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Review 2: "Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial"

This study suggests that budesonide, a corticosteroid used for COPD and asthma treatment, reduces the likelihood of urgent care, ED visit, or hospitalization in patients with early COVID-19; both reviewers found the study findings to be reasonable and potentially reliable.

Published onApr 26, 2021
Review 2: "Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial"
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key-enterThis Pub is a Review of
Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial

AbstractBackgroundMultiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness.MethodsWe conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment.Results146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care.ConclusionEarly administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.(Funded by Oxford NIHR Biomedical Research Centre and AstraZeneca; number, NCT04416399)Research in contextEvidence before this studyThe majority of interventions studied for the COVID-19 pandemic are focused on hospitalised patients. Widely available and broadly relevant interventions for mild COVID-19 are urgently needed.Added value of this studyIn this open label randomised controlled trial, inhaled budesonide, when given to adults with early COVID-19 illness, reduces the likelihood of requiring urgent care, emergency department consultation or hospitalisation. There was also a quicker resolution of fever, a known poor prognostic marker in COVID-19 and a faster self-reported and questionnaire reported symptom resolution. There were fewer participants with persistent COVID-19 symptoms at 14 and 28 days after budesonide therapy compared to usual care.Implications of all the available evidenceThe STOIC trial potentially provides the first easily accessible effective intervention in early COVID-19. By assessing health care resource utilisation, the study provides an exciting option to help with the worldwide pressure on health care systems due to the COVID-19 pandemic. Data from this study also suggests a potentially effective treatment to prevent the long term morbidity from persistent COVID-19 symptoms.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



The authors hypothesized that the low number of asthma/COPD patients affected with COVID could be due to a protective effect exerted by the use of inhaled corticosteroids. They conducted a randomized, open-label, parallel study of inhaled Budesonide versus usual care. The study was stopped by the DSMB.

The authors should address the following issues:


1.     Please justify the choice of open-label vs. placebo-controlled design

2.     Was the need for urgent care visits decided per protocol or left up to the subjects?


3.     Please discuss why you did not see a difference in viral load. This goes against your rationale on how the drug interferes with viral replication. Moreover, Spagnuolo et al. retrospectively reviewed the effect of steroids in moderate to severe COVID and did not find differences in time to PCR negativization. Fang et al. also reported that the use of steroids did delay viral clearance in COVID 19 patients. Please speculate on the mechanism of action of budesonide in light of these findings.


4.     Please clarify: your abstract states that the study was stopped by the drug safety monitoring board. However, the discussion states that it was stopped due to national pandemic control measures, and national prioritization rules in the UK.

5.     The authors need to state that their findings need to be confirmed in a randomized, double-blind placebo-controlled trial.

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