Effect of Vitamin D₃ Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial

Importance

Patients with COVID-19 may exhibit 25-hydroxyvitamin D deficiency, but the beneficial effects of vitamin D₃ supplementation in this disease remain to be proven by randomized controlled trials.

Objective

To investigate the efficacy and safety of vitamin D₃ supplementation in patients with severe COVID-19.

Design, Setting, and Participants

This is a multicenter, double-blind, randomized, placebo-controlled trial conducted in two centers (a quaternary hospital and a field hospital) in Sao Paulo, Brazil. The trial included 240 hospitalized patients with severe COVID-19. The study was conducted from June 2, 2020 to October 7, 2020.

Interventions

Patients were randomly allocated (1:1 ratio) to receive either a single oral dose of 200,000 IU of vitamin D₃ or placebo.

Main Outcomes and Measures

The primary outcome was hospital length of stay, defined as hospital discharge from the date of randomization or death. Secondary outcomes were mortality, admission to ICU, mechanical ventilation requirement, and serum levels of 25-hydroxyvitamin D, creatinine, calcium, C-reactive protein, and D-dimer.

Results

Of 240 randomized patients (mean age, 56 years; 56% men), 232 (96.7%) were included in the primary analysis. Log-rank test showed that hospital length of stay was comparable between the vitamin D₃ supplementation and placebo groups (7.0 days [95% CI, 6.1 to 7.9] and 7.0 days [95% CI, 6.2 to 7.8 days]; hazard ratio, 1.12 [95% CI, 0.9 to 1.5]; P = .379; respectively). The rate of mortality (7.0% vs 5.1%; P = .590), admission to ICU (15.8% vs 21.2%; P = .314), and mechanical ventilation requirement (7.0% vs 14.4%; P = .090) did not significantly differ between groups. Vitamin D₃ supplementation significantly increased serum 25-hydroxyvitamin D levels compared to placebo (difference, 24.0 ng/mL [95% CI, 21.0% to 26.9%]; P = .001). No adverse events were observed.

Conclusions and Relevance

Among hospitalized patients with severe COVID-19, vitamin D₃ supplementation was safe and increased 25-hydroxyvitamin D levels, but did not reduce hospital length of stay or any other relevant outcomes vs placebo. This trial does not support the use of vitamin D₃ supplementation as an adjuvant treatment of patients with COVID-19.

Key points