Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report
Gordon AC., Mouncey PR., Al-Beidh F., Rowan KM., Nichol AD., Arabi YM., Annane D., Beane A., van Bentum-Puijk W., Berry LR., Bhimani Z., Bonten MJM., Bradbury CA., Brunkhorst FM., Buzgau A., Cheng AC., Detry MA., Duffy EJ., Estcourt LJ., Fitzgerald M., Goossens H., Haniffa R., Higgins AM., Hills TE., Horvat CM., Lamontagne F., Lawler PR., Leavis HL., Linstrum KM., Litton E., Lorenzi E., Marshall JC., Mayr FB., McAuley D., McGlothlin A., McGuinness SP., McVerry BJ., Montgomery SK., Morpeth SC., Murthy S., Orr K., Parke RL., Parker JC., Patanwala AE., Pettilä V., Rademaker E., Santos MS., Saunders CT., Seymour CW., Shankar-Hari M., Sligl WI., Turgeon AF., Turner AM., van de Veerdonk FL., Zarychanski R., Green C., Lewis RJ., Angus DC., McArthur CJ., Berry S., Webb SA., Derde LPG.
AbstractBackgroundThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.MethodsWe 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.ResultsTocilizumab 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.ConclusionsIn 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)