Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome

Helmut Butzkueven; Anne-Louise Ponsonby; Mark S Stein; Robyn M Lucas; Deborah Mason; Simon Broadley; Trevor Kilpatrick; Jeannette Lechner-Scott; Michael Barnett; William Carroll; Peter Mitchell; Todd A Hardy; Richard Macdonell; Pamela McCombe; Andrew Lee; Tomas Kalincik; Anneke van der Walt; Chris Lynch; David Abernethy; Ernest Willoughby; Frederik Barkhof; David MacManus; Michael Clarke; Julie Andrew; Julia Morahan; Chao Zhu; Keith Dear; Bruce V Taylor; PREVANZ Investigators

doi:10.1093/brain/awad409

Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome

Brain. 2024 Apr 4;147(4):1206-1215. doi: 10.1093/brain/awad409.

Authors

Helmut Butzkueven¹, Anne-Louise Ponsonby², Mark S Stein³, Robyn M Lucas⁴, Deborah Mason⁵, Simon Broadley⁶, Trevor Kilpatrick², Jeannette Lechner-Scott⁷, Michael Barnett⁸, William Carroll⁹, Peter Mitchell¹⁰, Todd A Hardy¹¹, Richard Macdonell^{12

13

14}, Pamela McCombe¹⁵, Andrew Lee¹⁶, Tomas Kalincik^{17

18}, Anneke van der Walt¹, Chris Lynch¹⁹, David Abernethy²⁰, Ernest Willoughby²¹, Frederik Barkhof^{22

23}, David MacManus²⁴, Michael Clarke²⁵, Julie Andrew²⁶, Julia Morahan²⁷, Chao Zhu¹, Keith Dear²⁸, Bruce V Taylor²⁹; PREVANZ Investigators

Collaborators

PREVANZ Investigators:
Val Gebski, Thomas Kimber, Alan Barber, Paul Wraight, Sandeep Sampangi, Rashida Ali, David Miller, Lauren Krupp, Leonid Churilov, Michael Ching, Susanne Hodkinson, Ernie Butler, Cameron Shaw, Claire Fraser, John Mottershead

Affiliations

¹ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
² Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia.
³ Department of Diabetes and Endocrinology, The Royal Melbourne Hospital, Parkville, VIC 3010, Australia.
⁴ National Centre for Epidemiology and Public Health, Australian National University, Canberra, ACT 0200, Australia.
⁵ Department of Neurology, Christchurch Hospital, Christchurch 8011, New Zealand.
⁶ Department of Neurology, School of Medicine and Dentistry, Griffith University, Southport, QLD 4222, Australia.
⁷ Department of Neurology, John Hunter Hospital, Newcastle, NSW 2305, Australia.
⁸ Brain and Mind Research Institute University of Sydney, Sydney, NSW 2050, Australia.
⁹ Department of Neurology, Sir Charles Gairdner Hospital and Centre for Neuromuscular and Neurological Disorders and Perron Institute, University of Western Australia, WA 6009, Australia.
¹⁰ Department of Radiology, Royal Melbourne Hospital, Melbourne, VIC 3010, Australia.
¹¹ Department of Neurology, Concord Hospital, University of Sydney, Sydney, NSW 2139, Australia.
¹² Department of Neurology, Austin Health, Melbourne, VIC 3084, Australia.
¹³ Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁴ Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010Australia.
¹⁵ University of Queensland, Centre for Clinical Research, Brisbane, QLD 4029, Australia.
¹⁶ Department of Neurology, Flinders University College of Medicine and Public Health, Adelaide, SA 5042, Australia.
¹⁷ Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC 3010, Australia.
¹⁸ CORe, Department of Medicine, University of Melbourne, Melbourne, VIC 3010, Australia.
¹⁹ Midland Neurology, Hamilton, Waikato 3240, New Zealand.
²⁰ Department of Neurology, Wellington Hospital, Wellington 6021, New Zealand.
²¹ Department of Neurology, Auckland Hospital, Auckland 1023, New Zealand.
²² Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam 1081 HV, The Netherlands.
²³ Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, WC1N 3BG, UK.
²⁴ University College London Queen Square Institute of Neurology, Queen Square MS Centre, London WC1N 3BG, UK.
²⁵ Metabolomics Australia (WA), School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia.
²⁶ Neurosciences Trials Australia, North Melbourne, VIC 3051, Australia.
²⁷ Multiple Sclerosis Australia, North Sydney, NSW 2059, Australia.
²⁸ Department of Statistics, School of Public Health, University of Adelaide, SA 5005, Australia.
²⁹ MS Research Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.

Abstract

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Keywords: clinical trial; multiple sclerosis; vitamin D.

Publication types

Randomized Controlled Trial

MeSH terms

Calcifediol
Cholecalciferol / adverse effects
Cholecalciferol / therapeutic use
Demyelinating Diseases* / diagnostic imaging
Demyelinating Diseases* / drug therapy
Double-Blind Method
Female
Humans
Male
Multiple Sclerosis* / diagnostic imaging
Multiple Sclerosis* / drug therapy
Vitamin D* / therapeutic use
Vitamins / therapeutic use

Substances

Calcifediol
Cholecalciferol
Vitamin D
Vitamins

Grants and funding

PREVANZ