Abstract
SummaryBackgroundA 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.MethodsPRINCIPLE 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.FindingsThe 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).InterpretationInhaled 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.FundingNational Institute of Health Research and United Kingdom Research Innovation.
Highlights
There is an urgent need for effective and safe communitybased treatments for COVID-19, especially for older people and those with comorbidities who are at higher risk of hospital admission and death.[1]Inhaled corticosteroids are widely available, inexpen sive, and generally safe, and have been proposed as a COVID-19 treatment because of their targeted antiinflammatory effects in the lungs,[2,3] where they reduce expression of ACE-2 and TMPRSS2,4,5 which is Lancet 2021; 398: 843–55Published Online August 10, 2021 https://doi.org/10.1016/ S0140-6736(21)01744-XThis online publication has been corrected
On March 31, 2021, the trial steering committee advised the trial management group to stop randomisation to budesonide because the prespecified superiority criterion had been met on time to recovery, and accumulating enough data to reach futility or superiority criteria on hospital admission or death was unlikely because of decreases in hospital admissions associated with the UK lockdown and vaccination programme.[22]
38 520 patients were screened for eligibility, of whom 4700 were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639; figure 1). 3979 (87%) of 4594 eligible participants had a SARS-CoV-2 test result available, and 2655 (67%) of the 3979 tested positive
Summary
There is an urgent need for effective and safe communitybased treatments for COVID-19, especially for older people and those with comorbidities who are at higher risk of hospital admission and death.[1]Inhaled corticosteroids are widely available, inexpen sive, and generally safe, and have been proposed as a COVID-19 treatment because of their targeted antiinflammatory effects in the lungs,[2,3] where they reduce expression of ACE-2 and TMPRSS2,4,5 which is Lancet 2021; 398: 843–55Published Online August 10, 2021 https://doi.org/10.1016/ S0140-6736(21)01744-XThis online publication has been corrected. London, UK (Prof P J Barnes FRS); UQ Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia (D V Nicolau Jr); National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK (S Ramakrishnan MBBS) Correspondence to: Prof Christopher C Butler, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford OX2 6GG, UK.
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