Hydroxychloroquine vs. Azithromycin for Hospitalized Patients with COVID-19 (HAHPS): Results of a Randomized, Active Comparator Trial

Abstract

Rationale: The COVID-19 pandemic struck an immunologically naïve, 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.

Objective: Assess the relative efficacy of hydroxychloroquine and azithromycin among hospitalized patients with COVID-19.

Methods: We performed a randomized clinical trial of hydroxychloroquine vs. 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-, ICU-, and ventilator-free days at day 28. The trial was stopped early after 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 vs. 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 azithryomycin. Secondary outcomes displayed a similar, slight preference for azithromycin over hydroxychloroquine. QTc prolongation was rare and did not differ between groups. The twenty safety outcomes were similar between arms with the possible exception of post-randomization onset acute kidney injury, which was more common with hydroxychloroquine (15% vs. 0%). Patients in the hydroxychloroquine arm received remdesivir more often than in the azithromycin arm (19% vs. 2%). There was no apparent association between remdesivir use and acute kidney injury.

Conclusions: While 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 registration: This trial was prospectively registered (NCT04329832) before enrollment of the first patient.

Figure 1.

Flow of participants through the trial. *Adjusted for patients who met >1 exclusion criterion. **One patient in each arm (two patients total) did not receive study drug. azithro = azithromycin; COVID-19 = coronavirus disease; GFR = glomerular filtration rate; HAHPS = Hydroxychloroquine versus Azithromycin for Hospitalized Patients with COVID-19; HCQ = hydroxychloroquine; Hx = medical history; LAR = legally authorized representative; QT = measurement made on an electrocardiogram from the start of the Q wave to the end of the T wave; QTc = corrected QT.

Figure 2.

(A) COVID ordinal scale over time. (B) Level of oxygen support over time, among patients alive and in the hospital. Az = azithromycin; COVID = coronavirus disease; Hcq = hydroxychloroquine; HFNC = high-flow nasal cannula oxygen; NIV = noninvasive ventilation; w = with.