Adding azithromycin to a standard of care regimen that included hydroxychloroquine does not result in clinical improvement or mortality reduction in patients hospitalized with severe coronavirus disease 2019 (COVID-19), according to study results published in The Lancet.1
In this randomized, open-label trial (COALITION II; ClinicalTrials.gov identifier: NCT04321278), the investigators assessed whether the addition of azithromycin to the standard of care regimen, which included hydroxychloroquine, was superior to standard of care alone. The primary outcome was clinical status at day 15, assessed using a 6-level ordinal scale ranging from not hospitalized to death. Secondary outcome was a 29-day mortality of patients hospitalized with severe COVID-19.
Participants included individuals 18 years or older from 57 centers in Brazil admitted to a hospital with confirmed or suspected COVID-19 with fewer than 14 days since symptom onset and at least 1 of the following severity criteria: use of oxygen greater than 4 L/min, high-flow nasal cannula, non-invasive positive-pressure ventilation, or mechanical ventilation.
Hydroxychloroquine (400 mg twice daily for 10 days by oral or nasogastric route) was provided to all participants in the control group as part of standard of care treatment. Patients were randomly assigned in a 1:1 ratio to receive azithromycin (500 mg by oral, nasogastric, or intravenous administration once daily for 10 days) plus hydroxychloroquine or hydroxychloroquine alone.
The main analysis included 214 patients in the azithromycin group and 183 patients in the control group. The median age was 59.8 years (range, 50.6-70.1), 262 patients (66%) were men, and 196 patients (49%) were on mechanical ventilation at baseline. More than 80% of planned doses of the study drugs was received by 78% of patients in azithromycin group and 81% of patients in the control group.
There was no difference in the proportional odds of being at a higher level in the 6-point ordinal scale at 15 days between the azithromycin and control groups (odds ratio [OR], 1.36; 95% CI, 0.94-1.97; P =.11) or in the 29-day mortality (hazard ratio [HR], 1.08; 95% CI, 0.79-1.47; P =.63). Among patients on mechanical ventilation at baseline, there was no difference in the median number of ventilator-free days in the azithromycin vs control groups (mean difference, -3.33; 95% CI, -5.89 to -0.77; P =.37).
While there was no evidence of a difference in outcomes by sex, a prespecified subgroup analysis suggested potentially worse clinical status at 15 days in patients younger than 60 years receiving azithromycin. Data suggested that adding azithromycin to hydroxychloroquine “did not result in higher rates of [corrected QT interval prolongation], cardiac arrest, or ventricular arrhythmias,” stated the investigators.
A limitation of the study includes the primary inclusion of patients with severe COVID-19.
The results of this study corroborate with the results of the COALITION I trial (ClinicalTrials.gov identifier: NCT04322123), which was done by the same study group and evaluated hydroxychloroquine with or without azithromycin in patients admitted to the hospital with mild or moderate COVID-19.
“These findings do not support the routine use of azithromycin in combination with hydroxychloroquine for this patient population,” concluded study investigators.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
1. Furtado RHM, Berwanger O, Fonseca HA, et al; COALITION COVID-19 Brazil II Investigators. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): A randomised clinical trial. Lancet. 2020;396(10256):959-967. doi: 10.1016/S0140-6736(20)31862-6