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Background: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community.Methods: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 μg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing.Findings: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19).Interpretation: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications.Funding: National Institute of Health Research and United Kingdom Research Innovation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]