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Outpatient COVID Treatment – PRINCIPLE RCT Inhaled Steroids

October 19, 2021

Written by Rachel Jennings

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Inhaled budesonide improves time to recovery with a chance of also decreasing hospital admissions and/or deaths in high-risk patients with COVID-19 who are treated in the outpatient setting.

Why does this matter?
Since the beginning of the pandemic, the medical community has made advances in finding effective treatments for moderate to critically ill patients (e.g those who, at minimum, require supplemental oxygen) but have had difficulty finding therapies to help modify the progression of COVID-19 in those treated at home and other community settings. How can we as ED providers help our high-risk patients that don’t meet admission criteria when they show up in our departments? Inhaled budesonide might just be our answer.

COVID in the community
This was a large, open label, randomized trial which was conducted between April 2020 and March of 2021 in the UK. The trial initially enrolled 3,635 patients who were considered “high risk” for infection-related complications, limiting enrollment to patients 65 and older or 50 and older with comorbidities. Of those enrolled, all had symptoms for up to 14 days without hospital admission, along with a clinical diagnosis of COVID-19 or a positive test result. When testing became widely available, the authors ran a second analysis limited to the 2,530 patients who tested positive. 

The trial compared three different interventions: “usual care” which consisted of antipyretics and oral hydration, usual care plus inhaled budesonide, and lastly an “other therapies” arm which included therapies such as hydroxychloroquine, azithromycin, colchicine, and doxycycline. The authors then measured two primary endpoints at 28 days: number of days to a self-reported and sustained recovery, and the number of days until either hospitalization or death after enrollment.


  • The reported median time to recovery for people in the inhaled budesonide arm was 2.94 days shorter with a 95% Bayesian credible interval (CrI) of 1.19 to 5.11 days, corresponding to a > 0.999 probability of superiority. These patients also reported a greater sense of wellbeing while recovering and, once recovered, more often remained well.

  • For the hospital admission or death outcome, the estimated rate in the budesonide group was 6·8% vs 8·8% in the usual care group. The odds ratio was 0.75, with a 95%CrI of 0.55 to 1.03, with a probability of superiority of 0.963, which was lower than the prespecified superiority threshold of 0.975. The authors attributed this finding to a decrease in hospital admissions, which they postulated was secondary to the UK vaccination program rollout and additional lockdown measures.

So what now?
Inhaled budesonide is a widely available drug with a well described safety profile which we can offer to our high-risk patient population being treated in the community. It is important to mention that inhaled budesonide is more expensive here in the US, and that cost might be a significant drawback for a subset of our patients. Despite the study’s lack of data on the vaccinated patient population and the possible confounding factors related to the vaccine roll-out during the trial, the reduction of recovery time is an important, patient-specific outcome that simply can’t be ignored. 3 days less of headaches, myalgias, dyspnea and fevers… certainly sounds worth it to me.

Editor’s note: The dose of budesonide used was 800mcg BID, which is a very high dose and is not available in the US. However, one could use a budesonide 180mcg dose x 4 inhalations BID. Other high-dose inhaled steroids (such as fluticasone 220mcg 2 puffs BID) could also be considered but have not been studied. ~Clay Smith

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. Lancet. 2021 Sep 4;398(10303):843-855. doi: 10.1016/S0140-6736(21)01744-X. Epub 2021 Aug 10.

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