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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-19A Randomized Clinical Trial

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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 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

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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.

Data Sharing Statement: See Supplement 3.

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.

References
1.
Liu  PT , Stenger  S , Li  H ,  et al.  Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.   Science. 2006;311(5768):1770-1773. doi:10.1126/science.1123933PubMedGoogle ScholarCrossref
2.
Aglipay  M , Birken  CS , Parkin  PC ,  et al; TARGet Kids! Collaboration.  Effect of high-dose vs standard-dose wintertime vitamin D supplementation on viral upper respiratory tract infections in young healthy children.   JAMA. 2017;318(3):245-254. doi:10.1001/jama.2017.8708PubMedGoogle ScholarCrossref
3.
Campbell  GR , Spector  SA .  Autophagy induction by vitamin D inhibits both Mycobacterium tuberculosis and human immunodeficiency virus type 1.   Autophagy. 2012;8(10):1523-1525. doi:10.4161/auto.21154PubMedGoogle ScholarCrossref
4.
van Etten  E , Mathieu  C .  Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.   J Steroid Biochem Mol Biol. 2005;97(1-2):93-101. doi:10.1016/j.jsbmb.2005.06.002PubMedGoogle ScholarCrossref
5.
Laplana  M , Royo  JL , Fibla  J .  Vitamin D receptor polymorphisms and risk of enveloped virus infection: a meta-analysis.   Gene. 2018;678:384-394. doi:10.1016/j.gene.2018.08.017PubMedGoogle ScholarCrossref
6.
Bilezikian  JP , Bikle  D , Hewison  M ,  et al.  Mechanisms in endocrinology: vitamin D and COVID-19.   Eur J Endocrinol. 2020;183(5):R133-R147. doi:10.1530/EJE-20-0665PubMedGoogle ScholarCrossref
7.
Autier  P , Boniol  M , Pizot  C , Mullie  P .  Vitamin D status and ill health: a systematic review.   Lancet Diabetes Endocrinol. 2014;2(1):76-89. doi:10.1016/S2213-8587(13)70165-7PubMedGoogle ScholarCrossref
8.
Aibana  O , Huang  CC , Aboud  S ,  et al.  Vitamin D status and risk of incident tuberculosis disease: a nested case-control study, systematic review, and individual-participant data meta-analysis.   PLoS Med. 2019;16(9):e1002907. doi:10.1371/journal.pmed.1002907PubMedGoogle Scholar
9.
Martineau  AR , Jolliffe  DA , Hooper  RL ,  et al.  Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.   BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583PubMedGoogle ScholarCrossref
10.
Sabetta  JR , DePetrillo  P , Cipriani  RJ , Smardin  J , Burns  LA , Landry  ML .  Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults.   PLoS One. 2010;5(6):e11088. doi:10.1371/journal.pone.0011088PubMedGoogle Scholar
11.
Mitchell  F .  Vitamin-D and COVID-19: do deficient risk a poorer outcome?   Lancet Diabetes Endocrinol. 2020;8(7):570. doi:10.1016/S2213-8587(20)30183-2PubMedGoogle ScholarCrossref
12.
Martineau  AR , Forouhi  NG .  Vitamin D for COVID-19: a case to answer?   Lancet Diabetes Endocrinol. 2020;8(9):735-736. doi:10.1016/S2213-8587(20)30268-0PubMedGoogle ScholarCrossref
13.
Meltzer  DO , Best  TJ , Zhang  H , Vokes  T , Arora  V , Solway  J .  Association of vitamin D status and other clinical characteristics with COVID-19 test results.   JAMA Netw Open. 2020;3(9):e2019722. doi:10.1001/jamanetworkopen.2020.19722PubMedGoogle Scholar
14.
Kaufman  HW , Niles  JK , Kroll  MH , Bi  C , Holick  MF .  SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels.   PLoS One. 2020;15(9):e0239252. doi:10.1371/journal.pone.0239252PubMedGoogle Scholar
15.
Ilie  PC , Stefanescu  S , Smith  L .  The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.   Aging Clin Exp Res. 2020;32(7):1195-1198. doi:10.1007/s40520-020-01570-8PubMedGoogle ScholarCrossref
16.
Kearns  MD , Alvarez  JA , Tangpricha  V .  Large, single-dose, oral vitamin D supplementation in adult populations: a systematic review.   Endocr Pract. 2014;20(4):341-351. doi:10.4158/EP13265.RAPubMedGoogle ScholarCrossref
17.
Bacchetti  P .  Current sample size conventions: flaws, harms, and alternatives.   BMC Med. 2010;8:17. doi:10.1186/1741-7015-8-17PubMedGoogle ScholarCrossref
18.
Bacchetti  P , McCulloch  CE , Segal  MR .  Simple, defensible sample sizes based on cost efficiency.   Biometrics. 2008;64(2):577-585. doi:10.1111/j.1541-0420.2008.01004_1.xPubMedGoogle ScholarCrossref
19.
Franco  AS , Freitas  TQ , Bernardo  WM , Pereira  RMR .  Vitamin D supplementation and disease activity in patients with immune-mediated rheumatic diseases: a systematic review and meta-analysis.   Medicine (Baltimore). 2017;96(23):e7024. doi:10.1097/MD.0000000000007024PubMedGoogle Scholar
20.
Cannell  JJ , Vieth  R , Umhau  JC ,  et al.  Epidemic influenza and vitamin D.   Epidemiol Infect. 2006;134(6):1129-1140. doi:10.1017/S0950268806007175PubMedGoogle ScholarCrossref
21.
Carpagnano  GE , Di Lecce  V , Quaranta  VN ,  et al.  Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19.   J Endocrinol Invest. Published online August 9, 2020. doi:10.1007/s40618-020-01370-xPubMedGoogle Scholar
22.
Annweiler  G , Corvaisier  M , Gautier  J ,  et al.  Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: the GERIA-COVID quasi-experimental study.   Nutrients. 2020;12(11):e3377. doi:10.3390/nu12113377PubMedGoogle Scholar
23.
Hernández  JL , Nan  D , Fernandez-Ayala  M ,  et al.  Vitamin D status in hospitalized patients with SARS-CoV-2 infection.   J Clin Endocrinol Metab. 2020;dgaa733. doi:10.1210/clinem/dgaa733PubMedGoogle Scholar
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