Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial

Abstract

Importance: The efficacy of vitamin D3 supplementation in coronavirus disease 2019 (COVID-19) remains unclear.

Objective: To investigate the effect of a single high dose of vitamin D3 on hospital length of stay in patients with COVID-19.

Design, setting, and participants: This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020.

Interventions: Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120).

Main outcomes and measures: The primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein.

Results: Of 240 randomized patients, 237 were included in the primary analysis (mean [SD] age, 56.2 [14.4] years; 104 [43.9%] women; mean [SD] baseline 25-hydroxyvitamin D level, 20.9 [9.2] ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D3 (7.0 [4.0-10.0] days) and placebo groups (7.0 [5.0-13.0] days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82-1.39]; P = .62). The difference between the vitamin D3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% [95% CI, -4.1% to 9.2%]; P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, -5.2% [95% CI, -15.1% to 4.7%]; P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, -6.8% [95% CI, -15.1% to 1.2%]; P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3 vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL [95% CI, 19.5-28.7]; P < .001). There were no adverse events, but an episode of vomiting was associated with the intervention.

Conclusions and relevance: Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19.

Trial registration: ClinicalTrials.gov Identifier: NCT04449718.

Figure 1.. Flow of Patients in a Study of the Effect of a High Dose of Vitamin D₃ on Patients With Moderate to Severe Coronavirus Disease 2019 (COVID-19)

All analyses were completed according to the patients’ randomization group. There was no imputation for missing data, except for laboratory parameters, in which missingness appeared to be at random and was modeled using generalized estimating equations. 25(OH)D indicates 25-hydroxyvitamin D.

Figure 2.. Hospital Discharge in a Study of the Effect of a High Dose of Vitamin D₃ on Patients With Moderate to Severe Coronavirus Disease 2019

Vertical bars represent single censored events. A, The median (interquartile range) observation time was not significantly different between the vitamin D₃ group (7.0 [4.0-10.0] d) and the placebo group (7.0 [5.0-13.0] d). B, Among the patients with 25-hydroxyvitamin D deficiency, there was no significant difference observed in the median (interquartile range) observation time between the vitamin D₃ group (8.0 [4.0-11.5] d) and the placebo group (7.0 [6.0-13.3] d).

Figure 3.. Serum 25-Hydroxyvitamin D Levels in a Study of the Effect of a High Dose of Vitamin D₃ on Patients With Moderate to Severe Coronavirus Disease 2019

Serum 25-hydroxyvitamin D levels were measured on the day of randomization (baseline) and on hospital discharge (postintervention). A, For all patients, a single high dose of vitamin D₃ significantly increased 25-hydroxyvitamin D levels compared with placebo (difference, 24.1 ng/mL [95% CI, 19.5-28.7]; P < .001). Median (interquartile range) observation time of the postintervention period was 7.0 (4.0-10.0) days for the vitamin D₃ group and 7.0 (5.0-13.0) days for the placebo group. B, For patients with 25-hydroxyvitamin D deficiency, a single high dose of vitamin D₃ significantly increased 25-hydroxyvitamin D levels compared with placebo (difference, 22.7 ng/mL [95% CI, 19.3-26.1]; P < .001). Median (interquartile range) observation time of the postintervention period was 8.0 (4.0-11.5) days for the vitamin D₃ group and 7.0 (6.0-13.3) days for the placebo group. Boxes represent median and interquartile range and whiskers extend to the highest and lowest values within 1.5 times the interquartile range of the 25th and 75th percentiles. Circles represent outliers.