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Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19A Randomized Clinical Trial

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

Question  Does ivermectin, 400 μg/kg, daily for 3 days, compared with placebo, shorten symptom duration among adult (≥30 years) outpatients in the US with symptomatic mild to moderate COVID-19?

Findings  In this double-blinded, randomized, placebo-controlled platform trial conducted in the US during a period of Delta and Omicron variant predominance, and that included 1591 adult outpatients with COVID-19, the posterior probability of improvement in time to recovery in those treated with ivermectin vs placebo had a hazard ratio of 1.07, with a posterior probability of benefit of .91. This did not meet the prespecified threshold of posterior probability greater than .95.

Meaning  These findings do not support the use of ivermectin in outpatients with mild to moderate COVID-19.

Abstract

Importance  The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown.

Objective  To evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19.

Design, Setting, and Participants  ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US.

Interventions  Participants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774).

Main Outcomes and Measures  Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28.

Results  Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]).

Conclusions and Relevance  Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.

Trial Registration  ClinicalTrials.gov Identifier: NCT04885530

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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: Susanna Naggie, MD, MHS, Duke Clinical Research Institute, Duke University School of Medicine, 300 W Morgan St, Ste 800, Durham, NC 27701 (susanna.naggie@duke.edu).

Accepted for Publication: September 20, 2022.

Published Online: October 21, 2022. doi:10.1001/jama.2022.18590

Author Contributions: Drs Naggie and Hernandez 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: Naggie, Boulware, Lindsell, Stewart, Gentile, Collins, McCarthy, Thicklin, Felker, Ginde, Gabriel, Dunsmore, Adam, Wilson, Hernandez.

Acquisition, analysis, or interpretation of data: Naggie, Boulware, Lindsell, Stewart, Gentile, Jayaweera, Castro, Sulkowski, McTigue, Felker, Bramante, Slandzicki, Shah, Lenert, Dunsmore, DeLong, Hanna, Remaly, Wilder, Shenkman, Hernandez.

Drafting of the manuscript: Naggie, Boulware, Lindsell, Stewart, Collins, Thicklin, Gabriel, Wilson.

Critical revision of the manuscript for important intellectual content: Lindsell, Stewart, Gentile, McCarthy, Jayaweera, Castro, Sulkowski, McTigue, Felker, Ginde, Bramante, Slandzicki, Shah, Lenert, Dunsmore, Adam, DeLong, Hanna, Remaly, Wilder, Shenkman, Hernandez.

Statistical analysis: Lindsell, Stewart.

Obtained funding: Naggie, Adam, Hernandez.

Administrative, technical, or material support: Naggie, Boulware, Lindsell, Collins, Jayaweera, McTigue, Felker, Slandzicki, Gabriel, Lenert, Dunsmore, Adam, DeLong, Hanna, Remaly, Wilder, Wilson, Hernandez.

Supervision: Naggie, Lindsell, McCarthy, Jayaweera, Castro, Sulkowski, McTigue, Felker, Gabriel, Shah, Lenert, Hernandez.

Other - clinical protocol development and protocol oversight: Gentile.

Other - project management: Dunsmore.

Conflict of Interest Disclosures: Dr Naggie reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and grants from Gilead Sciences and AbbVie; personal fees from Pardes Biosciences, Personal Health Insights Inc, and Bristol Myers Squibb/PRA Health Services; and stock options from Vir Biotechnology as well as providing unpaid consultation to Silverback Therapeutics outside the submitted work. Dr Boulware reported receiving grants from the NIH during the conduct of the study. Dr Lindsell reported receiving grants from the National Center for Advancing Translational Sciences (NCATS) during the conduct of the study and grants from the NIH, Centers for Disease Control and Prevention, and Department of Defense to his institution and contracts to his institution for research services from Endpoint Health, bioMerieux, Entegrion Inc, AbbVie, and AstraZeneca outside the submitted work. In addition, Dr Lindsell had a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center. Dr Stewart reported receiving grants from the NIH NCATS during the conduct of the study and grants from the NIH outside the submitted work. Dr Gentile reported receiving personal fees from Duke University during the conduct of the study and grants from the NIH outside the submitted work. Dr Collins reported receiving personal fees from Vir Biotechnology during the conduct of the study. Dr Jayaweera reported receiving grants from NCATS during the conduct of the study and grants from Gilead, Pfizer, Janssen, and ViiV and serving as a consultant for Theratechnologies outside the submitted work. Dr Castro reported receiving grants from the NIH, American Lung Association, Patient-Centered Outcomes Research Institute, AstraZeneca, GlaxoSmithKline, Novartis, Pulmatrix, Sanofi, and Shionogi and personal fees from Genentech, Teva, Sanofi, Merck, Novartis, Arrowhead, OM Pharma, Allakos, Amgen, AstraZeneca, GlaxoSmithKline, Regeneron, and Elsevier outside the submitted work. Dr Sulkowski reported receiving personal fees from AbbVie, Gilead, GlaxoSmithKline, Atea Pharmaceuticals, Antios Therapeutics, Precision BioSciences, Viiv, and Virion and grants from Janssen to Johns Hopkins University outside the submitted work. Dr McTigue reported receiving grants to her institution from the NIH during the conduct of the study and research contracts to her institution from Pfizer and Janssen outside the submitted work. Dr Felker reported receiving grants from the NIH during the conduct of the study and grants from Novartis outside the submitted work. Dr Ginde reported receiving grants from the NIH during the conduct of the study and grants from the NIH, Centers for Disease Control and Prevention, Department of Defense, AbbVie (investigator-initiated), and Faron Pharmaceuticals (investigator-initiated) outside the submitted work. Dr Adam reported receiving funding from the US government (funding through Operation Warp Speed) during the conduct of the study. Dr DeLong reported receiving grants from NCATS during the conduct of the study. Dr Hanna reported receiving grants from the US Biomedical Advanced Research and Development Authority during the conduct of the study and personal fees from Merck & Co and AbPro outside the submitted work. Dr Remaly reported receiving grants from NCATS during the conduct of the study. Dr Wilder reported receiving grants from NCATS during the conduct of the study. Dr Wilson reported receiving grants from NCATS during the conduct of the study. Dr Hernandez reported receiving grants from American Regent, Amgen, Boehringer Ingelheim, Merck, Verily, Somologic, and Pfizer, and personal fees from AstraZeneca, Boston Scientific, Bristol Myers Squibb, Cytokinetics, and Merck outside the submitted work. No other disclosures were reported.

Funding/Support: ACTIV-6 is funded by NCATS (3U24TR001608-05W1) and the Vanderbilt University Medical Center Recruitment Innovation Core (U24TR001579). Additional support for this study was provided by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (contract No.75A50122C00037). The Vanderbilt University Medical Center Clinical and Translational Science Award from NCATS (UL1TR002243) supported the REDCap infrastructure.

Role of the Funder/Sponsor: NCATS participated 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.

Group Information: The Accelerating Covid-19 Therapeutic Interventions and Vaccines (ACTIV-6) Study Group and Investigators are listed in Supplement 4.

Data Sharing Statement: See Supplement 5

Additional Contributions: We thank Samuel Bozzette, MD, PhD, and Eugene Passamani, MD, both of NCATS, for their roles in the trial design and protocol development. We also thank the ACTIV-6 Data Monitoring Committee and Clinical Events Committee members (listed below) for their contributions. Data monitoring committee: Clyde Yancy, MD, MSc, Northwestern University Feinberg School of Medicine; Adaora Adimora, MD, University of North Carolina, Chapel Hill; Susan Ellenberg, PhD, University of Pennsylvania; Kaleab Abebe, PhD, University of Pittsburgh; Arthur Kim, MD, Massachusetts General Hospital; John D. Lantos, MD, Children’s Mercy Hospital; Jennifer Silvey-Cason, participant representative; Frank Rockhold, PhD, Duke Clinical Research Institute; Sean O’Brien, PhD, Duke Clinical Research Institute; Frank Harrell, PhD, Vanderbilt University Medical Center; Zhen Huang, MS, Duke Clinical Research Institute. Clinical Events Committee: Renato Lopes, MD, PhD, MHS, W. Schuyler Jones, MD, Antonio Gutierrez, MD, Robert Harrison, MD, David Kong, MD, Robert McGarrah, MD, Michelle Kelsey, MD, Konstantin Krychtiuk, MD, and Vishal Rao, MD, all of the Duke Clinical Research Institute, Duke University School of Medicine. They received compensation for their contributions.

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