TY - JOUR
T1 - Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients with COVID-19
T2 - A Randomized Clinical Trial
AU - Self, Wesley H.
AU - Semler, Matthew W.
AU - Leither, Lindsay M.
AU - Casey, Jonathan D.
AU - Angus, Derek C.
AU - Brower, Roy G.
AU - Chang, Steven Y.
AU - Collins, Sean P.
AU - Eppensteiner, John C.
AU - Filbin, Michael R.
AU - Files, D. Clark
AU - Gibbs, Kevin W.
AU - Ginde, Adit A.
AU - Gong, Michelle N.
AU - Harrell, Frank E.
AU - Hayden, Douglas L.
AU - Hough, Catherine L.
AU - Johnson, Nicholas J.
AU - Khan, Akram
AU - Lindsell, Christopher J.
AU - Matthay, Michael A.
AU - Moss, Marc
AU - Park, Pauline K.
AU - Rice, Todd W.
AU - Robinson, Bryce R.H.
AU - Schoenfeld, David A.
AU - Shapiro, Nathan I.
AU - Steingrub, Jay S.
AU - Ulysse, Christine A.
AU - Weissman, Alexandra
AU - Yealy, Donald M.
AU - Thompson, B. Taylor
AU - Brown, Samuel M.
N1 - Funding Information:
Details of the trial’s rationale and design were previously published16 and are available in the trial protocol and statistical analysis plan included in Supplement 1 and Supplement 2, respectively. We conducted a multicenter, blinded, randomized clinical trial comparing hydroxychloroquine vs placebo among hospitalized adults with respiratory illness from COVID-19. Patients were enrolled between April 2, 2020, and June 19, 2020, at 34 hospitals in the US within the Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network (eTable 1 in Supplement 3). The final outcome assessment was scheduled on July 17, 2020. The trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) of the NIH. A central institutional review board at Vanderbilt University Medical Center approved the study. A data and safety monitoring board (DSMB) appointed by the NHLBI provided trial oversight. The Food and Drug Administration (FDA) issued an investigational new drug exemption (IND No. 149243). Patients or legally authorized representatives provided informed consent for participation, primarily using electronic consent procedures, including electronic consent forms and video conferencing for informed consent discussions, to reduce the risk of spreading the virus and to conserve personal protective equipment.16
Funding Information:
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
Funding Information:
Funding/Support: This study was supported by
Funding Information:
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.
Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1001/jama.2020.22240
DO - 10.1001/jama.2020.22240
M3 - Article
C2 - 33165621
AN - SCOPUS:85095803407
SN - 0002-9955
VL - 324
SP - 2165
EP - 2176
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 21
ER -