. A signiﬁcant mean reduction of new T1 lesions (rate were screened, and 129 were randomized, constituting the ratio rR = 0.494, 95% CI 0.267–0.913; p =0.03) and a de- ITT population (ﬁgure). The most common reason for failure crease in the volume of hypointense T1-weighted MRI to be randomized was a normal blood 25OHD level. De- lesions (−312 mm ,95% CI −596 to −29; p = 0.03) were mographics and baseline characteristics of ITT population are recorded in the cholecalciferol group vs placebo. There shown in table 1. A total of 39 dropouts were recorded during were no signiﬁcant changes in either of the other MRI the 2-year follow-up. Most reasons of dropout were related to parameters studied (number of Gd-enhancing T1 and new the treatment of RRMS with either a lack of eﬃcacy (relapse) T2 lesions, as well as brain, T2 lesions, and gray matter and Figure Trial flowchart 4 Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 5 | September 2019 Neurology.org/NN Table 1 Patient characteristics Mean Placebo Cholecalciferol Baseline characteristics (n = 66) (n = 63) p Value Age (SD), y 36.73 (8.37) 38.40 (9.31) 0.29 Sex, female, n (%) 39 (59.1) 50 (79.4) 0.01 Height (SD), m 1.71 (0.08) 1.67 (0.09) 0.009 Weight (SD), kg 70.84 (13.28) 68.29 (13.12) 0.28 BMI (SD), kg/m 24.12 (3.72) 24.41 (3.99) 0.67 No. of relapses since disease onset (SD) 2.74 (1.62) 2.89 (2.26) 0.68 No. of relapses in the last 2 y (SD) 1.82 (0.98) 1.94 (1.52) 0.61 Disease duration (SD), y 5.59 (4.83) 5.13 (5.33) 0.61 Time since diagnosis (SD), y 2.21 (2.45) 3.00 (4.48) 0.21 EDSS score at baseline (SD) 1.22 (1.16) 1.66 (1.43) 0.05 EQ-5D-3L score at baseline (SD) 1.32 (0.29) 1.34 (0.32) 0.67 25OHD serum concentration (SD), nmol/L 48.25 (16.22) 49.19 (17.54) 0.76 Abbreviations: BMI = body mass index; EDSS = Expanded Disability Status Scale. white matter volumes). Average progression of the EDSS p = 0.002). The proportion of relapse-free patients at last score was signiﬁcantly lower in the cholecalciferol group visit (V6) was not signiﬁcantly higher in the cholecalciferol (−0.06 ± 0.78) compared with the placebo group (0.32 ± group (69.8%) vs placebo (62.1%, OR = 1.70, 95% CI 0.87, 95% CI −0.614 to −0.043; p = 0.03). There was no 0.77–3.76; p = 0.19). When considering the ITT pop- diﬀerence in change of quality of life measured by the EQ- ulation and assimilating drug-related dropouts as re- 5D-3L or the PASAT-3 total score between the 2 experi- lapsing, these proportions became 65.1% and 45.5% and mental groups. were signiﬁcantly diﬀerent (OR = 3.22, 95% CI 1.45–7.19; p = 0.004). Similarly, in the completers’ population, these VDC at baseline was similar between treatment groups, proportions of relapse-free patients between cholecalcif- whereas cholecalciferol administration roughly tripled, at V6, erol and placebo groups were signiﬁcantly diﬀerent (75.6% mean VDC compared with the placebo group: 156.92 mmol/ and 60%, respectively, OR = 3.24, 95% CI 1.14–9.22; p = L vs 57.23 mmol/L, p < 0.001. VDC showed a signiﬁcant 0.03). A bias being possible in case of an unbalance be- reduction eﬀect on ARR (rR = 0.995 per nmol/L [95% CI tween completers and noncompleters, baseline de- 0.990–0.999], p = 0.04) and on EDSS progression with mographics were compared between these 2 groups with a mean decrease of EDSS of −0.003 per 1 nmol/L increase of the same set of parameters as for the ITT population in VDC (95% CI −0.006 to −0.001; p = 0.006). table 1. There was a female predominance in the non- completers group, 82.1%, compared with completers, Post hoc analysis 63.3% (p = 0.03). No statistical diﬀerence could be noted There were 39 dropouts, almost 3 times higher than ini- between the 2 groups for any of the other demographic tially estimated. Drug-related dropouts were the most parameters. frequent cause. The corrected ARR ,usedtoavoid the potential bias of early dropout on ARR estimate, was sig- When responders were deﬁned by the absence of relapse niﬁcantly lower in the cholecalciferol group both in the (ARR = 0) and progression (EDSS -EDSS ≤ 1), 49.2% and f b ITT (rR = 0.502, 95% CI 0.326–0.764; p = 0.001) and in 31.2% responders were found in the cholecalciferol group the completers’ population (rR = 0.395, 95% CI and the placebo group (OR = 2.18, 95% CI 1.05–4.53; p = 0.186–0.801; p = 0.01). When dropouts were considered as 0.04). Similarly, the radiologic disease-free status was also relapse, the observed eﬀect of the cholecalciferol treatment in favor of the cholecalciferol treatment (OR = 2.172, 95% was signiﬁcant (HR = 0.508, 95% CI 0.286–0.901; p = CI 1.016–4.640; p = 0.045). The NEDA-3 binary end point 0.02). When considering drug-related dropout as a failure, was met by 22.1% patients in the cholecalciferol group 66% fewer relapses were found in the cholecalciferol group compared with 9.1% with placebo (OR = 3.44, 95% CI = compared with placebo (HR = 0.333, 95% CI 0.164–0.675; 1.14–10.33; p = 0.03). Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 5 | September 2019 5 works showing that patients with low VDC were more likely Safety to have MRI lesions, worse EDSS score, and more relapses. A total of 126 subjects (61 cholecalciferol, 65 placebo) were Of interest, in the present study, the number of relapses, known to have been treated at least once during this study adjusted for baseline, signiﬁcantly decreased with increased either by cholecalciferol or placebo (table 2). No patient mean 25OHD concentrations, and a beneﬁt on EDSS pro- died during the study. At least one TEAE was recorded in 78 gression was also noted. subjects (61.9%): 43 in the cholecalciferol group (70.5%) and 35 in the placebo group (53.8%). Serious TEAEs were To date, CHOLINE is the largest 2-year randomized noted in 16.7% of the patients: 15.4% in the cholecalciferol controlled trial in RRMS using cholecalciferol. It was group and 18% with placebo. A total of 6 TEAEs (4.8%) constructed with a cautious selection of patients to prevent leading to treatment discontinuation were recorded: 3 some caveats from previous studies. Three selection crite- (4.9%) in the cholecalciferol and 3 (4.6%) in the placebo ria, at least, seemed key ones. The ﬁrst one was to recruit group. Nine subjects (7.1%) discontinued treatment because clinically active RRMS patients, as ARR was the primary of severe or life-threatening TEAEs: 5 patients (8.2%) in the endpoint. Second, cholecalciferol was started in patients cholecalciferol group and 4 (6.2%) for placebo. In the VD already treated with interferon beta-1a, as it has been group, TEAEs were appendicitis, back pain, skin necrosis, proposed that those 2 molecules may act either synergis- fetal death, and breast cancer. The 4 severe or life- tically or additively on blood monocytes and on MS threatening TEAEs in the placebo group were abdominal 18–21 parameters of activity. Third, a low 25OHD blood abscess, lung malignant neoplasm, peripheral arterial oc- level was required for inclusion, a large literature showing clusive disease, and nephrolithiasis. A total of 15 subjects deleterious eﬀects of VD deﬁciency on human health with (11.9%) had drug-related TEAEs, and 3 others (2.4%) had the lowest blood levels being associated with the worst SDRAEs. conditions. An important limitation of this study is its statistical power. Discussion One ﬁrst reason for that was the diﬃculty to achieve inclusion The present study, in line with previous works, showed that goal (n = 210). This was likely due to the number of other cholecalciferol at 100,000 IU every 2 weeks was well tolerated. alternatives for treating RRMS. It thus was decided to extend The study did not demonstrate a reduction of the ARR, the the inclusion period from 2 years to 3.5 years, but only 181 primary eﬃcacy measure, in the ITT population. However, in patients could be screened. Second, the sample size had been the completers’ population, treatment with cholecalciferol calculated on the basis of 1 relapse per year. This was an was associated with a lower ARR, a reduction of the number of overestimation, all the more as interferon beta-1a was new T1 lesions, a lower volume of hypointense T1-weighted expected to reduce relapse rate. Third, dropouts, initially es- MRI lesions, and with a signiﬁcantly lower progression of timated at 10%, accounted in fact for 28.6% for the chole- EDSS. Although post hoc analysis may be considered as calciferol group and 31.8% for placebo. Although unexpected “hypothesis generating,” it is in accordance with previous and potentially explained by the numerous alternatives to the interferon treatment that led patients or physicians, or both, to discontinue the trial, we also considered this high dropout rate as potentially meaningful all the more as demographics of Table 2 Safety data completers and noncompleters were similar. This suggests Placebo Cholecalciferol p that dropouts were not biased by a diﬀerence in disease proﬁle Adverse events, n (%) (n = 65) (n = 61) Value or disease severity at onset, and this was the basis for post hoc TEAE 35 (53.8) 43 (70.5) Ns analyses. Serious TEAE 10 (15.4) 11 (18.0) Ns Although the present study did not meet the primary end TEAE leading to treatment 3 (4.6) 3 (4.9) Ns point of reducing the relapse rate in patients with RRMS, discontinuation results in the completer’s population are encouraging and Serious TEAE leading to 3 (4.6) 1 (1.6) Ns support the use of the methodological parameters deﬁned in treatment discontinuation this work. Further trials are warranted to reﬁne the thera- Severe or life-threatening 4 (6.2) 5 (8.2) Ns peutic interest of cholecalciferol in patients with RRMS. TEAE Drug-related TEAE 9 (13.8) 6 (9.8) Ns Study funding This study was funded by Merck France, a subsidiary of Merck Drug-related serious TEAE 2 (3.1) 1 (1.6) Ns KGaA, Darmstadt, Germany. Abbreviation: TEAE = treatment emergent adverse event. Not present before medical treatment or already present but worsens either in intensity or frequency following the treatment. Disclosure Considered by the investigator as at least possibly related to the studied W. Camu reports personal fees from Actelion, Eﬃk, Merck, drug. MedDay Pharmaceuticals, Novartis Pharma, Roche, and 6 Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 5 | September 2019 Neurology.org/NN Sanoﬁ. P. Lehert reports personal fees from Merck, Biogen, Appendix (continued) Teva, and Genzyme and grants from Novartis. C. Pierrot- Deseilligny reports personal fees from Novartis. P. Hau- Name Location Role Contribution tecoeur reports no disclosures. A. Besserve, J. Deleglise, Marianne Merck, Lyon, France Author Interpreted the data and M. Payet are employees of the sponsor, Merck. E. Payet, MD and revised the Thouvenot has received honoraria and travel grants or re- manuscript for intellectual content search grants from the following pharmaceutical compa- nies: Biogen, Genzyme, Merck Serono, Novartis, Roche, Eric CHU Caremeau, Author Interpreted the data, and Teva Pharma. J.-C. Souberbielle reports no disclosures. Thouvenot, Nımes, France, and drafted the MD, PhD Institut de manuscript, and Go to Neurology.org/NN for full disclosures. G´ enomique revised the Fonctionnelle, manuscript for Universit´ede intellectual content Montpellier, Publication history Montpellier, France Received by Neurology: Neuroimmunology & Neuroinﬂammation January 8, 2019. Accepted in ﬁnal form June 13, 2019. Jean Claude CHU Necker, Paris, Author Major role in the Souberbielle, France acquisition of data, MD interpreted the data, designed and conceptualized the study, and revised the manuscript for Appendix Authors intellectual content Name Location Role Contribution William CHU Gui de Chauliac, Author Major role in the Camu, MD, Universitede acquisition of data, References PhD Montpellier, interpreted the data, 1. Soelberg Sorensen P. Safety concerns and risk management of multiple sclerosis Montpellier, France designed and therapies. Acta Neurol Scand 2017;136:168–186. conceptualized the 2. Trojano M, Tintore M, Montalban X, et al. Treatment decisions in multiple sclerosis— study, drafted the insights from real-world observational studies. Nat Rev Neurol 2017;13:105–118. manuscript, and 3. Bscheider M, Butcher EC. Vitamin D immunoregulation through dendritic cells. revised the Immunology 2016;148:227–236. manuscript for 4. Ascherio A, Munger KL, Simon KC. 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Neurology® Neuroimmunology & Neuroinflammation – Pubmed Central
Published: Aug 6, 2019
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