The aim of this EUnetHTA (European Network for Health Technology Assessment) Rolling Collaborative Review on high dose vitamin D for the treatment of COVID-19 was to inform health policy at an early stage in the life cycle of therapies and to monitor ongoing studies in the format of a Living Document.

The systematic literature search was conducted in Medline, Pubmed, medRxiv, bioRxiv, arXivso, Cochrane COVID-19 Study Register, ClinicalTrials.gov, ISRCTN Registry, EU Clinical Trials Register. The first search was done in January 2021, and the last in November 2021. English and German randomized controlled studies (RCTs) investigating treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals with high dose vitamin D2, D3 or their metabolites were included if examining mortality, length of hospital stay, viral burden, clinical progression, hospitalization rates, intensive care unit (ICU) admission, mechanical ventilation, quality of life or adverse events. Two reviewers independently screened search results and assessed risk of bias and certainty of evidence. One reviewer extracted study data, checked by another.

Of the nine RCTs published to date, two investigate calcifediol, one calcitriol and six vitamin D3. All used different dosing regimens. Disease severity and proportion of vitamin D deficiency varied between studies. Calcifediol treated patients in one study required significantly less ICU admissions than untreated patients. Vitamin D3 in another study led to significantly more SARS-CoV-2 PCR-negative patients before day 21 than placebo. There were no other significant differences between groups. Twenty-five RCTs are ongoing, five of them with over 1,000 patients.

The current evidence is heterogenous regarding form and dosage of vitamin D, baseline disease severity and baseline vitamin D deficiency. There is currently no standardized/recommended level of what constitutes a (beneficial) “high dose”. Most results did not show significant differences between vitamin D treated groups and no vitamin D / placebo groups. Many of the studies are very small and certainty of evidence is predominantly low or very low.