Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial

  1. Sanjay Ramakrishnan
  2. Dan V Nicolau
  3. Beverly Langford
  4. Mahdi Mahdi
  5. Helen Jeffers
  6. Christine Mwasuku
  7. Karolina Krassowska
  8. Robin Fox
  9. Ian Binnian
  10. Victoria Glover
  11. Stephen Bright
  12. Christopher Butler
  13. Jennifer L Cane
  14. Andreas Halner
  15. Philippa C Matthews
  16. Louise E Donnelly
  17. Jodie L Simpson
  18. Jonathan R Baker
  19. Nabil T Fadai
  20. Stefan Peterson
  21. Thomas Bengtsson
  22. Peter J Barnes
  23. Richard E K Russell
  24. Mona Bafadhel

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Abstract

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  1. Version published to 10.1016/s2213-2600(21)00160-0
  2. Rapid Reviews Infectious Diseases

    Ariel Berlinski

    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.

  3. Rapid Reviews Infectious Diseases

    Ying-Rong Du, Hai-yan Fu

    Review 1: "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.

  4. Rapid Reviews Infectious Diseases

    Strength of evidence

    Reviewers: Ying-Rong Du, Hai-yan Fu (Dali University) | đŸ“—đŸ“—đŸ“—đŸ“—â—»ïž
    Ariel Berlinski (University of Arkansas for Medical Sciences) | đŸ“’đŸ“’đŸ“’â—»ïžâ—»ïž

  5. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/4663312.

    By Yash S. Huilgol[1] UC Berkeley-UCSF Joint Medical Program, Berkeley, CA, USA[2] Editorial Office, Rapid Reviews: COVID-19

     

    Main Claim & Relevance:

    In this preprint by Ramakrishnan et al [1], inhaled budesonide, a corticosteroid used for long-term COPD and asthma treatment, reducing the likelihood of urgent care, ED visit, or hospitalization among patients with early COVID-19 illness. This amounted to a relative risk reduction of 90%, or a difference in proportions of 13.1% between the budesonide and standard of care arms.

    Are the findings strong, reliable, potentially informative, not informative, or misleading? Why?

    The findings are reliable, though the findings need to be confirmed through further studies and assessment. The use of the randomized, open-label phase 2 trial among 149 adults in a per-protocol analysis is well powered, adding to the strength of these claims. The two randomized groups were well-matched, but O2 saturation in the treatment group appeared to have a larger confidence interval than that for the usual care group. However, the study could be improved by the recruitment of a more diverse patient population, of which 93% of participants were white in both arms, and of unknown sociodemographic characteristics.

    How might these ideas presented by the main claims further knowledge of the COVID-19 pandemic?

    Much of the literature has focused on later stages of COVID-19 disease progression, but there are limited studies of therapeutics for treating mild COVID-19 [2,3].

    However, this study claimed that there is a reduction in urgent care, ED, or hospital visits and a reduction in recovery time from COVID-19. Budesonide is also a well-tolerated, ubiquitous, and cheap therapeutic that could alleviate symptoms and reduce escalation of care among COVID-19 patients if taken over a median of 7 days. There remains a concern clinically that administering steroids early in treatment may prevent the immune system from adequately reacting in the early stages of the COVID-19 disease course. Additional studies are needed to verify these findings.

    References

    [1] Ramakrishnan S, Nicolau DV, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial. medRxiv. Published online January 1, 2021:2021.02.04.21251134. doi:10.1101/2021.02.04.21251134

    [2] The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330–1341. doi:10.1001/jama.2020.17023

    [3] The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. N Engl J Med. Published online July 17, 2020. doi:10.1056/NEJMoa2021436

    https://rapidreviewscovid19.mitpress.mit.edu/

    User: 2987330433

  6. ScreenIT

    SciScore for 10.1101/2021.02.04.21251134: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Participants were seen at their homes at randomisation (day 0), day 7 and day 14 by a trained respiratory research nurse to obtain written informed consent, provide inhalers and to obtain nasopharyngeal swabs for SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) testing (see supplementary methods for further details).
    IRB: Institutional Review: The trial was sponsored by the University of Oxford, and was approved by the Fulham London Research Ethics Committee (20/HRA/2531) and the National Health Research Authority.
    RandomizationParticipants are randomly allocated to UC or BUD, stratified for participant age,(≀40 years/ >40 years) gender, and number of co-morbidities (≀1/ ≄2).
    Blindingnot detected.
    Power AnalysisUsing 80% power at 0.05 level, we required 199 patients in each arm to demonstrate a 50% reduction of urgent care visits or hospitalisations.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There are limitations to our study. This is an open-labelled study, which was stopped early due to the impact of the national pandemic control measures and national prioritisation rules for clinical research trials in the UK. Our power calculations were made from the best available predictions in early 2020. Therapeutic randomised clinical trial design and sample size calculations are often dictated by statistical assumptions with treatment effect estimations based on the evidence of best available care. However, in trial design for a new disease, with no known effective treatment, statistical assumptions are thus arbitrary. In our study the event rate in the control arm was half of what was predicted, and this is consistent with subsequent primary care clinical trials performed in COVID-1929-31. We found that the budesonide treatment effect size, was larger than predicted; and independent statistical assessment concluded that the current sample size and treatment effect had a 99% power to reject the null hypothesis. Furthermore, the positive concordance of temperature and symptoms as secondary outcomes gives us confidence in our results. Our study design involved randomisation at home, with home visits for study assessments and a daily contact until symptom resolution by the study team. To our knowledge, the STOIC trial is first to assess daily physiological measures in early COVID-19. The robust study design meant very good participant retention and completion of symptom di...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04416399TerminatedSTerOids in COVID-19 Study

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  7. Version published to 10.1101/2021.02.04.21251134v1 on medRxiv