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Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19A Randomized Clinical Trial

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1 Credit CME
Key Points

Question  Does treatment with hydroxychloroquine improve clinical outcomes of adults hospitalized with coronavirus disease 2019 (COVID-19)?

Findings  In this randomized clinical trial that included 479 hospitalized adults with respiratory symptoms from COVID-19, the distribution of the day 14 clinical status score (measured using a 7-category ordinal scale) was not significantly different for patients randomized to receive hydroxychloroquine compared with placebo (adjusted odds ratio, 1.02).

Meaning  These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.

Abstract

Importance  Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed.

Objective  To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19.

Design, Setting, and Participants  This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.

Interventions  Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237).

Main Outcomes and Measures  The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality.

Results  Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]).

Conclusions and Relevance  Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.

Trial Registration  ClinicalTrials.gov: NCT04332991

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Article Information

Corresponding Author: Wesley H. Self, MD, MPH, Department of Emergency Medicine, Vanderbilt University Medical Center, 1313 21st Ave S, Oxford House 312, Nashville, TN 37232 (wesley.self@vumc.org).

Accepted for Publication: October 26, 2020.

Published Online: November 9, 2020. doi:10.1001/jama.2020.22240

Author Contributions: Drs Schoenfeld and Hayden 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. Drs Schoenfeld and Self take responsibility for the trial overall.

Concept and design: Self, Semler, Angus, Casey, Brower, Collins, Eppensteiner, Ginde, Gong, Johnson, Moss, Rice, Robinson, Schoenfeld, Shapiro, Steingrub, Weissman, Yealy, Thompson, Brown.

Acquisition, analysis, or interpretation of data: Self, Semler, Leither, Casey, Angus, Brower, Chang, Collins, Filbin, Files, Gibbs, Ginde, Gong, Harrell, Hayden, Hough, Johnson, Khan, Lindsell, Matthay, Park, Rice, Robinson, Schoenfeld, Steingrub, Ulysse, Weissman, Thompson, Brown.

Drafting of the manuscript: Self, Semler, Casey, Angus, Collins, Johnson, Khan, Matthay, Moss, Robinson, Shapiro, Steingrub, Ulysse, Weissman, Yealy, Thompson, Brown.

Critical revision of the manuscript for important intellectual content: Self, Semler, Leither, Casey, Angus, Brower, Chang, Collins, Eppensteiner, Filbin, Files, Gibbs, Ginde, Gong, Harrell, Hayden, Hough, Johnson, Schoenfeld, Khan, Lindsell, Matthay, Moss, Park, Rice, Robinson, Shapiro, Steingrub, Ulysse, Yealy, Thompson, Brown.

Statistical analysis: Semler, Casey, Angus, Gibbs, Harrell, Hayden, Lindsell, Schoenfeld, Steingrub, Ulysse.

Obtained funding: Self, Collins, Gong, Moss, Shapiro, Thompson.

Administrative, technical, or material support: Self, Semler, Casey, Angus, Ginde, Khan, Rice, Robinson, Shapiro, Thompson.

Supervision: Self, Semler, Casey, Angus, Brower, Chang, Collins, Ginde, Johnson, Moss, Rice, Robinson, Yealy, Thompson, Brown.

Conflict of Interest Disclosures: Dr Self reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and personal fees from Aerpio Pharmaceuticals outside the submitted work. Dr Semler reported receiving grants from the NHLBI during the conduct of the study. Dr Leither reported receiving grants from the NHLBI during the conduct of the study. Dr Casey reported receiving grants from the NHLBI during the conduct of the study. Dr Angus reported receiving grants from the NHLBI and National Center for Advancing Translational Sciences (NCATS) during the conduct of the study and personal fees from Ferring Pharmaceuticals, Bristol-Myers Squibb, and Bayer AG and stock from Alung Technologies. Dr Angus has patents pending through Ferring Pharmaceuticals and the University of Pittsburgh. Dr Chang reported receiving grants from the NHLBI during the conduct of the study and personal fees from PureTech Health and LaJolla Pharmaceuticals outside the submitted work. Dr Collins reported receiving grants from the NHLBI and personal fees from Vir Biotechnology outside the submitted work. Dr Filbin reported receiving grants from the NHLBI during the conduct of the study. Dr Files reported receiving grants from the NIH during the conduct of the study and personal fees from Cytovale and Medpace outside the submitted work. Dr Ginde reported receiving grants from the NIH during the conduct of the study. Dr Gong reported receiving grants from the NHLBI for the submitted work and research funding from the Agency for Healthcare Research and Quality and Regeneron outside the submitted work. Dr Harrell reported receiving grants from the NHLBI and the NCATS during the conduct of this study and personal fees from Adapt Health, Springer, Stanford, University of Texas, ICSB, Duke, Ottawa Hospital, American Statistical Association, Yale, Virginia Commonwealth University, and Arnold Foundation outside the submitted work. Dr Hough reported receiving grants from the NIH during the conduct of the study. Dr Khan reported receiving grants from GlaxoSmithKline, United Therapeutics, Reata Pharmaceuticals, Actelion Pharmaceuticals, and Lung LLC outside the submitted work. Dr Lindsell reported receiving grants from the NHLBI during the conduct of the study and grants from the Department of Defense, NCATS, the NHLBI, the Centers for Disease Control and Prevention, and Marcus Foundation; research contracts from Endpoint Health, Entegrion, and bioMerieux outside the submitted work; in addition, Dr Lindsell has a patent risk stratification in sepsis and septic shock issued. Dr Matthay reported receiving grants from the NHLBI during the conduct of the study and grants from Bayer Pharmaceuticals, Roche-Genentech, the Department of Defense, and the California Institute of Regenerative Medicine and personal fees from GEn1E LifeSciences, Citius Pharma, and Novartis outside the submitted work. Dr Moss reported receiving grants from the NHLBI during the conduct of the study. Dr Park reported receiving grants from NHLBI during the conduct of the study and grants from Eli Lilly and service on Council of the Society of Critical Care Medicine outside the submitted work. Dr Rice reported receiving grants from the NHLBI during the conduct of the study and personal fees from Cumberland Pharmaceuticals Inc, Avisa Pharmaceutical LLC consulting, and Cytovale Inc outside the submitted work. Dr Schoenfeld reported receiving grants from the NIH during the conduct of the study and personal fees from Immunity Pharma and Theravance outside the sumitted work. Dr Shapiro reported receiving grants from the NIH during the conduct of the study. Dr Steingrub reported receiving grants from the NHLBI during the conduct of the study. Dr Yealy reported receiving grants from the NHLBI during the conduct of the study and personal fees from McGraw Hill Inc, Lippincott Williams & Wilkins, Wolters Kluwer Inc, the American College of Emergency Physicians, multiple legal corporations, and UpToDate Inc outside the submitted work. Dr Thompson reported receiving grants from the NHLBI during the conduct of the study and personal fees from Bayer, Novartis, and Thetis outside the submitted work. Dr Brown reported receiving grants from the NHLBI during the conduct of the study and personal fees from Hamilton, Oxford University Press/Brigham Young University, and New York University and grants from Faron Pharmaceuticals, Sedana Pharmaceuticals, Janssen, the NIH, and Department of Defense outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grants from the NHLBI (3U01HL123009-06S1, U01HL123009, U01HL122998, U01HL123018, U01HL123023, U01HL123008, U01HL123031, U01HL123004, U01HL123027, U01HL123010, U01HL123033, U01HL122989, U01HL123022, and U01HL123020). The REDCap data tools used for this study were supported by a grant from NCATS (5UL1TR002243). The work at Massachusetts General Hospital was supported in part by the Harvard Catalyst/Harvard Clinical and Translational Science Center (NCATS, NIH awards UL1TR001102 and UL1TR002541-01). Sandoz, a Novartis division, supplied the hydroxychloroquine and placebo used in this trial.

Role of the Funders/Sponsor: The NHLBI supported the trial through funding, appointed a protocol review committee and data and safety monitoring board, and reviewed the manuscript prior to submission for publication but did not have the power to veto publication or select a journal. The NHLBI had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; in the preparation of the manuscript; and in the decision to submit the manuscript for publication. Representatives from Sandoz reviewed the manuscript prior to submission for publication but did not have the power to veto publication or select a journal. Sandoz had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; the preparation of the manuscript; and the decision to submit the manuscript for publication.

Disclaimer: Dr Angus is Senior Editor of JAMA, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Group Information: The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network members are listed in the eAppendix in Supplement 3.

Data Sharing Statement: See Supplement 4.

Additional Information: The data analyses for this trial were conducted at the PETAL Clinical Trials Network Data Coordinating Center at Massachusetts General Hospital by Drs Schoenfeld and Hayden and Ms Ulysse.

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