February 20, 2021

The STOIC Trial: Inhaled Budesonide in the Treatment of Early COVID-19

Background: COVID-19 typically starts as a mild illness that progresses over several days. Most treatment interventions for COVID-19 are focused on hospitalized patients who have progressed past this mild illness.  Monoclonal antibodies have been heavily touted in this role for patients at high-risk of decompensation but have fallen well short of expectations and are prohibitively expensive and resource intensive. [BLAZE-1] [REGN-COV2]Easily accessible effective treatments are badly needed for patients with mild COVID-19 not requiring hospitalization.

Many reports have shown an under representation of patients with asthma and chronic obstruct pulmonary disease in patients hospitalized with COVID-19. One hypothesis is this may be due to the use of inhaled glucocorticoids in these patients.  Inhaled glucocorticoids have been shown to reduce exacerbations of both asthma and COPD.

Paper: Ramakrishnan S et al. Inhaled Budesonide in the Treatment of Early COVID-19 Illness: A Randomised Controlled Trial. medRxiv Preprint 2021 [Link is HERE]

Clinical Question: In adult patients with mild COVID-19 not requiring hospitalization, does inhaled budesonide reduce COVID-19 related urgent care visits, emergency department assessments, or hospitalizations vs usual care alone?

What They Did:

  • Steroids in COVID-19 (STOIC) trial
  • Phase 2, randomized, open-label, parallel group, clinical trial of adults within 7 days of onset of mild COVID-19 symptoms performed in the UK
  • Randomized patients to:
    • Usual care alone (UC)
    • Inhaled budesonide (BUD)
      • 800ug BID
    • Trial stopped early after independent statistical review
    • Per protocol population was defined as the population that received the study treatment and had at least 1 day of study observations
    • The intention to treat population was defined as all participants that were randomized to a study arm

Outcomes:

  • Primary: COVID-19 related urgent care visit, emergency department assessment, or hospitalization
  • Secondary:
    • Self-reported time to symptom resolution
    • Viral symptoms measured by the Common Cold Questionnaire (CCQ) and InFLUenza Patient-Reported Outcome (FluPRO) questionnaire
    • Blood oxygen saturations
    • Body temperature
    • SARS0CoV-2 vial load

Inclusion:

  • Adults ≥18 years of age
  • Symptoms suggestive of COVID-19
  • Within 7d 

Exclusion:

  • Known allergy or contraindication to interventional medication
  • Recent use (within 7d) of inhaled or systemic glucocorticoids 

Results:

  • 146 patients underwent randomization
  • 139 patients were in the per protocol population
  • 94% of patients had COVID-19 infection confirmed by RT-PcR
  • Median duration of symptoms prior to randomization was 3d
  • Per Protocol COVID-19 Related Urgent Care Visit, Emergency Department assessment, or Hospitalization:
    • UC: 10/69 (14.5%)
    • BUD: 1/70 (1.4%)
    • Difference in Proportion: 0.131; 95% CI 0.43 to 0.218; p = 0.004
    • NNT = 8
  • Self-reported clinical recovery was 1 day shorter in budesonide arm (median of 7d vs 8d)
  • Fewer participants randomized to budesonide had persistent symptoms at 14d (10% vs 30%) and 28d compared to usual care alone
  • Mean proportion of days with documented fever (≥37.5C) during the first 14d was less in the budesonide group (2.1% vs 7.7%)
  • No difference in patients with O2 sats ≤94% over the 1st 14 days 

Strengths:

  • Studies an important question of out-of-hospital treatment option for patients with COVID-19 mild illness
  • AstraZeneca had no role in the study design, data collection, data analysis, and decision to publish
  • Groups were well balanced at baseline
  • Broad inclusion criteria increases generalizability

Limitations:

  • Open-label study with subjective outcomes could lead to bias of results
  • Trial stopped early with a small sample size could cause overestimation of benefit seen
  • Per-protocol analysis will overestimate what we would see in real life.
  • Due to early stoppage, we see fairly wide confidence intervals
  • Composite outcome of urgent care/emergency department visits and hospitalizations are not equal outcomes

Discussion:

  • Study required 199 patients in each arm to demonstrate a 50% reduction of urgent care visits or hospitalizations
  • Although this is not an earth-shattering study, inhaled budesonide is simple, safe, well studied, widely available, and inexpensive. Furthermore, any reduction in ED visits/hospitalizations can reduce pressure on health care systems
  • Cost of Budesonide is about $35 to $95 (GoodRx)

Author Conclusion: “Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.”

Clinical Take Home Point: This small, open-label trial with subjective outcomes that was, stopped early does not give high-quality evidence on the use of inhaled budesonide in adult patients with COVID-19 in the outpatient setting. ED visits and hospitalizations are simply not the same thing and combining these two outcomes gives us nothing useful. Inhaled budesonide is promising as it is readily available, inexpensive and has a low side effect profile. Additional studies should be performed to elucidate it’s utility.

References:

  1. Ramakrishnan S et al. Inhaled Budesonide in the Treatment of Early COVID-19 Illness: A Randomised Controlled Trial. medRxiv Preprint 2021 [Link is HERE]

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

Cite this article as: Salim Rezaie, "The STOIC Trial: Inhaled Budesonide in the Treatment of Early COVID-19", REBEL EM blog, February 20, 2021. Available at: https://rebelem.com/the-stoic-trial-inhaled-budesonide-in-the-treatment-of-early-covid-19/.
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Salim Rezaie

Emergency Physician at Greater San Antonio Emergency Physicians (GSEP)
Creator & Founder of REBEL EM

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