Effectiveness of Tocilizumab, Sarilumab, and Anakinra for critically ill patients with COVID-19 The REMAP-CAP COVID-19 Immune Modulation Therapy Domain Randomized Clinical Trial

  1. The REMAP-CAP Investigators
  2. Lennie P.G. Derde

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Abstract

BACKGROUND

The interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear.

METHODS

We evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-β1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility.

RESULTS

Statistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] –1, 16), 9 (IQR –1, 17), 0 (IQR –1, 15) and 0 (IQR –1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.20) and 0.97 (95%CrI 0.66, 1.40) for tocilizumab, sarilumab and anakinra respectively, compared to control, yielding 98.8%, 98.8% and 43.6% posterior probabilities of superiority, respectively, compared to control. All treatments appeared safe.

CONCLUSIONS

In patients with severe COVID-19 receiving organ support, tocilizumab and sarilumab are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population. ( ClinicalTrials.gov number: NCT02735707 )

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    SciScore for 10.1101/2021.06.18.21259133: (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

    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:
    In the face of an urgent global need and potential limitations of drug supply, the two agents can be considered equally effective, and this can help ensure as many patients as possible receive effective treatments. We did not observe a beneficial effect of anakinra in critically ill patients with COVID-19. Previous studies and a recent meta-analysis provided a rationale for the use of anakinra in COVID-19. 23 Anakinra treatment using soluble urokinase plasminogen activator receptor (sUPAR) to identify an at-risk group of patients for early targeting of IL-1 was effective in moderate COVID-19 in a recent study.24 There are several possible explanations for our findings. Firstly, we could have chosen the wrong dose. However, our choice of administration regimen was informed by pharmacometric modelling data, and it is unlikely that predicted drug concentrations varied significantly. Secondly, blocking IL-1 (and IL-1 mediated IL-6 release) may benefit non-critically ill, but not critically ill patients. Such potential differential effects could not be assessed in this study as a result of the low recruitment in non-critically ill patients. Finally, we did not use a strategy of early targeting of the IL-1 pathway in selected patients as used in the SAVE-MORE trial,24 because sUPAR is not commonly available. REMAP-CAP’s pragmatic, international design means that our results are likely generalizable to the wider critically ill patient population with COVID-19. Importantly, even once...

    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.
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    • No protocol registration statement was detected.

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

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  2. Version published to 10.1101/2021.06.18.21259133v2 on medRxiv
  3. Version published to 10.1101/2021.06.18.21259133v1 on medRxiv