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Randomized Controlled Trial
. 2021 Apr 22;384(16):1491-1502.
doi: 10.1056/NEJMoa2100433. Epub 2021 Feb 25.

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

REMAP-CAP Investigators; Anthony C Gordon  1 , Paul R Mouncey  1 , Farah Al-Beidh  1 , Kathryn M Rowan  1 , Alistair D Nichol  1 , Yaseen M Arabi  1 , Djillali Annane  1 , Abi Beane  1 , Wilma van Bentum-Puijk  1 , Lindsay R Berry  1 , Zahra Bhimani  1 , Marc J M Bonten  1 , Charlotte A Bradbury  1 , Frank M Brunkhorst  1 , Adrian Buzgau  1 , Allen C Cheng  1 , Michelle A Detry  1 , Eamon J Duffy  1 , Lise J Estcourt  1 , Mark Fitzgerald  1 , Herman Goossens  1 , Rashan Haniffa  1 , Alisa M Higgins  1 , Thomas E Hills  1 , Christopher M Horvat  1 , Francois Lamontagne  1 , Patrick R Lawler  1 , Helen L Leavis  1 , Kelsey M Linstrum  1 , Edward Litton  1 , Elizabeth Lorenzi  1 , John C Marshall  1 , Florian B Mayr  1 , Daniel F McAuley  1 , Anna McGlothlin  1 , Shay P McGuinness  1 , Bryan J McVerry  1 , Stephanie K Montgomery  1 , Susan C Morpeth  1 , Srinivas Murthy  1 , Katrina Orr  1 , Rachael L Parke  1 , Jane C Parker  1 , Asad E Patanwala  1 , Ville Pettilä  1 , Emma Rademaker  1 , Marlene S Santos  1 , Christina T Saunders  1 , Christopher W Seymour  1 , Manu Shankar-Hari  1 , Wendy I Sligl  1 , Alexis F Turgeon  1 , Anne M Turner  1 , Frank L van de Veerdonk  1 , Ryan Zarychanski  1 , Cameron Green  1 , Roger J Lewis  1 , Derek C Angus  1 , Colin J McArthur  1 , Scott Berry  1 , Steve A Webb  1 , Lennie P G Derde  1
Collaborators, Affiliations
Randomized Controlled Trial

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

REMAP-CAP Investigators et al. N Engl J Med. .

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 after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both.

Results: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.

Conclusions: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

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Figures

Figure 1
Figure 1. Screening, Enrollment, Randomization, and Inclusion in Analysis.
Patients who were ineligible for the platform or the Immune Modulation Therapy domain could meet more than one ineligibility criterion; full details are provided in the Supplementary Appendix. Contraindications to agents in the Immune Modulation Therapy domain include hypersensitivity, elevated levels of alanine aminotransferase or aspartate aminotransferase, thrombocytopenia, and pregnancy. Among patients who underwent randomization to an Immune Modulation Therapy domain intervention, the group assigned to receive no immune modulation only included patients when tocilizumab or sarilumab was a randomization option (i.e., direct concurrent controls). Other interventions included anakinra, interferon beta-1a, and no immune modulation when tocilizumab or sarilumab was not available as a randomization option (i.e., nondirect controls). The primary analysis of alternative interventions within the Immune Modulation Therapy domain is estimated from a model that adjusts for patient factors and for assignment to interventions in other domains. To obtain the most reliable estimation of the effect of these patient factors and of other interventions on the primary outcome, all the patients who were enrolled in the severe coronavirus disease 2019 (Covid-19) cohort (for whom there is consent and follow-up) are included. However, the model also factors eligibility for the Immune Modulation Therapy domain and its interventions, such that the final estimate of the effectiveness of an Immune Modulation Therapy domain intervention relative to any other within that domain is generated from the patients who might have been eligible to undergo randomization to those interventions within the domain. ICU denotes intensive care unit, and REMAP-CAP Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia.
Figure 2
Figure 2. Distributions of Organ Support–free Days.
Panel A shows the cumulative proportion of patients for each intervention group according to day, with death shown first. Curves that rise more gradually indicate a more favorable distribution in the number of days alive and free of organ support. The height of each curve at “−1” indicates the in-hospital mortality for each intervention. The height of each curve at any time point indicates the proportion of patients who had that number of organ support–free days or fewer (e.g., the height at day 10 indicates the proportion of patients with ≤10 organ support–free days). The difference in the height of the curves at any point represents the difference in the percentile in the distribution of organ support–free days associated with that number of days alive and free of organ support. Panel B shows organ support–free days as horizontally stacked proportions according to intervention group. Red represents worse outcomes, and blue represents better outcomes. The median adjusted odds ratios from the primary analysis, which used a Bayesian cumulative logistic model, were 1.64 (95% credible interval, 1.25 to 2.14) and 1.76 (95% credible interval, 1.17 to 2.91) for the tocilizumab and sarilumab groups, respectively, as compared with control, yielding probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. Panels C and D are similar to Panels A and B but with the tocilizumab and sarilumab groups pooled together. The median adjusted odds ratio was 1.65 (95% credible interval, 1.27 to 2.14), yielding a probability of superiority to control of more than 99.9%.
Figure 3
Figure 3. Time-to-Event Analyses.
Shown are Kaplan–Meier curves for survival according to individual intervention group (Panel A) and survival with the tocilizumab and sarilumab groups pooled together (Panel B). There were 109 deaths in the pooled intervention group (99 with tocilizumab and 10 with sarilumab) and 142 in the control group. This resulted in a hazard ratio of 1.61 (95% CI, 1.25 to 2.08), yielding a more than 99.9% posterior probability of superiority of the interleukin-6 receptor antagonists to control. Also shown are the time to ICU discharge according to individual intervention group (Panel C) and the time to hospital discharge according to individual intervention group (Panel D). All hazard ratios are for the comparison with control.
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