Still no definitive answer on Vitamin D3 to treat COVID-19

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Among patients with moderate to severe COVID-19 there was no difference in length of hospital stay in those given a single 200,000-IU dose of vitamin D3 versus those given placebo in a randomised trial in Brazil, reports MedicalBrief. However, a JAMA editorial warns that it was "important to remain open-minded", since the study did not address outpatients with mild COVID-19 or the use of vitamin D as prophylaxis

Median length of hospital stay was about 7 days for both groups, with no significant differences in secondary outcomes including in-hospital mortality, admission to ICU, or need for mechanical ventilation, reported Dr Rosa Pereira, of Universidade de Sao Paulo, and colleagues.

Pereira and colleagues examined data from hospitalised patients with moderate to severe COVID-19 at two sites in Sao Paulo from June to August 2020, with the final follow-up in October. Participants were eligible if they were adults who tested positive for SARS-CoV-2 via PCR or had a CT scan finding "compatible with the disease," as well as "diagnosis of flu syndrome with criteria for hospitalisation." Primary outcome was length of hospital stay, defined as date of randomisation to hospital discharge.

Overall, 240 patients were randomised: 120 to a single oral dose of 200,000 IU of vitamin D and 120 to placebo. Of these, 237 were included in the primary analysis. Participants' mean age was 56, about 44% were women, and mean baseline 25-hydroxyvitamin D level was 20.9. They were given the intervention after a mean of 10.3 days from symptom onset.

The adjusted hazard ratio for hospital discharge was 0.99 (95% CI 0.71-1.37, P=0.94). There were also non-significant differences between the intervention and placebo groups in secondary outcomes, including in-hospital mortality (7.6% vs 5.1%, respectively, P=0.43), admission to the ICU (16.0% vs 21.2%, P=0.30), and need for mechanical ventilation (7.6% vs 14.4%, P=0.09).

In the intervention group, 86.7% achieved 25-hydroxyvitamin D sufficiency versus 10.9% of the placebo group, meaning "the present null findings cannot be attributed to the failure of increasing serum 25-hydroxyvitamin D levels."

Researchers noted no adverse events, except a single episode of vomiting linked to the intervention. They also noted no significant differences between groups in any health-related laboratory markers following the intervention.

Limitations to the data included that a minimal clinically important difference in hospital length of stay among COVID-19 patients has yet to be determined, as well as the small and heterogeneous sample size, with different patients with co-existing diseases on different medication regimens.


A JAMA editorial notes that there have been "multiple lines of evidence" in support of a potential therapeutic role for vitamin D that have generated enthusiasm over the past decade for testing whether administration of large doses of vitamin D might improve outcomes in various groups of patients, including those with critical illness.

The editorial, written by Dr David Leaf, of Brigham and Women's Hospital in Boston, and Dr Adit Ginde, of University of Colorado School of Medicine in Aurora, comments:

"The Correction of Vitamin D Deficiency in Critically Ill Patients (VITdAL-ICU) study was a multicenter randomized clinical trial that tested the effect of vitamin D3 administration (540 000 IU) vs placebo in 475 critically ill patients with vitamin D deficiency. The primary end point, hospital length of stay, was similar between the groups, although hospital mortality (a secondary end point) was lower in patients who received vitamin D3 vs placebo among those with severe vitamin D deficiency.

"The Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial sought to examine the effect of the same dose of vitamin D3 (540 000 IU) vs placebo on 90-day mortality in 3000 critically ill patients with vitamin D deficiency, but was stopped early for futility after enrollment of 1360 patients demonstrated very low likelihood for benefit. Randomized clinical trials testing vitamin D3 administration as a therapeutic strategy for disease prevention in other settings have yielded similarly null results.

"The COVID-19 pandemic has spurred renewed interest in vitamin D to address viral replication and hyperinflammation that have a major role in the pathogenesis of severe COVID-19.

Although [the Murai study] is an important contribution as the largest published randomized, double-blind, placebo-controlled trial of vitamin D3 administration among hospitalized patients with COVID-19 to date, several limitations should be considered.

"First, the study was underpowered.

"Second, the authors excluded patients who required invasive mechanical ventilation and those admitted to the intensive care unit, and less than 15% of patients required noninvasive ventilation. Accordingly, most of the patient population would be considered moderately ill and the results cannot be generalized to critically ill patients, who were excluded. This is important because the benefit of other anti-inflammatory therapies among patients with COVID-19 (eg, dexamethasone, tocilizumab) is highly dependent on severity of illness, with moderately ill patients receiving little or no benefit and severely ill patients receiving a substantial benefit.

"Third, only 115 study participants (48.3%) had vitamin D deficiency and only about one-fourth of the patients had severe vitamin D deficiency.

"Fourth, although the authors demonstrated that circulating levels of 25(OH)D increased in the patients who received vitamin D3, they did not measure circulating levels of 1,25-dihydroxyvitamin D, the active form of vitamin D. Accordingly, it is unclear whether patients were able to efficiently convert 25(OH)D to 1,25-dihydroxyvitamin D, because this conversion is inhibited by the osteocyte-derived hormone fibroblast growth factor 23, which is elevated in acutely ill patients.

"When this clinical trial is taken is isolation, the findings may appear ambiguous; that is, the findings do not exclude clinically important benefit (or harm) from high-dose vitamin D3 administration in hospitalized patients with moderate to severe COVID-19. In addition, this study did not address the use of vitamin D for patients with mild (outpatient) COVID-19 who are early in their symptom course or for use as prophylaxis against COVID-19.

"Therapeutic agents, such as monoclonal antibodies, also have demonstrated divergent results across settings. lists at least 30 studies of vitamin D interventions in COVID-19, globally and across the spectrum of disease. Based on experience in the pandemic, it seems likely that many of these studies will be underpowered or will not achieve target enrollment.

"Given the lack of highly effective therapies against COVID-19, except perhaps for corticosteroids, it is important to remain open-minded to emerging results from rigorously conducted studies of vitamin D (despite smaller sample sizes and important limitations of some studies). However, taken together with existing randomized clinical trials of vitamin D administration in hospitalized patients with respiratory infection and critical illness, the results reported by Murai et al12 do not support routine administration of vitamin D in hospitalized patients with moderate to severe COVID-19."


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

Igor H Murai; Alan L Fernandes; Lucas P Sales; Ana J Pinto; Karla F Goessler; Camila SC Duran; Carla BR Silva; André S Franco; Marina B Macedo; Henrique HH Dalmolin; Janaina Baggio; Guilherme GM Balbi; Bruna Z Reis; Leila Antonangelo ; Valeria F Caparbo; Bruno Gualano; Rosa MR Pereira

Published in JAMA on 17 February 2021

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


Full MedPageToday report (Restricted access)


JAMA study (Open access)


Full JAMA editorial (Open access)

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