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Randomized Controlled Trial
. 2020 Dec 1;324(21):2165-2176.
doi: 10.1001/jama.2020.22240.

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

Wesley H Self  1 , Matthew W Semler  2 , Lindsay M Leither  3   4 , Jonathan D Casey  2 , Derek C Angus  5 , Roy G Brower  6 , Steven Y Chang  7 , Sean P Collins  1 , John C Eppensteiner  8 , Michael R Filbin  9 , D Clark Files  10 , Kevin W Gibbs  10 , Adit A Ginde  11 , Michelle N Gong  12 , Frank E Harrell Jr  13 , Douglas L Hayden  14 , Catherine L Hough  15 , Nicholas J Johnson  16 , Akram Khan  15 , Christopher J Lindsell  13 , Michael A Matthay  17 , Marc Moss  18 , Pauline K Park  19 , Todd W Rice  2 , Bryce R H Robinson  20 , David A Schoenfeld  14 , Nathan I Shapiro  21 , Jay S Steingrub  22 , Christine A Ulysse  14 , Alexandra Weissman  23 , Donald M Yealy  23 , B Taylor Thompson  24 , Samuel M Brown  3   4 ; National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Jay Steingrub, Howard Smithline, Bogdan Tiru, Mark Tidswell, Lori Kozikowski, Sherell Thornton-Thompson, Leslie De Souza, Peter Hou, Rebecca Baron, Anthony Massaro, Imoigele Aisiku, Lauren Fredenburgh, Raghu Seethala, Lily Johnsky, Richard Riker, David Seder, Teresa May, Michael Baumann, Ashley Eldridge, Christine Lord, Nathan Shapiro, Daniel Talmor, Thomas O’Mara, Charlotte Kirk, Kelly Harrison, Lisa Kurt, Margaret Schermerhorn, Valerie Banner-Goodspeed, Katherine Boyle, Nicole Dubosh, Michael Filbin, Kathryn Hibbert, Blair Parry, Kendall Lavin-Parsons, Natalie Pulido, Brendan Lilley, Carl Lodenstein, Justin Margolin, Kelsey Brait, Alan Jones, James Galbraith, Rebekah Peacock, Utsav Nandi, Taylor Wachs, Michael Matthay, Kathleen Liu, Kirsten Kangelaris, Ralph Wang, Carolyn Calfee, Kimberly Yee, Gregory Hendey, Steven Chang, George Lim, Nida Qadir, Andrea Tam, Rebecca Beutler, Joseph Levitt, Jenny Wilson, Angela Rogers, Rosemary Vojnik, Jonasel Roque, Timothy Albertson, James Chenoweth, Jason Adams, Skyler Pearson, Maya Juarez, Eyad Almasri, Mohamed Fayed, Alyssa Hughes, Shelly Hillard, Ryan Huebinger, Henry Wang, Elizabeth Vidales, Bela Patel, Adit Ginde, Marc Moss, Amiran Baduashvili, Jeffrey McKeehan, Lani Finck, Carrie Higgins, Michelle Howell, Ivor Douglas, Jason Haukoos, Terra Hiller, Carolynn Lyle, Alicia Cupelo, Emily Caruso, Claudia Camacho, Stephanie Gravitz, James Finigan, Christine Griesmer, Pauline Park, Robert Hyzy, Kristine Nelson, Kelli McDonough, Norman Olbrich, Mark Williams, Raj Kapoor, Jean Nash, Meghan Willig, Henry Ford, Jayna Gardner-Gray, Mayur Ramesh, Montefiore Moses, Michelle Ng Gong, Michael Aboodi, Ayesha Asghar, Omowunmi Amosu, Madeline Torres, Savneet Kaur, Jen-Ting Chen, Aluko Hope, Brenda Lopez, Kathleen Rosales, Jee Young You, Jarrod Mosier, Cameron Hypes, Bhupinder Natt, Bryan Borg, Elizabeth Salvagio Campbell, R Duncan Hite, Kristin Hudock, Autumn Cresie, Faysal Alhasan, Jose Gomez-Arroyo, Abhijit Duggal, Omar Mehkri, Andrei Hastings, Debasis Sahoo, Francois Abi Fadel, Susan Gole, Valerie Shaner, Allison Wimer, Yvonne Meli, Alexander King, Thomas Terndrup, Matthew Exline, Sonal Pannu, Emily Robart, Sarah Karow, Catherine Hough, Bryce Robinson, Nicholas Johnson, Daniel Henning, Monica Campo, Stephanie Gundel, Sakshi Seghal, Sarah Katsandres, Sarah Dean, Akram Khan, Olivia Krol, Milad Jouzestani, Peter Huynh, Alexandra Weissman, Donald Yealy, Denise Scholl, Peter Adams, Bryan McVerry, David Huang, Derek Angus, Jordan Schooler, Steven Moore, Clark Files, Chadwick Miller, Kevin Gibbs, Mary LaRose, Lori Flores, Lauren Koehler, Caryn Morse, John Sanders, Caitlyn Langford, Kristen Nanney, Masiku MdalaGausi, Phyllis Yeboah, Peter Morris, Jamie Sturgill, Sherif Seif, Evan Cassity, Sanjay Dhar, Marjolein de Wit, Jessica Mason, Andrew Goodwin, Greg Hall, Abbey Grady, Amy Chamberlain, Samuel Brown, Joseph Bledsoe, Lindsay Leither, Ithan Peltan, Nathan Starr, Melissa Fergus, Valerie Aston, Quinn Montgomery, Rilee Smith, Mardee Merrill, Katie Brown, Brent Armbruster, Estelle Harris, Elizabeth Middleton, Robert Paine, Stacy Johnson, Macy Barrios, John Eppensteiner, Alexander Limkakeng, Lauren McGowan, Tedra Porter, Andrew Bouffler, J. Clancy Leahy, Bennet deBoisblanc, Matthew Lammi, Kyle Happel, Paula Lauto, Wesley Self, Jonathan Casey, Matthew Semler, Sean Collins, Frank Harrell, Christopher Lindsell, Todd Rice, William Stubblefield, Christopher Gray, Jakea Johnson, Megan Roth, Margaret Hays, Donna Torr, Arwa Zakaria, David Schoenfeld, Taylor Thompson, Douglas Hayden, Nancy Ringwood, Cathryn Oldmixon, Christine Ulysse, Richard Morse, Ariela Muzikansky, Laura Fitzgerald, Samuel Whitaker, Adrian Lagakos, Roy Brower, Lora Reineck, Neil Aggarwal, Karen Bienstock, Michelle Freemer, Myron Maclawiw, Gail Weinmann, Laurie Morrison, Mark Gillespie, Richard Kryscio, Daniel Brodie, Wojciech Zareba, Anne Rompalo, Michael Boeckh, Polly Parsons, Jason Christie, Jesse Hall, Nicholas Horton, Laurie Zoloth, Neal Dickert, Deborah Diercks
Affiliations
Randomized Controlled Trial

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

Wesley H Self et al. JAMA. .

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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Participant Flow in a Randomized Clinical Trial of Hydroxychloroquine vs Placebo in Patients Hospitalized With Respiratory Symptoms of Coronavirus Disease 2019 (COVID-19)
aBetween April 2 and April 21, 2020, screened patients included both those with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and those with suspected SARS-CoV-2 infection. Between April 21, 2020, and the end of the trial (June 19, 2020), only patients with laboratory-confirmed SARS-CoV-2 infection were screened. bExclusion criteria were not mutually exclusive. cQTc was assessed as a study procedure during the screening process; patients must have had a QTc less than 500 ms at the time of screening to be eligible for the trial. dReasons for not randomizing were not mutually exclusive. eRandomization was stratified by enrolling hospital.
Figure 2.
Figure 2.. Clinical Status on the Coronavirus Disease (COVID) Outcomes Scale 14 Days and 28 Days After Randomization
ECMO indicates extracorporeal membrane oxygenation. There was no significant difference between the hydroxychloroquine group and placebo group in the overall distribution of scores at 14 days (adjusted odds ratio, 1.02 [95% CI, 0.73-1.42]) or 28 days (adjusted odds ratio, 0.97 [95% CI, 0.69-1.38]).
Figure 3.
Figure 3.. Survival and Hospital Discharge Through 28 Days Following Randomization
The survival curves are survival function (Kaplan-Meier) curves with a P value calculated by the log-rank test. Patients were followed up for death until 28 days following randomization using in-hospital records and telephone follow-up. Two patients had unknown vital status at 28 days and were not included in this analysis. The hospital discharge curves are cumulative incidence curves of hospital discharge accounting for the competing risk of death with a P value calculated by Gray test. For hospital discharge, all patients were followed up to discharge or 28 days after randomization. A patient was considered discharged from the hospital once discharged from the index hospitalization; rehospitalizations were not considered in this analysis. There was no difference between the hydroxychloroquine group and placebo group in survival (adjusted hazard ratio, 1.05 [95% CI, 0.60-1.85]) or time to discharge (adjusted hazard ratio, 1.09 [95% CI, 0.89-1.32]).
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