Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

Abstract

Background: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.

Methods: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.

Results: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.

Conclusions: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).

Figure 1. Status of Patients on Day 15.

The primary outcome was clinical status evaluated at 15 days according to a seven-level ordinal scale. The scores on the scale were defined as follows: a score of 1 indicated not hospitalized with no limitations on activities; 2, not hospitalized but with limitations on activities; 3, hospitalized and not receiving supplemental oxygen; 4, hospitalized and receiving supplemental oxygen; 5, hospitalized and receiving oxygen supplementation administered by a high-flow nasal cannula or noninvasive ventilation; 6, hospitalized and receiving mechanical ventilation; and 7, death. The percentages shown have been rounded to whole numbers.

Figure 2. Distribution of the Ordinal-Scale Results over Time.

Shown is the course of ordinal-scale results as assessed over the time since randomization. However, not all levels of the seven-level scale are shown. Because data on activity limitation were not available on a daily basis for outpatients, levels 1 and 2 (i.e., the levels for patients who were not hospitalized and had no limitations on activities and for those who were not hospitalized but who had limitations on activities, respectively) were combined (equivalent to the six-level scale described in the Methods section). Thus, in this figure, levels 1 and 2 indicate not hospitalized. A total of 36 patients were discharged after a 1-day hospital stay (7 patients who had been assigned to receive hydroxychloroquine plus azithromycin, 8 in the hydroxychloroquine-alone group, and 21 in the control group). Missing data are shown at the bottom of the graphs.