Azithromycin doesn't reduce recovery time or hospitalisation risk — PRINCIPLE trial

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Treatment with azithromycin had little effect on reducing the time to recovery or risk of hospitalisation in patients with suspected COVID-19, according to a randomised clinical trial.

In the UK-based PRINCIPLE trial, which is investigating interventions against COVID-19 in those at risk of adverse outcomes, investigators randomly assigned people 65 years and older, or 50 and older with at least one comorbidity, who had been feeling unwell with suspected COVID-19 for 14 days to receive usual care plus azithromycin for 3 days, usual care plus other interventions, or usual care alone.

Of the 2,265 participants who enrolled from 22 May to 30 November 2020, 2,120 were included in the final analysis, with 500 in the azithromycin plus usual care group, 797 in the usual care plus other interventions group, and 823 in the usual care alone group. 80% (402 of 500) of the patients in the azithromycin plus usual care group and 77% (631 of 823) of patients in the usual care alone group reported recovery within 28 days.

Using a Bayesian primary analysis model, the investigators found little evidence of benefit from azithromycin in the time to first reported recovery compared with usual care alone (hazard ratio, 1.08; 95% Bayesian credibility interval [BCI], 0.95 to 1.23), equating to an estimated benefit in median time to first recovery of 0.94 days (95% BCI 0.56 to 2.43). 3% of patients in both the azithromycin group and the usual care group were hospitalised (absolute benefit in percentage, 0.3%; 95% BCI -1.7 to 2.2), and no deaths were reported in either group.

Previous trials have found that azithromycin offers little to no benefit in hospitalised COVID-19 patients, but this is the first to examine azithromycin for COVID-19 in a community setting.

"In conclusion, our findings show that azithromycin should not be used routinely to treat COVID-19 in the community in older adults, in the absence of additional indications," the study authors wrote. "These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antibiotic resistance, and there is evidence that azithromycin use increased during the pandemic in the UK."

 

Study details
Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

PRINCIPLE Trial Collaborative Group

Published in The Lancet on 4 March 2021

Abstract
Background
Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications.
Methods
In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580.
Findings
The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 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. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI −0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 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 hospitalised (absolute benefit in percentage 0·3%, 95% BCI −1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19.
Interpretation
Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK.
Funding
UK Research and Innovation and UK Department of Health and Social Care.

 

CIDRAP material

 

The Lancet study (Open access)

 

 

See also MedicaBrief archives:

Hydroxychloroquine plus azithromycin doubles cardiovascular mortality risk

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