Matthias M. Engelen, Quentin Van Thillo, Albrecht Betrains, Iwein Gyselinck, Caroline P. Martens, Valérie Spalart, Anna Ockerman, Caroline Devooght, Joost Wauters, Jan Gunst, Carine Wouters, Christophe Vandenbriele, Steffen Rex, Laurens Liesenborghs, Alexander Wilmer, Philippe Meersseman, Greet Van den Berghe, Dieter Dauwe, Ann Belmans, Michiel Thomeer, Tom Fivez, Dieter Mesotten, David Ruttens, Luc Heytens, Ilse Dapper, Sebastiaan Tuyls, Brecht De Tavernier, Peter Verhamme, Thomas Vanassche, Eric Van Wijngaerden, Wim Janssens, Geert Meyfroidt, Robin Vos, Timothy Devos, Paul De Munter, Johan Neyts, Lieven Dupont, Isabel Spriet, Geert Verbeke, Kathleen Claes, Wim Robberecht, Chris Van Geet, Barbara Debaveye, Helga Ceunen, Veerle Servaes, Katrien Cludts, Kristine Vanheule, Cato Jacobs, Daimy Roebroek, Paulien Dreesen, Nele Smet, Jan Dolhain, Mieke Hoppenbrouwers, Kathleen Wens, Kristel Daems, Monique D’hondt, Engelen, Matthias M, Van Thillo, Quentin, Betrains, Albrecht, Gyselinck, Iwein, Martens, Caroline P, Spalart, Valérie, Ockerman, Anna, Devooght, Caroline, Wauters, Joost, Gunst, Jan, Wouters, Carine, Vandenbriele, Christophe, Rex, Steffen, Liesenborghs, Laurens, Wilmer, Alexander, Meersseman, Philippe, Van den Berghe, Greet, Dauwe, Dieter, Belmans, Ann, THOMEER, Michiel, Fivez, Tom, MESOTTEN, Dieter, RUTTENS, David, Heytens, Luc, Dapper, Ilse, Tuyls, Sebastiaan, De Tavernier, Brecht, Verhamme, Peter, Vanassche, Thomas, Dauwe, Dieter/0000-0002-9771-2543, Gyselinck, Iwein/0000-0002-4068-7228, Gunst, Jan/0000-0003-2470-6393, Martens, Caroline/0000-0002-2890-7072, NEYTS, Johan/0000-0002-0033-7514, Engelen, Matthias/0000-0002-5364-7751, Wouters, Carine/0000-0002-6426-8845, Engelen, Matthias M., Martens, Caroline P., Spalart, Valerie, Van den Berghe , Greet, and Dauwe , Dieter
Background Thromboinflammation plays a central role in severe COVID-19. The kallikrein pathway activates both inflammatory pathways and contact-mediated coagulation. We investigated if modulation of the thromboinflammatory response improves outcomes in hospitalized COVID-19 patients. Methods In this multicenter open-label randomized clinical trial (EudraCT 2020-001739-28), patients hospitalized with COVID-19 were 1:2 randomized to receive standard of care (SOC) or SOC plus study intervention. The intervention consisted of aprotinin (2,000,000 IE IV four times daily) combined with low molecular weight heparin (LMWH; SC 50 IU/kg twice daily on the ward, 75 IU/kg twice daily in intensive care). Additionally, patients with predefined hyperinflammation received the interleukin-1 receptor antagonist anakinra (100 mg IV four times daily). The primary outcome was time to a sustained 2-point improvement on the 7-point World Health Organization ordinal scale for clinical status, or discharge. Findings Between 24 June 2020 and 1 February 2021, 105 patients were randomized, and 102 patients were included in the full analysis set (intervention N = 67 vs. SOC N = 35). Twenty-five patients from the intervention group (37%) received anakinra. The intervention did not affect the primary outcome (HR 0.77 [CI 0.50-1.19], p = 0.24) or mortality (intervention n = 3 [4.6%] vs. SOC n = 2 [5.7%], HR 0.82 [CI 0.14-4.94], p = 0.83). There was one treatment-related adverse event in the intervention group (hematuria, 1.49%). There was one thrombotic event in the intervention group (1.49%) and one in the SOC group (2.86%), but no major bleeding. Conclusions In hospitalized COVID-19 patients, modulation of thromboinflammation with high-dose aprotinin and LMWH with or without anakinra did not improve outcome in patients with moderate to severe COVID-19. This studywas funded by Life SciencesResearchPartners (LSRP),Research Foundation Flanders (FWO) project G0G4720N and the COVID-19 fund of the KU Leuven. We are grateful to all patients, their family members, and all health care workers who help to perform clinical studies in extraordinary and challenging times during this COVID-19 pandemic, and by doing so contribute to fighting SARS-CoV-2. We would like to express our gratitude to all collaborators, the clinical trial center of UZ Leuven and all participating centers with their study teams for their collaboration and efforts. A list with all collaborators of the DAWn consortium is provided as in Appendix S2. We want to thank the following DAWn collaborators personally: Eric Van Wijngaerden, Wim Janssens, Geert Meyfroidt, Robin Vos, Timothy Devos, Paul De Munter, Johan Neyts, Lieven Dupont, Isabel Spriet, Geert Verbeke, Kathleen Claes, Wim Robberecht, Chris Van Geet, Barbara Debaveye, Helga Ceunen, Veerle Servaes, Katrien Cludts, Kristine Vanheule, Cato Jacobs, Daimy Roebroek, Paulien Dreesen, Nele Smet, Jan Dolhain, Mieke Hoppenbrouwers, Kathleen Wens, Kristel Daems, Monique D'hondt.