Re: vitamin D and COVID-19 – this is no time for procrastination
Dear Editor,
The recently updated NICE guideline on vitamin D and COVID-19 concludes that adults and children over 4 years should consider taking 10 micrograms (400 IU) per day of vitamin D “to maintain bone and muscle health”, but that they should not be offered a vitamin D supplement “solely to prevent COVID-19 except as part of a clinical trial”.[1,2] This is despite a large body of evidence that links COVID-19 risk and severity with ultraviolet exposure/latitude/seasonality, obesity, ethnicity – all factors associated with vitamin D deficiency; observational studies correlating vitamin D deficiency with more severe outcomes, and a positive randomised trial of calcifediol (25(OH)D) supplementation in hospitalised patients.[3]
NICE “agreed that there is a need for research into vitamin D supplementation for preventing COVID-19”. However, although this was a reasonable position during the “first wave”, preferably coupled with the incorporation of a vitamin D arm in the RECOVERY trial, there is now a need for much greater urgency. Calls for further randomised trials are simply procrastination.
The “ideal” trial to assess the efficacy of vitamin D supplementation in preventing COVID-19 would need to identify people with vitamin D deficiency (since there will likely be no benefit in supplementing people who are already replete) and then to invite a proportion of these to be randomised to placebo. Whilst this is perfectly reasonable when testing a new drug with unknown efficacy or safety, it may not be reasonable when testing a vitamin.
Consequently, the major UK trial currently underway – CORONAVIT NCT04579640 – does not have a rigorous placebo arm. It is comparing “standard of care” – national recommendation of 10 micrograms (400 IU) /day, with higher doses (800 IU/day and 3200 IU/day). However, the trial is primarily powered to assess impact of vitamin D supplementation on risk for acute respiratory infection of any cause, and it remains to be seen whether it will be adequately powered in respect of COVID-19 severity. Moreover, if as the UK Scientific Advisory Committee on Nutrition has concluded, 400 IU/day is adequate to ensure sufficiency, [4] then this trial might be destined to be negative. Finally, NICE may be unlikely to recommend vitamin D supplementation on the basis of a trial that has no clear placebo arm.
NICE notes that there are currently four other trial protocols registered world-wide that are addressing this topic: NCT04476680; NCT04483635; NCT04386850; NCT04535791.[5] Of these only two: NCT04386850 in Iran and NCT04535791 in Mexico are placebo-controlled and addressing COVID-19 severity. They are planned to complete in March and July 2021, respectively. If, as currently hoped, the pandemic may be waning by Easter, these trials, if successfully completed, will tell us retrospectively whether or not many lives might have been saved by a stronger promotion of vitamin D supplements that cost pence and are extremely safe. Is that really what evidence-based medicine is meant to be about?
1. Jacquie Wise, ‘ Covid-19: Evidence is lacking to support vitamin D’s role in treatment and prevention’, BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4912 (Published 17 December 2020)
2. National Institute for Health and Care Excellence. COVID-19 rapid guideline: vitamin D. December 2020. https://www.nice.org.uk/guidance/ng187
3. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, Subramanian S, Thickett D. Vitamin D and COVID-19: evidence and recommendations for supplementation Royal Soc Open Sci 2020. R. Soc. open sci.7201912http://doi.org/10.1098/rsos.201912
4. Scientific Advisory Committee on Nutrition. Update of rapid review: vitamin D and acute respiratory tract infections. UK govt. December 2020. https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
5. NICE guideline NG187 Evidence reviews underpinning recommendations 1.1 to 1.3 and research recommendations in the NICE guideline. December 2020. https://www.nice.org.uk/guidance/ng187/evidence/evidence-reviews-for-the...
Competing interests:
M.H. and D.T. have received speaking honoraria from Thornton Ross. RQ is a member of the Data Monitoring Committee for the CORONAVIT trial. No other competing interests.
22 December 2020
Jonathan M Rhodes
Emeritus Professor of Medicine
All authors (in alphabetical order please): George Griffin Emeritus Professor of Infectious Diseases and Medicine, St George’s University, London; Martin Hewison Professor of Molecular Endocrinology, University of Birmingham; Julian Hopkin Rector, Medicine and Health and Professor of Experimental Medicine, Swansea University; Rose Anne Kenny Professor of Medical Gerontology, Trinity College Dublin; Richard Quinton Senior Lecturer in Endocrinology, Newcastle University; Jonathan Rhodes Emeritus Professor of Medicine, University of Liverpool; Sreedhar Subramanian Consultant gastroenterologist, Royal Liverpool University Hospital; David Thickett Professor in Respiratory Medicine, University of Birmingham
Rapid Response:
Re: vitamin D and COVID-19 – this is no time for procrastination
Dear Editor,
The recently updated NICE guideline on vitamin D and COVID-19 concludes that adults and children over 4 years should consider taking 10 micrograms (400 IU) per day of vitamin D “to maintain bone and muscle health”, but that they should not be offered a vitamin D supplement “solely to prevent COVID-19 except as part of a clinical trial”.[1,2] This is despite a large body of evidence that links COVID-19 risk and severity with ultraviolet exposure/latitude/seasonality, obesity, ethnicity – all factors associated with vitamin D deficiency; observational studies correlating vitamin D deficiency with more severe outcomes, and a positive randomised trial of calcifediol (25(OH)D) supplementation in hospitalised patients.[3]
NICE “agreed that there is a need for research into vitamin D supplementation for preventing COVID-19”. However, although this was a reasonable position during the “first wave”, preferably coupled with the incorporation of a vitamin D arm in the RECOVERY trial, there is now a need for much greater urgency. Calls for further randomised trials are simply procrastination.
The “ideal” trial to assess the efficacy of vitamin D supplementation in preventing COVID-19 would need to identify people with vitamin D deficiency (since there will likely be no benefit in supplementing people who are already replete) and then to invite a proportion of these to be randomised to placebo. Whilst this is perfectly reasonable when testing a new drug with unknown efficacy or safety, it may not be reasonable when testing a vitamin.
Consequently, the major UK trial currently underway – CORONAVIT NCT04579640 – does not have a rigorous placebo arm. It is comparing “standard of care” – national recommendation of 10 micrograms (400 IU) /day, with higher doses (800 IU/day and 3200 IU/day). However, the trial is primarily powered to assess impact of vitamin D supplementation on risk for acute respiratory infection of any cause, and it remains to be seen whether it will be adequately powered in respect of COVID-19 severity. Moreover, if as the UK Scientific Advisory Committee on Nutrition has concluded, 400 IU/day is adequate to ensure sufficiency, [4] then this trial might be destined to be negative. Finally, NICE may be unlikely to recommend vitamin D supplementation on the basis of a trial that has no clear placebo arm.
NICE notes that there are currently four other trial protocols registered world-wide that are addressing this topic: NCT04476680; NCT04483635; NCT04386850; NCT04535791.[5] Of these only two: NCT04386850 in Iran and NCT04535791 in Mexico are placebo-controlled and addressing COVID-19 severity. They are planned to complete in March and July 2021, respectively. If, as currently hoped, the pandemic may be waning by Easter, these trials, if successfully completed, will tell us retrospectively whether or not many lives might have been saved by a stronger promotion of vitamin D supplements that cost pence and are extremely safe. Is that really what evidence-based medicine is meant to be about?
1. Jacquie Wise, ‘ Covid-19: Evidence is lacking to support vitamin D’s role in treatment and prevention’, BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4912 (Published 17 December 2020)
2. National Institute for Health and Care Excellence. COVID-19 rapid guideline: vitamin D. December 2020. https://www.nice.org.uk/guidance/ng187
3. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, Subramanian S, Thickett D. Vitamin D and COVID-19: evidence and recommendations for supplementation Royal Soc Open Sci 2020. R. Soc. open sci.7201912http://doi.org/10.1098/rsos.201912
4. Scientific Advisory Committee on Nutrition. Update of rapid review: vitamin D and acute respiratory tract infections. UK govt. December 2020. https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
5. NICE guideline NG187 Evidence reviews underpinning recommendations 1.1 to 1.3 and research recommendations in the NICE guideline. December 2020. https://www.nice.org.uk/guidance/ng187/evidence/evidence-reviews-for-the...
Competing interests: M.H. and D.T. have received speaking honoraria from Thornton Ross. RQ is a member of the Data Monitoring Committee for the CORONAVIT trial. No other competing interests.