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February - 2021


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

I Murai, A Fernandez, L Sales, etal JAMA, 2021, Online Feb


There has been a lot of interest in the use of vitamin D to enhance innate and adaptive immunity, through improved function of macrophages and dendritic cells. 

This multicentre RCT set out to examine the effect of a single high dose of vitamin D3 on hospital length of stay among hospitalized patients with moderate to severe coronavirus disease 2019 (COVID-19). 

What did they do;

  • Enrolled 240 hospitalized adults patients with moderate to severe COVID-19 (PCR or compatible CT + symptoms + RR >24, SpO2 <93% RA, or risk farrow for complications. 
  • Administered a single dose of 200?000 IU vitamin D3 orally, vs placebo
  • Excluded patients in ICU at screening

 What did they find;

  • Time from onset symptoms to randomisation 10.3 days, mean age 56 yrs, 90% required oxygen at baseline
  • Primary outcome: No difference hospital length of stay (median of 7.0 vs 7.0 days; unadj HR hospital discharge, 1.07).
  • No difference secondary outcomes (hospital mortality 7.6% vs 5.1%, p=0.43), ICU admission (16%vs 21%, p=0.3), need for MV (7,6% vs 14.4%, p=0.09)
  • Mean serum Vit D levels increased compared to placebo (21 to 44.4 ng/mL vs 21 to 20 ng/mL, p<.001).
  • Post-hoc analyses of patients with baseline vitamin D deficiency revealed no significant difference in primary or secondary outcomes (hosp mortality 7.0% vs 1.7%, ICU admit 19.3% vs 15.5%)

There are serious limitations to this study;

  1. Sample size was based on 80% power to detect 50% difference in hospital LOS, a very unlikely effect size. Accordingly the trial is underpowered. 
  2. Patients in ICU or requiring MV at enrolment were excluded, so it is really a study of moderate illness. 
  3. Only half of those enrolled has baseline vitamin D deficiency 

While the limitations raise the possibility a larger, different trial could detect an important clinical difference, the history of vitamin D research is not encouraging. The VITdAL-ICU trial compared high-dose vitamin D3 administration (540?000 IU) vs placebo in 475 critically ill patients with vitamin D deficiency, and found no difference in primary end point, hospital length of stay, although hospital mortality (a secondary end point) was lower in patients who received vitamin D3 among those with severe vitamin D deficiency. The VIOLET trial compared the effect of the same dose of vitamin D3 vs placebo on 90-day mortality in 3000 critically ill patients with vitamin D deficiency, but was stopped early for futility. 

Overall, this study, with methodological limitations, does not support the use of a single high dose of oral vitamin D3 for treatment of moderate to severe COVID-19 in hospitalized patients.



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.


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