Abstract
Objective: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS.
Methods: Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130–175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses.
Results: Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04).
Conclusion: We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation.
Classification of evidence: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130–175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.
GLOSSARY
- 25OHD=
- 25-hydroxyvitamin D;
- CI=
- confidence interval;
- CV=
- coefficient of variation;
- EAE=
- experimental autoimmune encephalomyelitis;
- EDSS=
- Expanded Disability Status Scale;
- eGFR=
- estimated glomerular filtration rate;
- FA=
- flip angle;
- FOV=
- field of view;
- GE=
- gadolinium-enhancing;
- IQR=
- interquartile range;
- MS=
- multiple sclerosis;
- OR=
- odds ratio;
- PTH=
- parathyroid hormone;
- RCT=
- randomized controlled trial;
- RRMS=
- relapsing-remitting multiple sclerosis;
- TE=
- echo time;
- TI=
- inversion time;
- TR=
- repetition time.
Vitamin D is synthesized after ultraviolet exposure1 and vitamin D nutrition is measured by serum 25-hydroxyvitamin D (25OHD).1 Lower ultraviolet exposure and lower 25OHD correlate directly with MS prevalence, relapses, and mortality,2,–,8 although this is not universally found,9,10 and indirectly with active MS lesions on brain MRI.11,12 Autoimmune mechanisms contribute to experimental autoimmune encephalomyelitis (EAE) and are implicated in relapsing-remitting MS (RRMS)13,14 and vitamin D metabolites suppress the pathogenic immune responses characteristic of autoimmune diseases8,15 and prevent or ameliorate EAE.16
Oral vitamin D3 in the form of cod liver oil (5,000 IU/day) reduced relapse rate in an uncontrolled MS trial17 and high-dose vitamin D3 appeared to retard progression of MS-related disability in an unblinded study.18 When 1,25-dihydroxyvitamin D [1,25(OHD)2D], a potent metabolite for calcium mobilization, was administered to people with MS, 4 of 15 required dose adjustment or withdrew due to hypercalcemia.19 A 1,25(OH)2D precursor (alfacalcidol) was, however, well-tolerated in an uncontrolled trial of 5 people with MS.20 A 1,25(OH)2D analog which is less likely to induce hypercalcemia was not beneficial for people with MS.21 That analog was not directly efficacious in EAE and the relevance of that trial to the potential efficacy of plain oral vitamin D in MS is equivocal.22 There is no randomized controlled trial (RCT) comparing high-dose vitamin D2 or D3 to low-dose supplementation in MS.
METHODS
Primary research question.
We performed a double-blind RCT in RRMS to examine whether adding high-dose oral vitamin D2 reduced MRI indices of disease activity in comparison with ongoing low-dose supplementation (level 1 evidence) and to provide effect size estimates for larger definitive RCTs.
Participants.
Inclusion criteria.
Inclusion criteria were RRMS (McDonald criteria23), age >18 years, relapse within the preceding 24 months despite immunomodulatory therapy, or declined or could not tolerate such therapy.
Exclusion criteria.
Exclusion criteria were primary or secondary progressive MS, pregnancy, clinical relapse or systemic glucocorticoid therapy within the prior 30 days, Expanded Disability Status Scale (EDSS)24 score >5, current MS treatment other than glatiramer acetate (Copaxone) or interferon, hypercalcemia, creatinine >0.2 mM, estimated glomerular filtration rate (eGFR) <60 mL/min, and uric acid >sex-matched laboratory reference range.
Standard protocol approvals, registrations, and patient consents.
Written informed consent and approval from Melbourne Health Human Research Ethics Committee was obtained. Trial registration: The Australian Clinical Trials Registry (registry number ACTRN12606000359538).
Screening.
Serum 25OHD, parathyroid hormone (PTH), calcium, albumin, phosphate, creatinine, eGFR, and uric acid were screened. Women had serum β human chorionic gonadotropin.
Corrected calcium was calculated as follows: total calcium (mM) + (40-albumin [g/L]) × 0.02. The 25OHD radioimmunoassay (Diasorin, Stillwater, MN) measures 25OHD2 and 25OHD325 with coefficient of variation (CV) at median 32, 60, and 117 nM of 9.5%, 9.5%, and 9.0%. PTH was measured by Immulite 2000 Intact (Siemens Los Angeles, CA); CV at median 3.4, 30, and 98 pM was 8%, 8%, and 7.5%. Calcium, albumin, uric acid, and creatinine were measured on an Olympus 2700 (Olympus, Tokyo).
Age, sex, medications, date of diagnosis, relapses in the past 24 months, and EDSS were documented by 1 of 2 blinded assessing neurologists.
Form of vitamin D.
Oral vitamin D increases serum 25OHD without elevating serum 1,25(OH)2D or inducing hypercalcemia or hypercalciuria.18,26,27 Humans may metabolize circulating 25OHD to active autocrine/paracrine tissue vitamin D metabolites, with a substrate to product conversion efficiency approaching 80%8,28 and enzymes for this metabolism are present in the CNS.29 As 25OHD circulates at nanomolar concentrations, a plain oral vitamin D supplement to elevate serum 25OHD may therefore lead to nanomolar tissue concentrations of vitamin D metabolites [including 1,25(OH)2D] for autocrine and paracrine activity. Conversely, oral 1,25(OHD)2D and its analogues are limited by hypercalcemia and hypercalciuria when present at only picomolar serum concentrations. If exogenous vitamin D is indeed efficacious in MS, then plain oral vitamin D may have greater efficacy, with less toxicity, than oral 1,25(OH)2D or its analogues.22
The 2 common choices for plain vitamin D supplementation are vitamin D2 or vitamin D3. Vitamin D2 was chosen because of its success in an RCT of falls prevention, demonstrating extraskeletal efficacy on neural or muscular function30; its additional metabolic pathway through serum 24OHD31 that could offer additional benefit for any given serum level of 25OHD; and its plant origin that minimizes risk of transmissible disease. In chronic low-dose administration (as opposed to single acute dosing), vitamin D2 is as efficacious as vitamin D3 in elevating serum 25OHD,32 although whether this occurs with chronic high-dose supplementation is not known.
Treatment: High-dose vitamin D2.
High-dose vitamin D2 (6,000 IU) was given in a vegetable capsule, custom formulated by Cardinal Health (Braeside, Victoria). Placebo capsules had the same formulation minus vitamin D2.
The initial dose of high-dose vitamin D2 was one high-dose capsule twice a day after food. Venipuncture was performed at 2 and 4 weeks and monthly thereafter to measure serum 25OHD. Each subject's capsule dose was adjusted empirically in the light of their serial venipuncture results to maintain their 25OHD, with a target range of 130–175 nM. One investigator was unblinded to advise study nurses of dose adjustments. Nurses remained blinded and contacted participants.
Treatment protocol.
Randomization.
Participants were recruited in 5 groups. Each group was subject to computer randomization by an off-site statistician blocking on specific MS therapy (glatiramer acetate, interferon, no specific therapy), except for the first 2 participants who were computer randomized by the unblinded investigator as the statistician was unavailable. Subjects within each group commenced randomized treatment at the same time, controlling for season.
In a separate random allocation, each participant on high-dose vitamin D2 was paired with a “buddy” on placebo. With every change in high-dose D2 capsule dose, the buddy was contacted by a study nurse to make the same capsule dose change.
Low-dose vitamin D2.
It was considered unethical to withhold low-dose D because of its putative benefit. Therefore all participants also received one capsule of low-dose (1,000 IU) vitamin D2 daily throughout randomized treatment (Ostelin capsule, Boots, North Ryde, NSW).
The manufacturer changed production to an otherwise identical 1,000 IU vitamin D3 capsule after trial commencement. We could not source the vitamin D2 version when our final 3 participants (2 on high-dose D2 and 1 on placebo high-dose) were 3 months from exit. We monitored their 25OHD and in their final month supplied all 3 with the vitamin D3 capsule daily to prevent vitamin D deficiency (defined as serum 25OHD <25 nM) for which one was then at risk.
Treatment groups.
One group (high-dose D2) received 1,000 IU vitamin D2 daily plus a high-dose vitamin D2 supplement. The other group (low-dose D2) received 1,000 IU vitamin D2 daily plus a placebo supplement.
Brain MRI.
Brain MRI at baseline, 4, 5, and 6 months was performed using a 3 T Siemens Magnetom Trio TIM scanner (Erlangen, Germany). Imaging sequences acquired for this study included 2 3-dimensional T1-weighted sequences, one acquired preinjection and one acquired postinjection with gadopentetate dimeglumine (0.1 mmol/kg, up to maximum of 20 mL of Gadovist©, Bayer Schering Pharma AG, Berlin, Germany). Three sets of conventional contrast MRI images were acquired using 3-dimensional sequences for lesion identification. Precontrast and postcontrast T1-weighted images were obtained with the following parameters: repetition time (TR) = 1,900 msec, echo time (TE) = 2.15 msec, inversion time (TI) = 900 msec, flip angle (FA) = 9°, slice thickness = 1 mm, matrix size = 256 × 215, field of view (FOV) = 224 × 256 mm2. Before contrast was administered, T2-weighted images were acquired with the following parameters: TR = 3,200 msec, TE = 579 msec, FA = 120°, slice thickness = 1 mm, matrix size = 320 × 288, FOV = 243 × 270 mm2. Scans were encoded to preserve blinding. The first 2 patients were scanned on a 1.5 T closed scanner (General Electric Echospeed HDX, Milwaukee, WI) prior to availability of the 3 T scanner and received triple dose gadolinium (Magnevist [dimeglumine gadopentetate], Bayer Schering Pharma AG, Germany). Subsequently, standard dose gadolinium was used due to emerging concerns regarding nephrogenic systemic fibrosis.
Blinded reading.
Two blinded study neuroradiologists evaluated scans to determine gadolinium-enhancing (GE) lesions. One also determined total volume of T2 lesions (baseline and 6 months) with a neuroradiology research scientist using semiautomated software (MRICRO [www.mricro.com]).
Biochemical monitoring.
Creatinine and eGFR at 4, 5, and 6 months and calcium, albumin, uric acid, and PTH at 3 and 6 months were monitored.
Clinical monitoring.
Neurologists were blinded to treatment allocation. EDSS was assessed at baseline and at 6 months or early exit visit. Relapses were defined by one of the participating neurologists as the development of new neurologic symptoms and signs at least 30 days after onset of last relapse (McDonald criteria27). Participants attended for relapse confirmation with the assessing neurologist.
Endpoints.
Primary endpoints were the cumulative number of new GE lesions and change in the total volume of T2 lesions.
Secondary endpoints were the change in EDSS and the number of clinical relapses.
Statistics.
Differences between cohorts were tested by Mann-Whitney or Kruskal-Wallis tests. For primary endpoints, a pure randomization test tested the significance of the difference (high-dose minus low-dose) of the mean cumulative number of new GE per person. The 95% confidence interval (CI) for the difference in mean cumulative number of new GE per person was calculated by bootstrap analysis. For secondary endpoints, ordinal logistic regression tested for a treatment effect on exit EDSS. Entry EDSS was entered as a series of dummy variables to reflect the ordinal nature of this variable. This method gives the odds ratio (OR) (95% CI) for a lower exit EDSS with high-dose compared to low-dose vitamin D2. The Fisher exact test determined the significance of the difference in proportions having relapse between the high-dose and low-dose cohorts. The 95% CIs for the difference in percentage experiencing relapse were calculated using the Newcombe-Wilson score method (corrected) as an approximation.33
Analyses were intention to treat (with last observation carried forward for GE and relapses). Separate completers analyses considered only those for whom there were 6-month data. Analyses were performed using Minitab versions 13 and 16 (www.minitab.com) and Poptools (www.poptools.org).34 A 2-tailed p value <0.05 was considered significant. There were no previous RCT data from which to estimate high-dose added to low-dose vitamin D2 effect. No power calculation was attempted. An a priori trial aim was to generate data helpful for larger definitive trial power calculations.
RESULTS
Participant progress through trial.
Twenty-five volunteers passed screening. Two withdrew before randomization (figure 1). Eleven were randomized to high-dose vitamin D2, 12 to low-dose vitamin D2. There were 3 withdrawals: 1 at 2 weeks with nausea (low-dose group), 1 after 4 months to electively enter a different MS trial (low-dose group), and 1 after relapse at 3 months in order to receive natalizumab (high-dose group). The latter 2 had exit MRI and EDSS. The first subject started treatment December 2006; the last finished May 2009.
eGFR = estimated glomerular filtration rate.
Baseline characteristics.
Baseline characteristics were median (interquartile range [IQR]) age 42 (31–47) years, time since diagnosis 6 (2–10.5) years, and entry EDSS 2 (1–4) units. High-dose and low-dose groups were well matched (table 1).
Participant characteristics at baseline
Serum 25OHD.
Baseline 25OHD did not significantly differ between the 2 groups with median (IQR) 59 (47–61) for high-dose vs 54 (35–74) nM for low dose. There was clear divergence after 2 weeks of treatment, with respective median (IQR) 25OHD of 110 (88–133) vs 55 (46–85) nM (p = 0.001). This difference persisted throughout with the 6-month median (range) 25OHD being 120 (89–170) high-dose vs 69 (49–110) nM low-dose (p = 0.002) (figure 2).
Plotted are participants allocated low-dose vitamin D2 (solid circles), high-dose D2 (open circles), and those on high-dose D2 who had relapse (open squares). Missing points reflect participant withdrawal or declined venipuncture or laboratory protocol error.
Other biochemistry.
There were no significant changes in PTH, calcium, corrected calcium, albumin, uric acid, creatinine, or eGFR during the study in either group.
Gadolinium-enhancing lesions.
Baseline.
Seven participants had baseline GE. Of these, 4 were randomized to high-dose (1, 1, 3, and 38 lesions) and 3 to low-dose D2 (2, 3, and 5 lesions). Baseline 25OHD was not significantly different between participants with and without baseline GE lesions with respective medians (IQR) of 61 (33–74) vs 56 (42–61) nM.
New GE lesions.
Six participants developed new lesions. Of these, 5 had at least one GE lesion at baseline. The sixth (high-dose D2) developed new GE at all timepoints (table 2).
Gadolinium-enhancing lesions
There was no significant difference between treatment groups in the cumulative number of new GE lesions, 14 (high-dose) vs 11 (low-dose), or the number of people with new GE lesions (tables 2 and 3). One participant (low-dose) missed the 5-month scan.
Primary and secondary endpoints (95% confidence intervals)
T2 volume.
Baseline.
The baseline volume of lesions on T2-weighted imaging for the entire trial cohort did not correlate with 25OHD, PTH, or corrected calcium.
Treatment.
There was no difference in the change in total volume of T2 lesions according to treatment (p = 0.6): median (IQR) changes −330 (−950 to −30) for high-dose vs −95 (−310 to −25) mm3 for low-dose (table 3).
One participant (low-dose) had brain surgery during study for an unrelated lesion and was excluded from all T2 analyses as removed tissue included T2 lesions.
EDSS.
Median (IQR) exit EDSS was higher in the high-dose group: 3 (2–4) vs 2 (1–2) in the low-dose group (p = 0.04). Exit EDSS correlated with entry EDSS (r = 0.79, p <0.001). In ordinal logistic regression that adjusted for entry EDSS, treatment with high-dose vitamin D2 was marginally associated with a higher exit EDSS (p = 0.051) (table 3).
Relapses.
Of 11 people randomized to high-dose vitamin D2, 4 (36.5%) had a relapse. Two were already on stable therapy with interferon-β, one on glatiramer acetate. Three received IV methylprednisolone approximately 5 weeks, 4 months, and 6 months into study. The fourth was withdrawn and commenced on natalizumab at the 3-month timepoint. Of 12 randomized to low-dose vitamin D2, none had relapse (p = 0.04 for the difference in proportions having relapse) (see table 3).
Two who developed relapse had baseline GE and also developed new GE lesions. No GE lesions were detected in the other 2 who developed relapse.
Potential outlier.
A participant with 38 baseline GE lesions and relapse at 5 weeks was excluded and endpoints reanalyzed (table 3). Treatment with high-dose vitamin D2 was no longer associated with higher exit EDSS (p = 0.092) or relapse (p = 0.08).
DISCUSSION
This trial tested for a benefit of high-dose vitamin D2 over low-dose in people with clinically active RRMS. There was no between-group difference in the primary MRI-based outcome measures. However, there was a higher exit EDSS and a higher proportion exhibiting relapse with high-dose vitamin D2. Changes in response to disease-modifying therapy in several subjects could account for the minor differences noted between the high-dose and low-dose groups, and this possibility cannot be ruled out on present data. These clinical outcomes, in the absence of worse MRI endpoints, need confirmation in larger trials. However, high-dose vitamin D2 does not appear to be of benefit in RRMS, especially by the most informative and reliable measure, MRI.
In contrast, an MS study using vitamin D3 reported a smaller proportion of subjects treated with high-dose vitamin D3 had worsening EDSS (p = 0.019) and a smaller proportion relapse (p = 0.09).18 However, that study was not blinded and did not adjust for baseline EDSS. Additionally, subjects not receiving high-dose vitamin D3 were permitted up to 4,000 IU vitamin D daily, confounding the comparison. Another group found the mean number of GE lesions fell after high-dose D3 supplementation, but that was an uncontrolled unblinded study.27
In theory, vitamin D supplementation could be detrimental if it increased expression of HLA DRB1*15,7,35 a protein isoform associated with increased risk for MS. Against this, people with MS who had the HLA DRB1*15 genotype did not have worse clinical outcome in association with higher serum 25OHD.7 In another study daily 1,000 IU vitamin D3 increased serum levels of an inflammatory cytokine in people with MS.36 However, in our 6-month study the entire low-dose group, which received 1,000 IU vitamin D2 daily, had no relapses and only 3 of 12 participants taking low-dose vitamin D2 developed new GE lesions.
We found no association between baseline serum 25OHD and the presence of GE lesions or the total volume of T2 lesions, consistent with other data.6,10.
In T cells, T-cell lines, and dendritic cells derived from people with RRMS and healthy people, 10 nM 1,25(OH)2D altered cell behavior toward a less pathogenic and more tolerogenic phenotype.8 The relevance of this has been questioned because the tested 1,25(OH)2D concentration far exceeds serum levels.37 However, similar concentrations could theoretically be achieved in CNS tissue after autocrine metabolism of nanomolar levels of circulating serum 25OHD. The serum 25OHD of our low-dose cohort rose from 54 nM to 69 nM. Raw data from a cross-sectional study38 suggest higher T-cell regulatory activity and less Th1:Th2 bias in people with RRMS at higher serum 25OHD up to levels of 50–70 nM, above which little further difference is apparent.
Correlations of lower MS prevalence, activity, and mortality with high levels of vitamin D3 nutrition have led to the hypothesis that high levels of vitamin D could be beneficial for MS. Our RCT outcomes do not support this hypothesis. A limitation of our trial is that our sample was selected for ongoing disease activity. Trials of primary prevention or conducted at earlier stages of disease, such as first demyelinating event, may find different outcomes as may larger trials, trials of vitamin D3, or trials that vary serum 25OHD more slowly.39 A trial that restricted enrollment to MS treatment-naive subjects could more clearly test a vitamin D2 benefit, however, inclusion of people already taking glatiramer acetate or interferon increases the clinical generalizability. It is also possible that any vitamin D benefit for MS occurs with low-level supplementation and oral vitamin D beyond that does not provide additional benefit. If this is the case, then epidemiologic correlations of better MS outcomes with higher serum 25OHD may simply reflect the identification of people with MS who have a low probability of experiencing vitamin D deficiency.40 In conclusion, in people with clinically active RRMS taking 1,000 IU of vitamin D2 per day, we did not find a therapeutic advantage from additional high-dose vitamin D2.
AUTHOR CONTRIBUTIONS
Dr. Stein: drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision or coordination, obtaining funding. Dr. Liu: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data. Dr. Gray: drafting/revising the manuscript for content, acquisition of data. J.E. Baker: drafting/revising the manuscript for content, acquisition of data, study supervision or coordination. Dr. Kolbe: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data, study supervision or coordination. Dr. Ditchfield: drafting/revising the manuscript for content, acquisition of data, study supervision or coordination. Dr. Egan: drafting/revising the manuscript for content, analysis or interpretation of data, acquisition of data, study supervision or coordination. Dr. Mitchell: drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, acquisition of data, study supervision or coordination, obtained funding. Dr. Harrison: drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, obtained funding. Dr. Butzkueven, drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, acquisition of data, study supervision or coordination. Dr. Kilpatrick: drafting/revising the manuscript for content, study concept or design, analysis or interpretation of data, acquisition of data, study supervision or coordination, obtained funding.
DISCLOSURE
Dr. Stein received research support from The Myer Foundation. Dr. Liu received the McDonald Fellowship from The Multiple Sclerosis International Federation and support from the National Science Foundation of China (No. 81101038). Dr. Gray served on a scientific advisory board for Merck Serono and has received unrestricted educational awards from Merck Serono and Biogen Idec. J.E. Baker has received funding for travel to attend educational meetings from Bayer Schering Pharma, Sanofi-Aventis, Biogen Idec, and Merck Serono. Dr. Kolbe received research/fellowship support from Multiple Sclerosis Research Australia and the National MS Society (USA). Dr. Ditchfield received speaker honoraria from Siemens and Toshiba. Dr. Egan serves on an Australian Research Council (ARC) college of experts panel; serves on a scientific advisory board for Neurosciences Victoria; serves as Associate Editor for Human Brain Mapping and on the editorial boards of Neuroimage and the Journal of Imaging Technology; and receives research support from National Health Medical Research Council Australia, ANZ Trustees, Melbourne, Australia, the Australian Research Council, the Australian Government Department of Industry, Innovation, Science and Research, the National Multiple Sclerosis Society (USA), and Cure Huntington's Disease initiative (CHDI). Dr. Mitchell serves as an Associate Editor for the Journal of Medical Imaging and Radiation Oncology; performs neuroimaging in his clinical practice (75% effort) and bills for these procedures; serves on scientific advisory boards for Cordis Corporation, Johnson & Johnson, and Boston Scientific; and receives research support from Boston Scientific, Talecris Biotherapeutics, The Myer Foundation, and National Health Medical Research Council Australia. Dr. Harrison serves on the editorial boards of Diabetes Metabolism Reviews, Diabetes Research and Clinical Practice, Current Diabetes Reports, and Pediatric Diabetes, as Contributing Editor for Molecular Medicine, and as Associate Editor for Human Vaccines; serves as a consultant for Bayhill Therapeutics; and receives research support from The Myer Foundation, National Health and Medical Research Council (NHMRC) of Australia, and the Juvenile Diabetes Research Foundation. Dr. Butzkueven has received funding for travel from and served on scientific advisory boards for Biogen Idec, Novartis, and Sanofi-Aventis; serves on the editorial board of Multiple Sclerosis International; holds patents for treatment application of LIF in MS and treatment application of EPHA4 blockade in MS; and receives research support from Merck Serono, Biogen Idec, Novartis, National Health and Medical Research Council (NHMRC), and National MS Society (USA). Dr. Kilpatrick has served on scientific advisory boards for GlaxoSmithKline, Neurosciences Victoria, and the Victorian Neurotrauma Initiative; has received funding for travel from Bayer Schering Pharma, Sanofi-Aventis, and Merck Serono; served on the editorial board of Therapeutic Advances in Neurological Disorders; is listed as an inventor on patents re: HIV test kit method for detecting anti-HIV-1 antibodies in saliva; A method of modulating cell survival and reagents useful for the same; Methods for the treatment and prophylaxis of demyelinating disease; and Method of treatment in the field of inflammatory neurodegeneration; and receives research support from Bayer Schering Pharma, Biogen Idec, the Australian Research Council, the National Health and Medical Research Council of Australia, MS Research Australia, and National Multiple Sclerosis Society (USA), and The Myer Foundation.
ACKNOWLEDGMENT
The authors thank The Myer Foundation for its generous funding of this study; Associate Professor Ian Gordon, Director, and Marnie Collins, Statistical Consulting Centre, University of Melbourne, for randomization and statistical analyses; Beth Spears and Gabrielle Browning, research nurses; and Maria Bisignano, Mairead Harrop, Max Goodwin, Cecilia Hsieh, and staff of The Biochemistry and Endocrinology Laboratories, Royal Melbourne Hospital.
Footnotes
Study funding: Funded by The Myer Foundation, which had no influence on trial design, data collection, or analyses. Dr. Liu was supported by a Multiple Sclerosis International Federation McDonald Fellowship and Prof. Harrison is NHMRC Senior Principal Research Fellow.
- Received January 19, 2011.
- Accepted July 18, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
REFERENCES
Letters: Rapid online correspondence
- An underpowered study with many biases and confounding factors might confuse more than clarify
- Sunlight and multiple sclerosis
- Unspecified doses of MKTVIF75HV are not level 1 evidence about vitamin D3
- Negative results from a trial with low power should not be class I evidence.
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