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Background The effectiveness of repurposed treatments with supportive evidence for higher risk individuals with COVID-19 in the community is unknown. In the UK PRINCIPLE national platform trial we aimed to determine whether 're-purposed medicines' (hydroxychloroquine, azithromycin, doxycycline, colchicine, inhaled budesonide, and other interventions) reduced time to recovery and COVID-19 related hospitalisations/deaths among people at higher risk of COVID-19 complications in the community. We mainly report the findings for budesonide arm here. Methods Participants in this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial were aged ≥65, or ≥50 years with comorbidities, and unwell ≤14 days with suspected COVID-19 in the community, and were randomised 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 hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Trial registration: ISRCTN86534580. Funded by United Kingdom Research Innovation (MC_PC_19079). Findings The trial opened on April 2, 2020, with the first 4 intervention arms stopped on futility grounds. Randomisation to the budesonide arm occurred from November 27, 2020 until March 31, 2021, when the pre-specified time to recovery superiority criterion was met. The primary analysis model includes 2530 SARS-CoV-2 positive participants, randomised to budesonide (n=787), usual care (n=1069), and other treatments (n=674). Time to first self-reported recovery was shorter in the budesonide group versus usual care (hazard ratio 1·21 [95% credible interval 1·08 to 1·36], probability of superiority >O·999, estimated benefit 2·94 [95% credible interval 1·19 to 5·12] days). An estimated 6·8% COVID-19 related hospitalisations/deaths occurred in the budesonide group versus 8·8% in usual care (estimated absolute difference, 2·0% [95% credible interval -0.2% to 4.5%], probability of superiority 0.963). In the main secondary analysis of admissions using only concurrent controls, admissions occurred in 6.6% (3.8 to 10.1%) in the budesonide group versus 8.8% (95% CI 5.2 to 13.1%), with an absolute difference of 2.2% (0.0 to 4.9%) and a hazard ratio of 0.73 (0.53 to 1.00), meeting the pre-specified superiority probability of 0.975. Three serious adverse events occurred in the budesonide group and three in usual care.

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