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Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 InfectionA Randomized Clinical Trial

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

Question  Does a single oral dose of azithromycin lead to absence of symptoms at day 14 in outpatients with COVID-19 compared with placebo?

Findings  In this randomized trial that included 263 participants with SARS-CoV-2 infection, treatment with a single oral dose of azithromycin, 1.2 g, vs placebo resulted in self-reported absence of COVID-19 symptoms at day 14 in 50% vs 50%; this was not statistically significant.

Meaning  Among outpatients with SARS-CoV-2 infection, treatment with a single dose of oral azithromycin compared with placebo did not result in a greater likelihood of being free of symptoms at day 14.


Importance  Azithromycin has been hypothesized to have activity against SARS-CoV-2.

Objective  To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14.

Design, Setting, and Participants  Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization.

Interventions  Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92).

Main Outcomes and Measures  The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21.

Results  Among 263 participants who were randomized (median age, 43 years; 174 [66%] women; 57% non-Hispanic White and 29% Latinx/Hispanic), 76% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50%; placebo: 50%; prevalence difference, 0%; 95% CI, −14% to 15%; P > .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4%; 95% CI, −1% to 9%; P = .16).

Conclusions and Relevance  Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection.

Trial Registration  ClinicalTrials.gov Identifier: NCT04332107

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Catherine E. Oldenburg, ScD, MPH, Francis I. Proctor Foundation, University of California, San Francisco, 490 Illinois St, Floor 2, San Francisco, CA 94143 (catherine.oldenburg@ucsf.edu).

Accepted for Publication: June 25, 2021.

Published Online: July 16, 2021. doi:10.1001/jama.2021.11517

Author Contributions: Drs Oldenburg and Arnold had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Oldenburg, Brogdon, Hinterwirth, Lebas, Redd, Lietman, Arnold, Doan.

Acquisition, analysis, or interpretation of data: Oldenburg, Pinsky, Brogdon, Chen, Ruder, Zhong, Nyatigo, Cook, Lebas, Redd, Porco, Arnold, Doan.

Drafting of the manuscript: Oldenburg, Arnold, Doan.

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

Statistical analysis: Oldenburg, Nyatigo, Arnold.

Obtained funding: Oldenburg, Lietman, Doan.

Administrative, technical, or material support: Oldenburg, Pinsky, Brogdon, Chen, Ruder, Zhong, Nyatigo, Cook, Hinterwirth, Lebas, Redd, Lietman, Doan.

Supervision: Oldenburg, Lebas, Doan.

Conflict of Interest Disclosures: Ms Cook reported receipt of grants from the National Institutes of Health. Dr Lietman reported receipt of grants from Pfizer Inc, the National Institutes of Health, and the Bill & Melinda Gates Foundation. Dr Arnold reported receipt of grants from the Bill & Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases and hotel/airfare reimbursement to attend global health meetings from the Bill & Melinda Gates Foundation. No other disclosures were reported.

Funding/Support: This trial was supported by the Bill & Melinda Gates Foundation (grant INV-017026). Azithromycin and matching placebo were donated by Pfizer Inc. Dr Doan was supported in part by a Research to Prevent Blindness Career Development Award.

Role of the Funder/Sponsor: The study sponsors 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; or decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank Chris Damman, MD, and Rebecca Brander, PhD, program officers from the trial’s sponsor, the Bill & Melinda Gates Foundation. We thank Charles Knirsch, MD, Pfizer Inc, for advice on azithromycin dosing. We also thank the members of the DSMC: Art Reingold, MD, University of California, Berkeley; Emily Gower, PhD, University of North Carolina; and David Glidden, PhD, University of California, San Francisco. Drs Reingold, Gower, and Glidden received honoraria for their role in the DSMC. We thank William Hernandez, RN, and Ada Victoria Cevallos, MS, for translation services. Mr Hernandez and Ms Cevallos were compensated for their roles in the study. We thank J. Daniel Kelly, MD, Seth Blumberg, MD, and Ying Lin, MS, for advice and logistical support during the conduct of the trial. These individuals were employees of the University of California, San Francisco, at the time of the study and were paid as part of their employment but did not receive additional compensation for their role in the study. We also thank the study participants.

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