Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19
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.
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. 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 U01HL123020). The REDCap data tools used for this study were supported by a grant from NCATS..
Administrative, Self, Semler, Casey, Angus et al., Supervision: Self
Beigel, Tomashek, Dodd, Remdesivir for the treatment of COVID-19: preliminary report: reply, N Engl J Med, doi:10.1056/NEJMoa2007764
Casey, Johnson, Semler, Rationale and design of ORCHID: a randomized placebo-controlled clinical trial of hydroxychloroquine for adults hospitalized with COVID-19, Ann Am Thorac Soc, doi:10.1513/AnnalsATS.202005-478SD
Cavalcanti, Zampieri, Rosa, Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19, N Engl J Med, doi:10.1056/NEJMoa2019014
Concept, Self, Semler, Angus, Casey et al., Critical revision of the manuscript for important intellectual content
Derwand, Scholz, Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today's battle against COVID-19?, Med Hypotheses, doi:10.1016/j.mehy.2020.109815
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents, doi:10.1186/s13054-020-03194-w
Herdman, Gudex, Lloyd, Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L), Qual Life Res, doi:10.1007/s11136-011-9903-x
Hoffmann, Mösbauer, Hofmann-Winkler, Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, Nature, doi:10.1038/s41586-020-2575-3
Horby, Mafham, Linsell, Effect of hydroxychloroquine in hospitalized patients with COVID-19, N Engl J Med, doi:10.1056/NEJMoa2022926
Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov, doi:10.1038/s41421-020-0156-0
Mercuro, Yen, Shim, Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease
Rl, Shumaker, Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19, Clin Infect Dis, doi:10.1093/cid/ciaa478
Rubin, Harrington, Hogan, Gatsonis, Baden et al., The urgency of care during the COVID-19 pandemic: learning as we go, N Engl J Med, doi:10.1056/NEJMe2015903
Schrezenmeier, Dörner, Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology, Nat Rev Rheumatol, doi:10.1038/s41584-020-0372-x
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res, doi:10.1038/s41422-020-0282-0
Wang, Lagakos, Ware, Hunter, Drazen, Statistics in medicine: reporting of subgroup analyses in clinical trials, N Engl J Med, doi:10.1056/NEJMsr077003
Yao, Ye, Zhang, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis, doi:10.1093/cid/ciaa237
Yehya, Harhay, Curley, Schoenfeld, Reeder, Reappraisal of ventilator-free days in critical care research, Am J Respir Crit Care Med, doi:10.1164/rccm.201810-2050CP