Abstract: ORIGINAL RESEARCH Hydroxychloroquine versus Azithromycin for Hospitalized Patients with COVID-19 Results of a Randomized, Active Comparator Trial Samuel M. Brown1,2*, Ithan Peltan1,2, Naresh Kumar1,3, Lindsay Leither1,2, Brandon J. Webb3,4,5, Nathan Starr6,7, Colin K. Grissom1,2, Whitney R. Buckel8, Rajendu Srivastava9,10, Allison M. Butler1, Danielle Groat1, Benjamin Haaland11, Jian Ying11, Estelle Harris2, Stacy Johnson7, Robert Paine III2, and Tom Greene11 1 Pulmonary and Critical Care Medicine, 3Infectious Diseases, and 6Hospital Medicine, Intermountain Medical Center, Murray, Utah; 2Pulmonary and Critical Care Medicine, 4Infectious Diseases, 7Hospital Medicine, 9Pediatric Inpatient Medicine, and 11Division of Biostatistics, Population Health Sciences, University of Utah, Salt Lake City, Utah; 5Infectious Diseases, Stanford University, Stanford, California; and 8Pharmacy Services and 10Healthcare Delivery Institute, Intermountain Healthcare, Murray, Utah ORCID IDs: 0000-0003-1206-6261 (S.M.B.); 0000-0003-1730-234X (I.P.); 0000-0002-1799-3315 (B.J.W.); 0000-0001-9505-2572 (W.R.B.). Abstract 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..