Abstract: Intensive Care Med (2021) 47:867–886 https://doi.org/10.1007/s00134-021-06448-5 ORIGINAL Lopinavir‑ritonavir and hydroxychloroquine for critically ill patients with COVID‑19: REMAP‑CAP randomized controlled trial Yaseen M. Arabi1,2,3* , Anthony C. Gordon4,5, Lennie P. G. Derde6,7, Alistair D. Nichol8,9,10, Srinivas Murthy11, Farah Al Beidh4, Djillali Annane12,13,14, Lolowa Al Swaidan2,3,15, Abi Beane16, Richard Beasley17, Lindsay R. Berry18, Zahra Bhimani19, Marc J. M. Bonten7,20, Charlotte A. Bradbury21,22, Frank M. Brunkhorst23, Meredith Buxton24, Adrian Buzgau25, Allen Cheng25,26, Menno De Jong27, Michelle A. Detry18, Eamon J. Duffy28, Lise J. Estcourt29,30, Mark Fitzgerald18, Rob Fowler31,32,33, Timothy D. Girard34,35, Ewan C. Goligher36, Herman Goossens37, Rashan Haniffa38,39,40, Alisa M. Higgins9, Thomas E. Hills17,41, Christopher M. Horvat34,35,42, David T. Huang34,35, Andrew J. King35, Francois Lamontagne43,44, Patrick R. Lawler31,36,45, Roger Lewis18,46, Kelsey Linstrum34,35, Edward Litton47,48,49, Elizabeth Lorenzi18, Salim Malakouti50, Daniel F. McAuley51,52, Anna McGlothlin18, Shay Mcguinness17,25,53, Bryan J. McVerry34,35, Stephanie K. Montgomery34,35, Susan C. Morpeth54, Paul R. Mouncey55, Katrina Orr56, Rachael Parke17,53,57, Jane C. Parker9, Asad E. Patanwala58,59, Kathryn M. Rowan60, Marlene S. Santos19, Christina T. Saunders18, Christopher W. Seymour34,35, Manu Shankar‑Hari61,62, Steven Y. C. Tong63,64, Alexis F. Turgeon65,66, Anne M. Turner17, Frank Leo Van de Veerdonk67, Ryan Zarychanski68, Cameron Green9, Scott Berry18, John C. Marshall19,69, Colin McArthur70, Derek C. Angus34,35 and Steven A. Webb9,48 on behalf of the REMAP-CAP Investigators © 2021 Springer-Verlag GmbH Germany, part of Springer Nature Abstract Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combina‑ tion therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, *Correspondence: arabi@ngha.med.sa 1 Intensive Care Department, Ministry of the National Guard-Health Affairs, ICU 1425, P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia Full author information is available at the end of the article The members of “The REMAP-CAP Investigators” are listed in Acknowledgements section. 868 compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ supportfree days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%,..