Effect of moderate or high versus low dose daily vitamin D on COVID-19 incidence: A double-blind, parallel-group...

Vitamin D affects immune function and is associated with lower COVID-19 risk in observational studies. However, randomized clinical trials vary in whether they find vitamin D supplementation affects COVID-19 risk. The objective of this trial was to determine whether moderate or high dose vitamin D (4000 or 10,000 IU/day) versus low dose vitamin D (400 IU/day) affects COVID-19 risk.

We conducted a double-blind, parallel-group randomized trial (clinicaltrials.gov, NCT0486890) enrolling participants from December 5, 2020 to May 23, 2023 who chose between study branches comparing moderate versus low dose or high versus low dose vitamin D for up to 9 months and were randomized between the doses in their chosen branch. Recruitment occurred at UChicago Medicine or Rush University Medical Center. Eligibility criteria excluded persons with increased risk from vitamin D supplementation. Recruitment concluded March 30, 2023, with 955 participants randomized, and 923 continuing their participation until receipt of study vitamin D, including 324 high-versus-low branch participants. The primary outcome was time from randomization to COVID-19 infection.

COVID-19 risk was not lower for pooled moderate or high versus low dose (10.9% (50/461) versus 14.7% (68/462), aHR:0.73; 95%-CI:0.51-1.06; P = 0.10). In prespecified secondary analyses, COVID-19 risk was lower for moderate versus low dose (aHR:0.62; 95%-CI:0.39-0.99; P = 0.045) but not high versus low dose (aHR:0.99; 95%-CI:0.53-1.86; P = 0.98). Prespecified time-varying analyses controlling for post-randomization 25(OH)D levels found similar treatment effects, with no effects of 25(OH)D levels on risk. In a final prespecified analysis, among 130 seroconverting participants, COVID-19 was not reported less for pooled moderate or high versus low dose (aOR:0.62; 95%-CI:0.27-1.41; P = 0.25) and moderate versus low dose (aOR:0.37; 95%-CI:0.13-1.04; P = 0.06).

Moderate or high versus low dose vitamin D supplementation did not decrease COVID-19 risk, but effects may vary by dose. Further study is warranted of the effects of higher doses and 25(OH)D levels on COVID-19 and other viral respiratory tract infections, and whether these infections become clinically evident.

clinicaltrials.gov, NCT04868903, https://clinicaltrials.gov/study/NCT04868903.