Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report

  1. The REMAP-CAP Investigators
  2. Anthony C. Gordon
  3. Paul R. Mouncey
  4. Farah Al-Beidh
  5. Kathryn M. Rowan
  6. Alistair D. Nichol
  7. Yaseen M. Arabi
  8. Djillali Annane
  9. Abi Beane
  10. Wilma van Bentum-Puijk
  11. Lindsay R. Berry
  12. Zahra Bhimani
  13. Marc J.M. Bonten
  14. Charlotte A. Bradbury
  15. Frank M. Brunkhorst
  16. Adrian Buzgau
  17. Allen C. Cheng
  18. Michelle A. Detry
  19. Eamon J. Duffy
  20. Lise J. Estcourt
  21. Mark Fitzgerald
  22. Herman Goossens
  23. Rashan Haniffa
  24. Alisa M. Higgins
  25. Thomas E. Hills
  26. Christopher M. Horvat
  27. Francois Lamontagne
  28. Patrick R. Lawler
  29. Helen L. Leavis
  30. Kelsey M. Linstrum
  31. Edward Litton
  32. Elizabeth Lorenzi
  33. John C. Marshall
  34. Florian B. Mayr
  35. Danny McAuley
  36. Anna McGlothlin
  37. Shay P McGuinness
  38. Bryan J. McVerry
  39. Stephanie K. Montgomery
  40. Susan C. Morpeth
  41. Srinivas Murthy
  42. Katrina Orr
  43. Rachael L. Parke
  44. Jane C. Parker
  45. Asad E. Patanwala
  46. Ville Pettilä
  47. Emma Rademaker
  48. Marlene S. Santos
  49. Christina T. Saunders
  50. Christopher W. Seymour
  51. Manu Shankar-Hari
  52. Wendy I. Sligl
  53. Alexis F. Turgeon
  54. Anne M. Turner
  55. Frank L. van de Veerdonk
  56. Ryan Zarychanski
  57. Cameron Green
  58. Roger J. Lewis
  59. Derek C. Angus
  60. Colin J. McArthur
  61. Scott Berry
  62. Steve A. Webb
  63. Lennie P.G. Derde
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Abstract

Background

The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.

Methods

We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.

Results

Tocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists.

Conclusions

In critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link>number:<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT02735707">NCT02735707</ext-link>)

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