Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial
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Abstract
BACKGROUND
Inhaled budesonide has shown efficacy for treating COVID-19 in the community but has not yet been tested in effectiveness trials.
METHODS
We performed a multicenter, open-label, multi-arm, adaptive platform randomized controlled trial involving people aged ≥65 years, or ≥50 years with comorbidities, and unwell ≤14 days with suspected COVID-19 in the community (PRINCIPLE). Participants were randomized to usual care, usual care plus inhaled budesonide (800µg twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalization/death related to COVID-19, both measured over 28 days from randomisation and analysed using Bayesian models.
RESULTS
The trial opened on April 2, 2020. Randomization to inhaled budesonide began on November 27, 2020 and was stopped on March 31, 2021 based on an interim analysis using data from March 4, 2021. Here, we report updated interim analysis data from March 25, 2021, at which point the trial had randomized 4663 participants with suspected COVID-19. Of these, 2617 (56.1%) tested SARS-CoV-2 positive and contributed data to this interim budesonide primary analysis; 751 budesonide, 1028 usual care and 643 to other interventions. Time to first self-reported recovery was shorter in the budesonide group compared to usual care (hazard ratio 1.208 [95% BCI 1.076 – 1.356], probability of superiority 0.999, estimated benefit [95% BCI] of 3.011 [1.134 – 5.41] days). Among those in the interim budesonide primary analysis who had the opportunity to contribute data for 28 days follow up, there were 59/692 (8.5%) COVID-19 related hospitalizations/deaths in the budesonide group vs 100/968 (10.3%) in the usual care group (estimated percentage benefit, 2.1% [95% BCI −0.7% – 4.8%], probability of superiority 0.928).
CONCLUSIONS
In this updated interim analysis, inhaled budesonide reduced time to recovery by a median of 3 days in people with COVID-19 with risk factors for adverse outcomes. Once 28 day follow up is complete for all participants randomized to budesonide, final analyses of time to recovery and hospitalization/death will be published. (Funded by the National Institute of Health Research/ United Kingdom Research Innovation [MC_PC_19079]; PRINCIPLE ISRCTN number, ISRCTN86534580 .)
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SciScore for 10.1101/2021.04.10.21254672: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The UK Medicines and Healthcare products Regulatory Agency and the South Central-Berkshire Research Ethics Committee (Ref: 20/SC/0158) approved the trial protocol and all recruitment processes.
Consent: Online consent is obtained from all participants.Randomization People were ineligible to be randomized to budesonide if they were already taking inhaled or systemic corticosteroids, were unable to use an inhaler, or if inhaled budesonide was contraindicated.20 Initially, eligible people were recruited, screened and enrolled through participating general medical practices, but from May 17, 2020, people across the UK could enroll online or by telephone. Blinding …SciScore for 10.1101/2021.04.10.21254672: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The UK Medicines and Healthcare products Regulatory Agency and the South Central-Berkshire Research Ethics Committee (Ref: 20/SC/0158) approved the trial protocol and all recruitment processes.
Consent: Online consent is obtained from all participants.Randomization People were ineligible to be randomized to budesonide if they were already taking inhaled or systemic corticosteroids, were unable to use an inhaler, or if inhaled budesonide was contraindicated.20 Initially, eligible people were recruited, screened and enrolled through participating general medical practices, but from May 17, 2020, people across the UK could enroll online or by telephone. Blinding not detected. Power Analysis In brief, for the primary outcome analyses, assuming a median time to recovery of nine days in the usual care group, approximately 400 participants per group would provide 90% power to detect a 2-day difference in median recovery time. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title ISRCTN86534580 NA NA Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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