Tocilizumab, sarilumab and anakinra in critically ill patients with COVID-19: a randomised, controlled, open-label, adaptive platform trial
Lennie Derde, Anthony Gordon, Paul Mouncey, Farah Al-Beidh, Kathy Rowan, Alistair Nichol, Yaseen M. Arabi, Djillali Annane, Abigail Beane, Richard Beasley, Marc J. M. Bonten, Charlotte Bradbury, Frank M. Brunkhorst, Adrian Buzgau, Meredith Buxton, Allen Cheng, Nicola Cooper, Matthew E. Cove, Olaf L. Cremer, Michelle A. Detry, Eamon Duffy, Lise J Estcourt, Mark Fitzgerald, James Galea, Herman Goossens, Rashan Haniffa, Thomas Hills, David T. Huang, Nao Ichihara, Andrew T. King, Fran�ois Lamontagne, Patrick R. Lawler, Helen L. Leavis, Roger J. Lewis, Edward Litton, John C. Marshall, Florian Mayr, Daniel F McAuley, Anna McGlothlin, Shay McGuinness, Bryan J. McVerry, Susan C. Morpeth, Srinivas Murthy, M. G. Netea, Kayode Ogungbenro, Katrina Orr, Rachael Parke, Rachael Parke, Asad E. Patanwala, Ville Pettilä, Luis Felipe Reyes, Hiroki Saito, Marlene Santos, Christina Saunders, Christopher W. Seymour, Manu Shankar‐Hari, Wendy Sligl, Alexis F Turgeon, Anne Turner, Steven Y. C. Tong, Suvi T. Vaara, Taryn Youngstein, Ryan Zarychanski, Cameron Green, Alisa M. Higgins, Colin McArthur, Lindsay R. Berry, Elizabeth Lorenzi, Scott Berry, Steve Webb, Derek Angus, Frank L. van de Veerdonk
Abstract
INTRODUCTION: Tocilizumab improves outcomes in critically ill patients with COVID-19. Whether other immune-modulator strategies are equally effective or better is unknown. METHODS: We 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. RESULTS: Of 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. CONCLUSIONS: In 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 NUMBER: NCT02735707.