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 L, Bafadhel M, Dorward J, et al
        Lancet 2021; 398: 843-55
        COVID-19 infections placed a heavy burden in the community. Multiple studies looked for potential treatments to decrease hospitalization and death. Speculation that inhaled corticosteroids could be protective during the beginning of the pandemic due to low prevalence of admitted patients with asthma and chronic obstructive pulmonary disease. Early studies had mixed results, and none of the studies were large prospective trials. This study sought to understand the effectiveness of inhaled budesonide in reducing the recovery time and rates of COVID-19 related admissions and death of high-risk patients.
        The PRINCIPLE trial is an open-label, multi-arm, prospective, randomized controlled trial involving patients with COVID-19. PRINCIPLE studied interventions with hydroxychloroquine, azithromycin, doxycycline, colchicine, favipiravir, and inhaled budesonide. This was a multi-center study, and participants across the UK could enroll online or by telephone. Patients were eligible at 65 years old or 50 years old with comorbidities and had ongoing symptoms of COVID-19. The comorbidities included were heart disease, hypertension, asthma or lung disease, diabetes, hepatic impairment, stroke or neurological problems, weakened immune system, and obesity. Patients were allocated 1:1 to open groups of budesonide and usual care and were stratified by their age and presence of comorbidity. The intervention group received inhaled budesonide 800 µg twice daily in addition to usual care. Participants were followed up using an online symptom diary for 28 days after randomization. The primary outcome was hospital admission or death within 28 days, but illness duration was included later due to lower rates of hospital admission in the UK.
        Patients in PRINCIPLE were enrolled into the budesonide group between April 2, 2020, and March 31, 2021. Of the 38,520 patients screened for eligibility, 2,530 (95%) of 2,655 SARS-CoV-2 positive participants were randomly assigned to inhaled budesonide (n=787), usual care alone (n=1,069), and other treatments (n=674). The observed median time to recovery was 11 days in the budesonide group compared to 15 days in the usual care group. There was evidence of benefit of time-to-first-recovery in the intervention group versus the usual care group, with a hazard ratio of 1.21 (95% Bayesian credible interval [BCI] 1.08-1.36), an estimated 11.8 days (95% BCI 10.0-14.1) versus 14.7 days (12.3-18.0), and an estimated median benefit of 2.94 days (1.19-5.11). Of the budesonide group, 72 (9%) of 787 patients were admitted or died (71 hospital admissions with 5 deaths and one death without admission) compared to 116 (11%) of 1,069 patients in the usual care group (114 hospital admissions with 9 deaths and two deaths without admission). The odds ratio was 0.75 (95% BCI 0.55 to 1.03) with an estimated rate of 6.8% (95% BCI 4.1-10.2) versus 8.8% (5.5-12.7) and an estimated absolute percentage difference of 2.0% (-0.2-4.5).
        From these data, the authors concluded that high risk patients with COVID-19 treated with inhaled budesonide recovered approximately 3 days sooner, felt better while recovering, and often had sustained recovery. The study reported that the budesonide group initially did not meet the prespecified superior threshold rate for hospital admissions or death due to a decreased in hospital admissions and deaths in the UK, presumably from vaccinations and lockdown measures. Main limitations discussed were the open-label design and the change in primary outcome after initiation of the trial due to low rates of admissions and deaths.
        Nhan “Marc” Phan, MD
        University of Arkansas for Medical Sciences
        Little Rock, Arkansas
        Comment: With recent COVID-19 surges and vaccine hesitancy, hospitals have been overwhelmed. While open-label and not showing a statistical improvement in hospitalizations or deaths, this study provides moderate to high quality evidence for ED providers that inhaled budesonide is an inexpensive and safe treatment to reduce time to recovery for patients who are older and have comorbidities. More studies are needed, particularly evidence for vaccinated individuals, as the proportion of those vaccinated in this study was low.