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Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 InfectionThe COVID A to Z Randomized Clinical Trial

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To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Do high-dose zinc, high-dose ascorbic acid, and/or a combination of the 2 reduce the duration of symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?

Findings  In this randomized clinical trial of 214 patients with confirmed SARS-CoV-2 infection receiving outpatient care, there was no significant difference in the duration of symptoms among the 4 groups.

Meaning  These findings suggest that treatment with zinc, ascorbic acid, or both does not affect SARS-CoV-2 symptoms.


Importance  There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression.

Objective  To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection.

Design, Setting, and Participants  This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020.

Intervention  Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care.

Outcomes  The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements.

Results  A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups.

Conclusions and Relevance  In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care.

Trial Registration  ClinicalTrials.gov Identifier: NCT04342728

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Article Information

Accepted for Publication: January 9, 2021.

Published: February 12, 2021. doi:10.1001/jamanetworkopen.2021.0369

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Thomas S et al. JAMA Network Open.

Corresponding Author: Milind Y. Desai, MD, MBA, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk J1-5, Cleveland, OH 44195 (desaim2@ccf.org).

Author Contributions: Dr Desai 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.

Concept and design: Thomas, Patel, Bittel, Kumar, Mehra, McWilliams, Nissen, Desai.

Acquisition, analysis, or interpretation of data: Thomas, Patel, Bittel, Wolski, Wang, Kumar, Il’Giovine, Mehra, Nissen, Desai.

Drafting of the manuscript: Thomas, Patel, Bittel, Kumar, Il’Giovine, Mehra, Desai.

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

Statistical analysis: Wolski, Wang, Kumar, Desai.

Obtained funding: Thomas, Kumar, Desai.

Administrative, technical, or material support: Thomas, Bittel, Kumar, Nissen, Desai.

Supervision: Thomas, Bittel, Kumar, Il’Giovine, Nissen, Desai.

Conflict of Interest Disclosures: Dr McWilliams reported receiving consulting fees from Gilead Sciences outside the submitted work. Dr Desai reported receiving grants from Myokardia outside the submitted work and being supported by the Haslam Family Endowed Chair in Cardiovascular Medicine. No other disclosures were reported.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Serpil Erzurum, MD, James Young, MD, Daniel Culver, MD, Joan Booth, RN, Nancy Obuchowski, MPH, and John Petrich, RPh (Cleveland Clinic), were members of the operational and safety monitoring board. They were not compensated for their time. We would like to thank Samantha Xu, BS (Cleveland Clinic), for help with logistics of study set-up and coordination. She was compensated for her time.

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