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Azithromycin for Suspected COVID-19 in People at Increased Risk
Quick Takes
- There are over 80 clinical trials of azithromycin for COVID-19 planned or underway; the majority of which are targeting hospitalized patients.
- PRINCIPLE is the UK National Urgent Public Health Priority open-label, multi-group, prospective, adaptive platform, randomized clinical trial in community care, through which multiple treatments for the same disease can be tested simultaneously.
- Azithromycin was not effective at reducing time to recovery or decreasing the incidence of hospitalization in outpatients with suspected COVID-19.
Study Questions:
Is 500 mg of azithromycin daily for 3 days effective at improving the time to recovery or decreasing the risk of hospitalization and death of outpatients with suspected coronavirus disease 2019 (COVID-19)?
Methods:
PRINCIPLE is the UK National Urgent Public Health Priority open-label, multi-group, prospective, adaptive platform, randomized clinical trial in community care, through which multiple treatments for the same disease can be tested simultaneously. For the azithromycin evaluation, outpatients ≥65 years old and those ≥50 years old with ≥1 comorbidity with <14 days of symptoms attributed to COVID-19 were enrolled and randomized 1:1 to oral azithromycin 500 mg once daily for 3 days plus usual care or usual care alone. Confirmation of a positive SARS-CoV-2 test was not a requirement for enrollment. The trial had coprimary endpoints: time to first self-reported recovery within 28 days defined by answering the question, “Do you feel recovered today?”; and hospital admission or death within 28 days of random assignment.
Results:
The trial was stopped because the prespecified futility criterion was met. A total of 540 participants were randomly allocated to azithromycin plus usual care and 875 to usual care alone. The mean participant age was 60.7 years (standard deviation [SD], 7.8), 1,233 (88%) of 1,388 participants had comorbidities, and the median duration of illness before randomization was 6 days (interquartile range [IQR], 4-10). 1,148 (83%) of 1,388 participants had a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) result available, and 434 (31%) of 1,388 participants had a positive result. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. Median time to recovery for patients in the azithromycin group was 7 days (IQR, 3-17) and for patients in the usual care group was 8 days (IQR, 2-23). 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalized. There were no deaths in either study group. There were no major differences in the secondary outcomes or subgroup analyses, notably when comparing age strata, those with and without comorbidities, or those with a positive SARS-CoV-2 test.
Conclusions:
In outpatients with suspected COVID-19, use of azithromycin did not shorten time to recovery or decrease the risk of hospitalization compared to usual care alone.
Perspective:
There are over 80 clinical trials of azithromycin for COVID-19 planned or underway, the majority of which are targeting hospitalized patients. The vast majority of completed clinical trials have shown no benefit for the use of azithromycin in the treatment of COVID-19; either alone or in combination with hydroxychloroquine. Despite its lack of benefit, azithromycin continues to be commonly prescribed across the world as a treatment for COVID-19. The PRINCIPLE study is set in the community rather than the hospital setting, and assesses whether intervention earlier in the disease process can speed recovery and decrease hospitalization. A major limitation of the study is that a positive SARS-CoV-2 test was not a requirement for enrollment—meant to reflect the UK primary care practice in which testing is not readily available. Only a third of patients tested positive for SARS-CoV-2. However, analysis in this subgroup was consistent with the overall findings of the trial. Azithromycin should not be used routinely to treat COVID-19 in outpatients with risk factors.
Clinical Topics: COVID-19 Hub, Prevention, Novel Agents, Statins
Keywords: Azithromycin, Comorbidity, Coronavirus, COVID-19, Hydroxychloroquine, Medical Futility, Outpatients, Polymerase Chain Reaction, Primary Health Care, Primary Prevention, Risk Factors, SARS-CoV-2
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