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

Reviewed by

Read the full article

Listed in

Log in to save this article

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. ( ClinicalTrials.gov number: NCT02735707 )

Article activity feed

  1. Rapid Reviews Infectious Diseases

    Mike Samsonov

    Review 2: "Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report"

    IL-6 receptor inhibitor therapy likely reduces morbidity and mortality in a select group of patients if used within 24 hours of worsening clinical status. Both reviewers considered the multi-center, placebo-controlled randomized control trial results to be strong.

  2. Rapid Reviews Infectious Diseases

    Manish Sagar

    Review 1: "Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report"

    IL-6 receptor inhibitor therapy likely reduces morbidity and mortality in a select group of patients if used within 24 hours of worsening clinical status. Both reviewers considered the multi-center, placebo-controlled randomized control trial results to be strong.

  4. ScreenIT

    SciScore for 10.1101/2021.01.07.21249390: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    , SPSS version 26, and Stata version 14.2.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    It, of course, has limitations. Most notably, it uses an open-label design but awareness of intervention assignment is unlikely to affect the primary outcome. Furthermore, as IL-6 inhibition is known to have a profound effect on CRP,24,25 even if the study drug was blinded, intervention assignment would become “revealed” rapidly after administration. As this is an early, preliminary report some data are missing including 11 outcomes. Some patients still remain in hospital and so long-term outcomes may differ from the short-term outcomes presented here. The multifactorial design also allows multiple different interventions to be evaluated simultaneously, providing more efficient results and accounting for potential treatment-by-treatment interactions. Many of these interventions continue, and their effects and possible interactions are still to be reported. In conclusion, in critically ill adult patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcomes, including survival.

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

    IdentifierStatusTitle
    NCT02735707RecruitingRandomized, Embedded, Multifactorial Adaptive Platform Trial…

    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.

  5. ScreenIT

    SciScore for 10.1101/2021.01.07.21249390: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementThe trial is approved by relevant regional ethics committees (see Supplementary Appendix for more detail) and is conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.Randomization, New Zealand University of Sydney, Sydney, Australia Royal Prince Alfred Hospital, Sydney, Australia University of Helsinki and Helsinki University Hospital, Helsinki, Finland King's College London, London, United Kingdom Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom University of Alberta, Edmonton, Canada Université Laval, Québec City, Canada Radboudumc, Nijmegen, The Netherlands University of Manitoba, Winnipeg, Canada Harbor-UCLA Medical Center, Torrance, CA, United States St John of God Hospital, Subiaco, Australia Keywords 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).BlindingThe trial is overseen by a blinded International Trial Steering Committee (ITSC) and an unblinded independent Data and Safety Monitoring Board (DSMB).Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Experimental Models: Organisms/Strains
    SentencesResources
    5) Control (397) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion OSFD −1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Figure 2 C Cumulative Proportion of Patients 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 Organ support free days Pooled IL−6ra (395) Control (397) D Pooled IL−6ra (395) Control (397) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion OSFD −1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Figure 3 A + Tocilizumab + Sarilumab + Control Survival probability 1.00 + ++ + ++ + ++++ ++++++++ + +++++ + + ++ + + +++ + ++ +++ + ++ 0.75 + + + ++ + + + + + 0.50 0.25 0.00 0 15 30 45 60 75 90 242 31 242 230 31 231 226 31 226 224 31 225 45 60 75 90 Days Number at risk Tocilizumab Sarilumab Control 353 48 402 300 42 323 266 37 268 0 15 30 Days B + Pooled IL−6ra + Control Survival probability 1.00 ++ +++++ ++++++++ + +++++ + + ++ + ++++ + ++ ++++ ++ 0.75 + + + ++ + + + + 0.50 0.25 0.00 0 15 30 45 60 75 90 273 242 261 231 257 226 255 225 45 60 75 90 Days Number at risk Pooled IL−6ra Control 401 402 342 323 303 268 0 15 30 Days Figure 3 C + Tocilizumab + Sarilumab + Control ICU discharge probability 1 0.75 ++ ++ ++ + + +++ + + ++ +++++ ++ ++ +++ ++ + +++ ++ +++ + + + + 0.5 + + ++ + + + + + 0.25 0 0 15 30 45 60 75 90 99 7 157 91 7 140 90 7 134 89 7 132 45 60 75 90 Days Number at risk Tocilizumab Sarilumab Control 353 48 402 162 18 236 125 14 184 0 15 30 Days D + Tocilizumab + Sarilumab + Control Hospital discharge probability 1 0.75 + + ++ + +++++ + + ++++ ++++++ + + + ++ + + ++++ ++ +++ ++ + + + 0.5 + + + + ++ + + + + 0.25 0 0 15 30 45 60 75 90 118 10 182 106 10 159 103 10 148 101 10 145 45 60 75 90 Days Number at risk Tocilizumab Sarilumab Control 353 48 402 234 26 297 163 19 218 0 15 30 Days
    ++ + ++ + ++++ ++++++++ + +++++ + + ++ + + +++ + ++ +++ + ++ 0.75 + + + ++ + + + +
    suggested: None
    +++++ ++++++++ + +++++ + + ++ + ++++ + ++ ++++ ++ 0.75 + + + ++ + + +
    suggested: None
    0.75 ++ ++ ++ + + +++ + + ++ +++++ ++ ++ +++ ++ + +++ ++ +++ + + + + 0.5 + + ++ + + + +
    suggested: None
    0.75 + + ++ + +++++ + + ++++ ++++++ + + + ++ + + ++++ ++ +++ ++ + + + 0.5 + + + + ++ + + +
    suggested: None
    Software and Algorithms
    SentencesResources
    SPSS version 26, and Stata version 14.2.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:

    It, of course, has limitations. Most notably, it uses an open-label design but awareness of intervention assignment is unlikely to affect the primary outcome. Furthermore, as IL-6 inhibition is known to have a profound effect on CRP,24,25 even if the study drug was blinded, intervention assignment would become “revealed” rapidly after administration. As this is an early, preliminary report some data are missing including 11 outcomes. Some patients still remain in hospital and so longterm outcomes may differ from the short-term outcomes presented here. The multifactorial design also allows multiple different interventions to be evaluated simultaneously, providing more efficient results and accounting for potential treatment-by-treatment interactions. Many of these interventions continue, and their effects and possible interactions are still to be reported. In conclusion, in critically ill adult patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcomes, including survival.

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

    IdentifierStatusTitle
    NCT02735707RecruitingRandomized, Embedded, Multifactorial Adaptive Platform Trial...

    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.

    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.

  6. Version published to 10.1101/2021.01.07.21249390v2 on medRxiv
  7. Version published to 10.1101/2021.01.07.21249390v1 on medRxiv