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

Type Journal Article Author The REMAP-CAP Investigators Author Anthony C. Gordon Author Paul R. Mouncey Author Farah Al-Beidh Author Kathryn M. Rowan Author Alistair D. Nichol Author Yaseen M. Arabi Author Djillali Annane Author Abi Beane Author Wilma van Bentum-Puijk Author Lindsay R. Berry Author Zahra Bhimani Author Marc J. M. Bonten Author Charlotte A. Bradbury Author Frank M. Brunkhorst Author Adrian Buzgau Author Allen C. Cheng Author Michelle A. Detry Author Eamon J. Duffy Author Lise J. Estcourt Author Mark Fitzgerald Author Herman Goossens Author Rashan Haniffa Author Alisa M. Higgins Author Thomas E. Hills Author Christopher M. Horvat Author Francois Lamontagne Author Patrick R. Lawler Author Helen L. Leavis Author Kelsey M. Linstrum Author Edward Litton Author Elizabeth Lorenzi Author John C. Marshall Author Florian B. Mayr Author Danny McAuley Author Anna McGlothlin Author Shay P. McGuinness Author Bryan J. McVerry Author Stephanie K. Montgomery Author Susan C. Morpeth Author Srinivas Murthy Author Katrina Orr Author Rachael L. Parke Author Jane C. Parker Author Asad E. Patanwala Author Ville Pettilä Author Emma Rademaker Author Marlene S. Santos Author Christina T. Saunders Author Christopher W. Seymour Author Manu Shankar-Hari Author Wendy I. Sligl Author Alexis F. Turgeon Author Anne M. Turner Author Frank L. van de Veerdonk Author Ryan Zarychanski Author Cameron Green Author Roger J. Lewis Author Derek C. Angus Author Colin J. McArthur Author Scott Berry Author Steve A. Webb Author Lennie P. G. Derde URL https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1 Rights © 2021, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/ Pages 2021.01.07.21249390 Publication medRxiv Date 07/01/2021 Extra Publisher: Cold Spring Harbor Laboratory Press DOI 10.1101/2021.01.07.21249390 Library Catalog www.medrxiv.org Language en 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)