Hydroxychloroquine versus Azithromycin for Hospitalized Patients with COVID-19. Results of a Randomized, Active Comparator Trial

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 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).

Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial

“…Characteristics of participants assigned to azithromycin and to standard care were similar (table 1; appendix pp [12][13][14][15][16][17][18][19][20][21][22]. The mean participant age was 45•9 years (SD 14•9); 152 (52%) of 295 were men and 143 (49%) were women; 201 (68%) were White, 47 (16%) were Asian or Asian British, 11 (4%) were Black or Black British, and 36 (12%) were Mixed or other race; 70 (24%) participants had comorbidities; and the median duration of symptoms before enrolment was 6•02 days (3•52).…”

“…12 Despite these theoretical considerations, large-scale clinical trials of azithromycin either alone or coadministered with hydroxychloroquine have not shown clinical efficacy in reducing mortality, need for invasive mechanical ventilation, duration of hospital admission, or clinical status on ordinal outcome scores in patients admitted to hospital with COVID-19. [13][14][15][16] However, these trials were all done in late-stage, severe disease with 17-40% mortality. They did not study patients at earlier stages of disease in the community and are not able to make conclusions about the effectiveness of azithromycin outside the hospital setting.…”

COVID-19: Can early home treatment with Azithromycin alone or with Zinc help prevent hospitalisation, death, and long-COVID-19? A review

“…Gautret et al [31] were the first to highlight the effectiveness of dual therapy, showing better results with HCQ + AZM than with HCQ alone, under rigorous cardiological surveillance, in reducing hospitalisation and mortality. Many other studies concluded that given the efficacy of HCQ + AZM in early outpatient treatment, the evidence on the use of HCQ alone or HCQ + AZM in inpatients is irrelevant to its use in high-risk outpatients in early stages of the disease [32, 33]. In addition, triple therapy with HCQ + AZM + Zn improved the outcomes and reduced the duration of hospitalisation [34].…”

A Systematic Review and Network Meta-Analysis for COVID-19 Treatments

“…A total of 74 studies 2, 5, 15-18, 36-39, 41-44, 47-54, 56, 57, 59-63, 65-67, 69, 70, 72, 74-76, 78, 79, 82, 83, 85, 87, 88, 90-92, 94-97, 99, 100, 103-121, 125 including 48622 patients reported all-cause mortality. After filtering out treatments with small sample size following the specified criteria, the network included azithromycin, hydroxychloroquine, hydroxychloroquine plus azithromycin, colchicine, arbidol (umifenovir), favipiravir, remdesivir, lopinavir/ritonavir, convalescent plasma, methylprednisolone, dexamethasone, hydrocortisone, immunoglobulin, interferon beta, recombinant human granulocyte colony-stimulating factor (GCSF), tocilizumab, vitamin D 3 , baricitinib plus remdesivir, sulodexide and SOC.…”

“…Overall, 48 studies reported the number of patients required for MV during the study period. 2, 5, 15-17, 36-39, 41-44, 47-50, 56, 57, 60-63, 65, 69, 72, 76, 78, 82, 83, 87, 92, 95-97, 100, 103-105, 108-110, 112-114, 116, 117, 120 with 41405 patients and 4455 events. We included azithromycin, hydroxychloroquine, hydroxychloroquine plus azithromycin, remdesivir, lopinavir/ritonavir, convalescent plasma, methylprednisolone, dexamethasone, hydrocortisone, immunoglobulin, interferon beta, recombinant human GCSF, tocilizumab, vitamin D 3 , baricitinib plus remdesivir, sulodexide and SOC as treatment nodes in the NMA.…”