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Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
Yu, Ly-Mee; Bafadhel, Mona; Dorward, Jienchi; Hayward, Gail; Saville, Benjamin R; Gbinigie, Oghenekome; Van Hecke, Oliver; Ogburn, Emma; Evans, Philip H; Thomas, Nicholas P B; Patel, Mahendra G; Richards, Duncan; Berry, Nicholas; Detry, Michelle A; Saunders, Christina; Fitzgerald, Mark; Harris, Victoria; Shanyinde, Milensu; de Lusignan, Simon; Andersson, Monique I; Barnes, Peter J; Russell, Richard E K; Nicolau, Dan V; Ramakrishnan, Sanjay; Hobbs, F D Richard; Butler, Christopher C.
  • Yu LM; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Bafadhel M; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
  • Dorward J; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.
  • Hayward G; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Saville BR; Berry Consultants, Austin, TX, USA; Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Gbinigie O; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Van Hecke O; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Ogburn E; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Evans PH; College of Medicine and Health, University of Exeter, Exeter, UK; National Institute for Health Research Clinical Research Network, National Institute for Health Research, London, UK.
  • Thomas NPB; National Institute for Health Research Clinical Research Network, National Institute for Health Research, London, UK; Royal College of General Practitioners, London, UK.
  • Patel MG; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Richards D; Oxford Clinical Trials Research Unit, Botnar Research Centre, University of Oxford, Oxford, UK.
  • Berry N; Berry Consultants, Austin, TX, USA.
  • Detry MA; Berry Consultants, Austin, TX, USA.
  • Saunders C; Berry Consultants, Austin, TX, USA.
  • Fitzgerald M; Berry Consultants, Austin, TX, USA.
  • Harris V; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Shanyinde M; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • de Lusignan S; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
  • Andersson MI; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
  • Barnes PJ; National Heart and Lung Institute, Imperial College, London, UK.
  • Russell REK; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
  • Nicolau DV; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; UQ Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.
  • Ramakrishnan S; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.
  • Hobbs FDR; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. Electronic address: richard.hobbs@phc.ox.ac.uk.
  • Butler CC; Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. Electronic address: christopher.butler@phc.ox.ac.uk.
Lancet ; 398(10303): 843-855, 2021 09 04.
Article in English | MEDLINE | ID: covidwho-1599473
ABSTRACT

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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Budesonide / COVID-19 / Glucocorticoids Type of study: Controlled clinical trial / Etiology study / Observational study / Prognostic study / Randomized controlled trials / Risk factors Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: Lancet Year: 2021 Document Type: Article Affiliation country: S0140-6736(21)01744-x

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Budesonide / COVID-19 / Glucocorticoids Type of study: Controlled clinical trial / Etiology study / Observational study / Prognostic study / Randomized controlled trials / Risk factors Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: Lancet Year: 2021 Document Type: Article Affiliation country: S0140-6736(21)01744-x