Tocilizumab, sarilumab and anakinra in critically ill patients with COVID-19: a randomised, controlled, open-label, adaptive platform trial.
Derde L., Gordon AC., Mouncey PR., Al-Beidh F., Rowan KM., Nichol AD., Arabi YM., Annane D., Beane A., Beasley R., Bonten MJM., Bradbury CA., Brunkhorst FM., Buzgau A., Buxton M., Cheng AC., Cooper N., Cove M., Cremer OL., Detry MA., Duffy EJ., Estcourt LJ., Fitzgerald M., Galea J., Goossens H., Haniffa R., Hills TE., Huang DT., Ichihara N., King A., Lamontagne F., Lawler PR., Leavis HL., Lewis RJ., Litton E., Marshall JC., Mayr FB., McAuley DF., McGlothlin A., McGuinness SP., McVerry BJ., Morpeth SC., Murthy S., Netea MG., Ogungbenro K., Orr K., Parke RL., Parker JC., Patanwala AE., Pettila V., Reyes LF., Saito H., Santos MS., Saunders CT., Seymour CW., Shankar-Hari M., Sligl WI., Turgeon AF., Turner AM., Tong SYC., Vaara S., Youngstein T., Zarychanski R., Green C., Higgins AM., McArthur CJ., Berry LR., Lorenzi E., Berry S., Webb SA., Angus DC., van de Veerdonk FL.
IntroductionTocilizumab improves outcomes in critically ill patients with COVID-19. Whether other immune-modulator strategies are equally effective or better is unknown.MethodsWe investigated treatment with tocilizumab, sarilumab, anakinra and no immune modulator in these patients. In this ongoing, adaptive platform trial in 133 sites in 9 countries, we randomly assigned patients with allocation ratios dependent on the number of interventions available at each site. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21 in survivors. The trial used a Bayesian statistical model with predefined triggers for superiority, inferiority, efficacy, equivalence or futility.ResultsOf 2274 critically ill participants enrolled between 25 March 2020 and 10 April 2021, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (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 ORs were 1.46 (95% credible intervals (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 relative to control, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared with control. All treatments appeared safe.ConclusionsIn critically ill patients with COVID-19, tocilizumab and sarilumab have equivalent effectiveness at reducing duration of organ support and death. Anakinra is not effective in this population.Trial registration numberNCT02735707.