High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial

Annweiler et al., PLoS Medicine, doi:10.1371/journal.pmed.1003999, COVIT-TRIAL, NCT04344041, May 2022

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Vitamin D for COVID-19

8th treatment shown to reduce risk in October 2020, now with p < 0.00000000001 from 125 studies, recognized in 18 countries.

Lower risk for mortality, ICU, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,700+ studies for 141 treatments. c19early.org

RCT comparing single dose 400,000IU and single dose 50,000IU vitamin D in France, showing lower mortality with the higher dose, statistically significant only at day 14.

The aHR for days 0-5 was 1.30 [0.31-5.35], compared to 0.11 [0.02-0.52] for days 6-14, which in part may reflect the conversion delay for cholecalciferol treatment. The lower efficacy at day 28 vs. day 14 may in part reflect use of only a single dose.

Bolus treatment is less effective. Pharmacokinetics and the potential side effects of high bolus doses suggest that ongoing treatment spread over time is more appropriate. Research has confirmed that lower dose regular treatment with vitamin D is more effective than intermittent high-dose bolus treatment for various conditions, including rickets and acute respiratory infections1,2. The biological mechanisms supporting these findings involve the induction of enzymes such as 24-hydroxylase and fibroblast growth factor 23 (FGF23) by high-dose bolus treatments. These enzymes play roles in inactivating vitamin D, which can paradoxically reduce levels of activated vitamin D and suppress its activation for extended periods post-dosage. Evidence indicates that 24-hydroxylase activity may remain elevated for several weeks following a bolus dose, leading to reduced levels of the activated form of vitamin D. Additionally, FGF23 levels can increase for at least three months after a large bolus dose, which also contributes to the suppression of vitamin D activation1.

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risk of death, 30.0% lower, HR 0.70, p = 0.29, treatment 19 of 126 (15.1%), control 21 of 126 (16.7%), Cox proportional hazards, day 28, intention-to-treat.

risk of death, 38.0% lower, HR 0.62, p = 0.17, treatment 17 of 121 (14.0%), control 21 of 121 (17.4%), Cox proportional hazards, day 28, per-protocol.

risk of death, 61.0% lower, HR 0.39, p = 0.049, treatment 8 of 127 (6.3%), control 14 of 127 (11.0%), Cox proportional hazards, day 14, intention-to-treat.

risk of death, 65.0% lower, HR 0.35, p = 0.03, treatment 7 of 122 (5.7%), control 14 of 122 (11.5%), Cox proportional hazards, day 14, per-protocol.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Griffin et al., Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19, Clinical Medicine, doi:10.7861/clinmed.2021-0035.sciencedirect.com, doi.org.

2. Martineau et al., Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, BMJ 2017, 356, doi:10.1136/bmj.i6583.bmj.com, doi.org.

Annweiler et al., 31 May 2022, Randomized Controlled Trial, France, peer-reviewed, 17 authors, study period 15 April, 2020 - 17 December, 2020, dosage 400,000IU single dose, trial NCT04344041 (history) (COVIT-TRIAL).

This Paper Vitamin D All

High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial

Cédric Annweiler, Mélinda Beaudenon, Jennifer Gautier, Justine Gonsard, Sophie Boucher, Guillaume Chapelet, Astrid Darsonval, Bertrand Fougère, Olivier Guérin, Marjorie Houvet, Pierre Ménager, Claire Roubaud-Baudron, Achille Tchalla, Jean-Claude Souberbielle, Jérémie Riou, Elsa Parot-Schinkel, Thomas Célarier

PLOS Medicine, doi:10.1371/journal.pmed.1003999

¶ Membership of the COVIT-TRIAL study group is provided in S1 Supplemental Appendix.

Supporting information S1

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