Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial

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.)

Recommendations for use of topical inhalant budesonide in COVID-19

“…This fits with the interim results of a still-ongoing larger phase III trial of 2617 patients, also testing inhaled budesonide therapy for acute SARS-CoV-2 infection [17]. This showed a 3-day shorter time to self-reported clinical improvement of symptoms, but the small effect on COVID-19-related hospitalizations or deaths (budesonide: 59/692 [8.5%] vs. 100/968 [10.3%] patients) was not statistically significant.…”

“…A cautious interpretation of these data is all the more warranted given that an updated interim analysis of data from a larger phase III trial that included 2617 participants with risk factors for unfavorable outcomes with COVID-19 did not show such favorable results [17]-inhaled budesonide shortened time to selfreported recovery by a median of 3 days, but did not meet the primary outcome parameter (predefined superiority threshold for the probability that COVID-19 hospitalizations/deaths were lower in the budesonide group compared with standard therapy): budesonide: 59/692 (8.5%) vs. standard therapy: 100/968 (10.3%) [17].…”

PRINCIPLE trial demonstrates scope for in-pandemic improvement in primary care antibiotic stewardship: a retrospective sentinel network cohort study

“…The PRINCIPLE trial has provided a robust in-pandemic trials platform 2,3,13 The strength of this analysis is that the RSC has good data quality and is able to capture routine data about RTIs and their incidence. 14,15 Comparing the use of azithromycin and doxycycline between years, and their use in RTIs is complex and we are reporting relative change in antibiotic use, their absolute level of use in RTIs is very low.…”

Where are we with drug treatments for covid-19?

“…The Principle trial has shown some promising signs regarding the inhaled drug budesonide, which is usually used to treat asthma and COPD. Interim data from a preprint study, which is yet to be peer reviewed, suggested that the use of budesonide at home for two weeks shortened average recovery times by a median of three days 9…”