Hydroxychloroquine versus Azithromycin for Hospitalized Patients with COVID-19. Results of a Randomized, Active Comparator Trial
M.D Samuel M Brown, Ithan Peltan, Naresh Kumar, Lindsay Leither, Brandon J Webb, Nathan Starr, Colin K Grissom, Whitney R Buckel, Rajendu Srivastava, Allison M Butler, Danielle Groat, Benjamin Haaland, Jian Ying, Estelle Harris, Stacy Johnson, Robert Paine III, Tom Greene, Rilee Smith, Brent Armbruster, Katie Brown, Valerie Aston, Mardee Merrill, Amanda Nelson, Diana Grant, Bri Crook, Heather Maestas, Jacki Anderson, Prathyusha Kodakandla, Lisa Weaver, Jorden Greer, Macy Barrios
Annals of the American Thoracic Society, doi:10.1513/annalsats.202008-940oc
Rationale: The coronavirus disease (COVID-19) pandemic struck an immunologically naive, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates. Objectives: To assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19. Methods: We performed a randomized clinical trial of hydroxychloroquine versus azithromycin among hospitalized patients with COVID-19. Treatment was 5 days of study medication. The primary endpoint was the COVID ordinal outcomes scale at Day 14. Secondary endpoints included hospital-, intensive care unit-, and ventilator-free days at Day 28. The trial was stopped early after the enrollment of 85 patients when a separate clinical trial concluded that a clinically important effect of hydroxychloroquine over placebo was definitively excluded. Comparisons were made a priori using a proportional odds model from a Bayesian perspective. Results: We enrolled 85 patients at 13 hospitals over 11 weeks. Adherence to study medication was high. The estimated odds ratio for less favorable status on the ordinal scale for hydroxychloroquine versus azithromycin from the primary analysis was 1.07, with a 95% credible interval from 0.63 to 1.83 with a posterior probability of 60% that hydroxychloroquine was worse than azithromycin. Secondary outcomes displayed a similar slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The 20 safety outcomes were similar between arms, with the possible exception of postrandomization-onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than those in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury. Conclusions: Although early termination limits the precision of our results, we found no suggestion of substantial efficacy for hydroxychloroquine over azithromycin. Acute kidney injury may be more common with hydroxychloroquine than azithromycin, although this may be due to the play of chance. Differential use of remdesivir may have biased our results in favor of hydroxychloroquine. Our results are consistent with conclusions from other trials that hydroxychloroquine cannot be recommended for inpatients with COVID-19; azithromycin may merit additional investigation. Clinical trial registered with www.clinicaltrials.gov (NCT04329832).
Author Contributions: S.M.B., I.P., B.J.W., R.S., B.H., R.P., and T.G. conceived and designed the study. S.M.B., I.P., N.K., L.L., B.J.W., W.R.B., E.H., and S.J. acquired the data. N.K., N.S., C.K.G., A.M.B., D.G., and J.Y. participated in conception and design, analytical plan, and data analysis. All authors were involved in critical revision of the manuscript for important intellectual content and approval of the final version to be published.
References
Akram, Singanayagam, Choudhury, Mandal, Chalmers et al., Incidence and prognostic implications of acute kidney injury on admission in patients with community-acquired pneumonia, Chest
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of Covid-19-preliminary report, N Engl J Med,
doi:10.1056/NEJMoa2007764Bessi Ère, Roccia, Delini Ère, Charri Ère R, Chevalier et al., Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit, JAMA Cardiol
Biot, Daher, Chavain, Fandeur, Khalife et al., Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities, J Med Chem
Borba, Val, Sampaio, Alexandre, Melo et al., CloroCovid-19 Team. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial, JAMA Netw Open
Brown, Peltan, Webb, Kumar, Starr et al., Hydroxychloroquine versus Azithromycin for hospitalized patients with suspected or confirmed COVID-19 (HAHPS): protocol for a pragmatic, open-label, active comparator trial, Ann Am Thorac Soc
Cao, Wang, Wen, Liu, Wang et al., A trial of lopinavirritonavir in adults hospitalized with severe Covid-19, N Engl J Med
Castro, Placebo versus best-available-therapy control group in clinical trials for pharmacologic therapies: which is better?, Proc Am Thorac Soc
Cavalcanti, Zampieri, Rosa, Azevedo, Veiga et al., Coalition Covid-19 Brazil I Investigators
Charlson, Pompei, Ales, Mackenzie, A new method of classifying prognostic comorbidity in longitudinal studies: development and validation, J Chronic Dis
Chen, Hu, Zhang, Jiang, Han et al., Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial,
doi:10.1101/2020.03.22.20040758v3Coca, Peixoto, Garg, Krumholz, Parikh, The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis, Am J Kidney Dis
Edelstein, Venkatachalam, Dong, Autophagy inhibition by chloroquine and hydroxychloroquine could adversely affect acute kidney injury and other organ injury in critically ill patients with COVID-19, Kidney Int
Gibson, Yang, Upham, Reynolds, Hodge et al., Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial, Lancet
Gielen, Johnston, Edwards, Azithromycin induces anti-viral responses in bronchial epithelial cells, Eur Respir J
Goldman, Lye, Hui, Marks, Bruno et al., GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2015301Horby, Mafham, Linsell, Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multicentre, randomized, controlled trial,
doi:10.1101/2020.07.15.20151852v1Jang, Choi, Byun, Jue, Chloroquine inhibits production of TNF-a, IL-1b and IL-6 from lipopolysaccharidestimulated human monocytes/macrophages by different modes, Rheumatology
Jun, Danping, Liu, Liu, Xu et al., Hydroxychloroquine sulfate for the treatment of common 2019 coronavirus disease (COVID-19) Preliminary study of patients Journal of Zhejiang University
Kawamura, Ichikado, Takaki, Sakata, Yasuda et al., Efficacy of azithromycin in sepsis-associated acute respiratory distress syndrome: a retrospective study and propensity score analysis, Springerplus
Liu, Yang, Shi, Bao, Yang et al., Effects of hydroxychloroquine on proteinuria in IgA nephropathy: a randomized controlled trial, Am J Kidney Dis
Matthay, Aldrich, Gotts, Treatment for severe acute respiratory distress syndrome from COVID-19, Lancet Respir Med
Mccambridge, Sorhaindo, Quirk, Nanchahal, Patient preferences and performance bias in a weight loss trial with a usual care arm, Patient Educ Couns
Menzel, Akbarshahi, Bjermer, Uller, Azithromycin induces antiviral effects in cultured bronchial epithelial cells from COPD patients, Sci Rep
Mercuro, Yen, Shim, Maher, Mccoy et al., Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19), JAMA Cardiol
Picot, Peyron, Vuillez, Polack, Ambroise-Thomas, Chloroquine inhibits tumor necrosis factor production by human macrophages in vitro, J Infect Dis
Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis
Simonis, De Iudicibus, Cremer, Ong, Van Der Poll et al., MARS consortium. Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients, Ann Transl Med
Smelt, Van Der Weele, Blom, Gussekloo, Assendelft, How usual is usual care in pragmatic intervention studies in primary care? An overview of recent trials, Br J Gen Pract
Sperber, Quraishi, Kalb, Panja, Stecher et al., Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells, J Rheumatol
Tang, Lv, Pan, Wen, Wang et al., Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation, Cell Death Dis
Thompson, Schoenfeld, Usual care as the control group in clinical trials of nonpharmacologic interventions, Proc Am Thorac Soc
Van Den Borne, Be, Dijkmans, De Rooij, Le Cessie et al., Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells, J Rheumatol
Vincent, Bergeron, Benjannet, Erickson, Rollin et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J
Walkey, Wiener, Macrolide antibiotics and survival in patients with acute lung injury, Chest
Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Yao, Ye, Zhang, Cui, Huang et al., 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
Ómez-Guzm Án, Énez, Romero, Zarzuelo, Ómez-Morales, Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus, Hypertension
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