High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial

PLoS ONE

May 2022

DOI: 10.1371/journal.pone.0267918

Citations:49

Influential Citations:4

Interventional (Human) Studies

Enhanced Details

Methods

Multicentre, randomized, double-blind, sequential, placebo-controlled trial conducted in 17 hospitals across four provinces in Argentina. Participants: adults ≥18 years, hospitalized in general wards with PCR-confirmed SARS-CoV-2 infection, with mild-to-moderate COVID-19 and at least one risk factor for progression (e.g., age ≥45, hypertension, diabetes, COPD/asthma, cardiovascular disease, BMI ≥30). Randomization 1:1 to vitamin D3 or placebo; two-stage adaptive design (stage 1: respiratory SOFA; stage 2: clinical events); results analyzed by intention-to-treat. Baseline characteristics: mean age 59.1 years; 47.2% women.

Intervention

Single oral dose of 500,000 IU vitamin D3 (five capsules of 100,000 IU) given as soon as possible after randomization.

Results

In hospitalized adults with mild-to-moderate COVID-19 and risk factors, a single high-dose vitamin D3 did not prevent respiratory worsening or improve key clinical outcomes. Primary outcome (change in rSOFA from baseline to day 7) did not differ between groups (median 0.0 [0.0–1.0] in both; p = 0.925). Secondary outcomes showed no significant differences: length of stay 6.0 days in both groups (p = 0.632); ICU admission 7.8% vs 10.7% (p = 0.622); in-hospital mortality 4.3% vs 1.9% (p = 0.451); serious adverse events 14.8% vs 11.7% (p = 0.631). In a small subset (n = 16), post-treatment serum 25‑OH vitamin D rose to 102.0 ng/mL with vitamin D3 vs 30.0 ng/mL with placebo (baseline ~32.5 vs 30.5 ng/mL). Authors conclude that a single high oral dose of vitamin D3 at admission does not prevent respiratory deterioration in this patient population; results were consistent across prespecified subgroups.

Limitations

Single-dose regimen; follow-up limited to hospitalization; underpowered for several clinically important outcomes; early termination after stage 1; generalizability limited to adults in Argentina with mild-to-moderate disease; vitamin D levels measured in a small subset; primary outcome based on a SpO2/FiO2-derived rSOFA surrogate.

Abstract

Background The role of oral vitamin D3 supplementation for hospitalized patients with COVID-19 remains to be determined. The study was aimed to evaluate whether vitamin D3 supplementation could prevent respiratory worsening among hospitalized patients with COVID-19. Methods and findings We designed a multicentre, randomized, double-blind, sequential, placebo-controlled clinical trial. The study was conducted in 17 second and third level hospitals, located in four provinces of Argentina, from 14 August 2020 to 22 June 2021. We enrolled 218 adult patients, hospitalized in general wards with SARS-CoV-2 confirmed infection, mild-to-moderate COVID-19 and risk factors for disease progression. Participants were randomized to a single oral dose of 500 000 IU of vitamin D3 or matching placebo. Randomization ratio was 1:1, with permuted blocks and stratified for study site, diabetes and age (≤60 vs >60 years). The primary outcome was the change in the respiratory Sepsis related Organ Failure Assessment score between baseline and the highest value recorded up to day 7. Secondary outcomes included the length of hospital stay; intensive care unit admission; and in-hospital mortality. Overall, 115 participants were assigned to vitamin D3 and 105 to placebo (mean [SD] age, 59.1 [10.7] years; 103 [47.2%] women). There were no significant differences in the primary outcome between groups (median [IQR] 0.0 [0.0–1.0] vs 0.0 [0.0–1.0], for vitamin D3 and placebo, respectively; p = 0.925). Median [IQR] length of hospital stay was not significantly different between vitamin D3 group (6.0 [4.0–9.0] days) and placebo group (6.0 [4.0–10.0] days; p = 0.632). There were no significant differences for intensive care unit admissions (7.8% vs 10.7%; RR 0.73; 95% CI 0.32 to 1.70; p = 0.622), or in-hospital mortality (4.3% vs 1.9%; RR 2.24; 95% CI 0.44 to 11.29; p = 0.451). There were no significant differences in serious adverse events (vitamin D3 = 14.8%, placebo = 11.7%). Conclusions Among hospitalized patients with mild-to-moderate COVID-19 and risk factors, a single high oral dose of vitamin D3 as compared with placebo, did not prevent the respiratory worsening. Trial registration ClincicalTrials.gov Identifier: NCT04411446. show less