An adaptive randomized controlled trial of non-invasive respiratory strategies in acute respiratory failure patients with COVID-19

  1. Gavin D Perkins
  2. Chen Ji
  3. Bronwen A Connolly
  4. Keith Couper
  5. Ranjit Lall
  6. J Kenneth Baillie
  7. Judy M Bradley
  8. Paul Dark
  9. Chirag Dave
  10. Anthony De Soyza
  11. Anna V Dennis
  12. Anne Devrell
  13. Sara Fairbairn
  14. Hakim Ghani
  15. Ellen A Gorman
  16. Christopher A Green
  17. Nicholas Hart
  18. Siew Wan Hee
  19. Zoe Kimbley
  20. Shyam Madathil
  21. Nicola McGowan
  22. Benjamin Messer
  23. Jay Naisbitt
  24. Chloe Norman
  25. Dhruv Parekh
  26. Emma M Parkin
  27. Jaimin Patel
  28. Scott E Regan
  29. Clare Ross
  30. Anthony J Rostron
  31. Mohammad Saim
  32. Anita K Simonds
  33. Emma Skilton
  34. Nigel Stallard
  35. Michael Steiner
  36. Rama Vancheeswaran
  37. Joyce Yeung
  38. Daniel F McAuley

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Abstract

Background

Both continuous positive airway pressure (CPAP) and high-flow nasal oxygenation (HFNO) have been recommended for acute respiratory failure in COVID-19. However, uncertainty exists regarding effectiveness and safety.

Methods

In the Recovery-Respiratory Support multi-center, three-arm, open-label, adaptive, randomized controlled trial, adult hospitalized patients with acute respiratory failure due to COVID-19, deemed suitable for treatment escalation, were randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Comparisons were made between each intervention and conventional oxygen therapy. The primary outcome was a composite of tracheal intubation or mortality within 30-days.

Results

Over 13-months, 1272 participants were randomized and included in the analysis (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). The need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). There was no difference between HFNO and conventional oxygen therapy (HFNO 184 of 414 participants (44.4%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85).

Conclusions

CPAP, compared with conventional oxygen therapy, reduced the composite outcome of intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. There was no effect observed, compared with conventional oxygen therapy, with the use of HFNO.

(Funded by the UK National Institute for Health Research; ISRCTN 16912075 ).

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  1. ScreenIT

    SciScore for 10.1101/2021.08.02.21261379: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The trial protocol was approved by the London-Brighton & Sussex Research Ethics Committee and the Health Research Authority, sponsored by the University of Warwick, co-ordinated by Warwick Clinical Trials Unit, and funded and prioritized as an urgent public health COVID-19 study by the National Institute for Health Research.
    Sex as a biological variablenot detected.
    RandomizationTrial design: Recovery-Respiratory Support was a parallel group, open-label, three-arm, adaptive, randomized controlled trial designed to evaluate the clinical effectiveness of CPAP and HFNO, compared with conventional oxygen therapy, in hospitalized patients with acute respiratory failure due to COVID-19.
    BlindingDue to the nature of the trial interventions and context, we were unable to blind patients, treating clinicians, or outcome assessors.
    Power AnalysisThe sample size calculation assumed 11 interim analyses (and the final one) would be conducted.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our trial has several limitations. Firstly, we did not achieve our planned sample size with the decision to stop recruitment driven by practical reasons linked to reducing numbers of COVID-19 in the UK, and an ethical obligation to share accumulated data with the international clinical community. Secondly, we observed crossover between allocated treatment arms, principally from the conventional oxygen therapy arm to one or both of the interventions. This is a common challenge in trials of non-invasive respiratory strategies, and reduces the observed effect size of a clinically effective treatment.23,24 Thirdly, we determined that it would be impractical to collect screening data, meaning we are unable to describe the number of non-randomized patients and reasons for non-randomization. Finally, the trial was rapidly set-up early in the pandemic, prior to the development of a core outcome set for COVID-19 trials.25 Whilst our outcome list aligns closely to most of the core outcomes subsequently identified, we did not capture information on patient recovery following hospital discharge. In conclusion, in this randomized trial of hospitalized adults with acute respiratory failure due to COVID-19, CPAP, compared with conventional oxygen therapy, reduced the composite outcome of tracheal intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. There was no effect observed, compared with conventional oxygen therapy, w...

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

    IdentifierStatusTitle
    ISRCTN16912075NANA

    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.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2021.08.02.21261379v1 on medRxiv