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Complementary and Alternative Medicine

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

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To identify the key insights or developments described in this article

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JAMA

Published Online: February 17, 2021

Original Investigation

Article Information and Disclosures

Igor H. Murai, PhD¹;

Alan L. Fernandes, PhD¹;

Lucas P. Sales, MSc¹;

Ana J. Pinto, BSc²;

Karla F. Goessler, PhD²;

Camila S. C. Duran, MD¹;

Carla B. R. Silva, MD¹;

André S. Franco, MD¹;

Marina B. Macedo, MD, MSc¹;

Henrique H. H. Dalmolin, MD¹;

Janaina Baggio, MD¹;

Guilherme G. M. Balbi, MD¹;

Bruna Z. Reis, PhD¹;

Leila Antonangelo, MD, PhD³;

Valeria F. Caparbo, PhD¹;

Bruno Gualano, PhD^2,4;

Rosa M. R. Pereira, MD, PhD¹

Author Affiliations

¹Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
²Applied Physiology & Nutrition Research Group, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
³Clinical Pathology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
⁴Food Research Center, Universidade de Sao Paulo, Sao Paulo, Brazil

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Key Points

Question What is 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)?

Findings In this randomized clinical trial that involved 240 hospitalized patients with moderate to severe COVID-19, a single dose of 200 000 IU of vitamin D₃, compared with placebo, did not significantly reduce hospital length of stay (median of 7.0 vs 7.0 days; unadjusted hazard ratio for hospital discharge, 1.07).

Meaning The study does not support the use of a high dose of vitamin D₃ for treatment of moderate to severe COVID-19 in hospitalized patients.

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 D₃group 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

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Article information

Corresponding Author: Rosa Maria Rodrigues Pereira, MD, PhD, Rheumatology Division, Faculdade de Medicina FMUSP, 3° andar, Universidade de Sao Paulo, Sao Paulo, SP, BR. Av. Dr. Arnaldo, 455, Pacaembu, Sao Paulo, SP, Brazil, 01246-903 (rosamariarp@yahoo.com).

Accepted for Publication: February 3, 2021.

Published Online: February 17, 2021. doi:10.1001/jama.2020.26848

Author Contributions: Dr Pereira had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Murai and Fernandes contributed equally.

Concept and design: Murai, Fernandes, Pinto, Macedo, Gualano, Pereira.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Murai, Fernandes, Franco, Macedo, Gualano, Pereira.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Murai, Fernandes, Reis, Pereira.

Obtained funding: Gualano, Pereira.

Administrative, technical, or material support: Sales, Pinto, Duran, Silva, Franco, Dalmolin, Baggio, Balbi, Antonangelo, Caparbo.

Supervision: Gualano, Pereira.

Conflict of Interest Disclosures: Dr Murai reported receiving grants from the Sao Paulo Research Foundation (FAPESP; grant 19/24782-4) during the conduct of the study. Dr Fernandes reported receiving grants from FAPESP during the conduct of the study. Dr Silva reported receiving grants from FAPESP during the conduct of the study. Dr Baggio reported receiving grants from FAPESP during the conduct of the study. Dr Balbi reported receiving grants from FAPESP during the conduct of the study. Dr Pereira reported receiving grants from FAPESP (grant 20/05752-4) and grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant 305556/2017-7) during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by FAPESP (grants 20/05752-4; 19/24782-4; 20/11102-2; 16/00006-7; 17/13552-2; 15/26937-4; 19/18039-7) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (305556/2017-7).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The authors are thankful to Monica Pinheiro, MD, MSc, and Roberta Costa, MSc (Ibirapuera field hospital), for assistance with the study; Cleuber Esteves Chaves, BSc (pharmacy unit of the clinical hospital), for the vitamin D₃ and placebo solution preparation; Rogério Ruscitto do Prado, PhD (Albert Einstein Hospital), for conducting statistical analyses; Cibele Russo, PhD (University of Sao Paulo), for statistical review; Mayara Diniz Santos, MS (School of Medicine of University of Sao Paulo), for technical support; all of the staff members from both centers; and all of the patients who participated in this study. None of these individuals received compensation for their participation.

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