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.
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.
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.
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.
In this open-label, multicenter, randomized, controlled trial involving hospitalized patients with confirmed mild-to-moderate Covid-19, a 7-day course of hydroxychloroquine either with azithromycin or alone did not result in better clinical outcomes as measured by a seven-level ordinal scale at 15 days. There was also no effect on any of the secondary outcomes. Occurrence of any adverse event, elevation of liver-enzyme levels, and prolongation of the QTc interval was more frequent in patients receiving hydroxychloroquine with azithromycin or hydroxychloroquine alone than in those receiving neither agent.
The prescription of short courses (<28 days) of hydroxychloroquine or chloroquine in the United States increased almost 2000% between March 21, 2019, and March 21, 2020, with a subsequent decrease. In Brazil, hydroxychloroquine has been formally recommended for the treatment of Covid-19 by the Ministry of Health since March 25, 2020, for severe cases and since May 20, 2020, for mild cases. However, no clinical benefit has been observed to date in randomized, controlled trials evaluating hydroxychloroquine for the treatment of Covid-19.In addition, higher doses of chloroquine (600 mg twice daily for 10 days) were possibly associated with higher mortality. Our trial enrolled patients with mild-to-moderate Covid-19 who were receiving no more than 4 liters per minute of supplemental oxygen. Hydroxychloroquine was administered relatively early after symptom onset (median, 7 days), which is earlier than the median time from symptom onset to treatment in a trial of remdesivir treatment for Covid-19. Furthermore, the addition of azithromycin did not improve outcomes as had been suggested by observational case series.
Our trial has several limitations. First, although the point estimate of effect suggests no major difference between the groups with respect to the primary outcome, the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm. For the comparison between hydroxychloroquine and control, for example, our data are compatible with odds ratios as low as 0.69 and as high as 2.11. Second, the trial was not blinded. Third, despite intense efforts to maintain adherence to the assigned treatments, a lack of medications that were perceived as beneficial by clinicians and patients led to some protocol deviations. Fourth, the use of hydroxychloroquine plus azithromycin was widespread among patients hospitalized with Covid-19 in participating hospitals. We did not specify in our protocol the exclusion of such patients until late in the course of the trial, and as a consequence, 9.3% of the trial participants had previous use of hydroxychloroquine and 36.1% had previous use of azithromycin. However, in most instances, the duration of previous use was only 24 to 48 hours before enrollment, primarily because, before May 13, we required that patients be enrolled in the trial within 48 hours after hospital admission and because outpatient use of these drugs (before admission) was infrequent. After May 13, we specified that use of these drugs for more than 24 hours was an exclusion criterion. Finally, although the median time from symptom onset to randomization was 7 days, we included patients up to 14 days after the beginning of symptoms; it is conceivable that interventions that may limit viral replication (e.g., hydroxychloroquine) may be more effective earlier in the course of the disease.
In this trial involving hospitalized patients with mild-to-moderate Covid-19, we did not find a significant difference in a 15-day ordinal clinical-status outcome among groups that received standard care, hydroxychloroquine alone, or hydroxychloroquine plus azithromycin. Patients who received hydroxychloroquine, either with azithromycin or alone, had more frequent events of QTc interval prolongation and elevation of liver-enzyme levels than patients who did not receive either agent.
Reference & Source information: https://www.nejm.org/
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