Article
Author: Perez, Romulo Omar Flores ; Pabel, Steffen ; Fernandez, Alberto A. ; Pink, Isabell ; Terskikh, Mikhail M. ; Amido, Florencia Heredia ; Kiseleva, Maria ; Bhatnagar, Sushma ; Ortega, Maria L. Morales ; Singh, Ram ; Bauernfeind, Stilla ; Agrawal, Ankit ; Kist, Graziela Regina ; Marcos, Maria Celeste ; Rodriguez, Brenda Nohemi Lozano ; Gatlik, Ewa ; Vasileva, Elena ; Cardozo, Celia ; Rodionova, Olga Vasilievna ; Sag, Sabine ; Vishnevsky, Alexander ; VanDen Berg, Jan Williem ; Ramirez, Erick Joel Rendon ; de Carvalho Rezende, Ederlon Alves ; Paraeva, Olga Sergeevna ; Fernandez, Alberto Alfredo ; Sementsov, Konstantin Valerievich ; Barbosa, Gynara Rezende ; Ganova, Olga Sergeevna ; Datta, Avijatri ; Vergara, Adrian Martinez ; Bachman, Marcus ; Shearman, Nicole ; Farronay, Milagros Ivette Maguina ; Lancee, Gerieke ; Pashkevich, Vladimir Vladimirovich ; Kurguzova, Dariya ; Zerega, Natalia ; Bhopale, Shweta ; Repnikov, Ilia ; Ore, Danilo Joel Salazar ; Flores, Ernesto Moises Zavala ; Gaygolnik, Tamara Valerievna ; Perez, Diego Luis Carrillo ; Ramos, Eduarda Annoni ; Krylov, Andrey Alexandrovich ; Belekhov, George Arkadievich ; Olzik, Ilona ; Goebeler, Maria-Elisabeth ; Velayuthaswamy, Nandagopal ; Fernandes, Caio Cesar ; Pinzhina, Valeria Nikolaevna ; Hitzenbichler, Florian ; Gans, Stephanus J. ; Maier, Lars ; Bacci, Marcelo Rodrigues ; Pandit, Anuja ; Unnithan, Mauila Raghavan Jaymohan ; Zeller, Judith ; Leisner, Ulf ; Saha, Amitabha ; Ripfel, Sarah ; Martynov, Aleksey Viktorovich ; Geismann, Florian ; Srinivasan, Nagarajan ; Kaneesan, Kalaiyamishan ; Costa, Maria Belen ; Lazarenko, Ilya Vyacheslavovich ; Mehes, Beata ; Serrano, Diego Rodriguez ; de Olivera, Ellen Pierre ; Osornio, Jose Sifuentes ; Smolyarchuk, Elena Anatolievna ; Bhattacharjee, Abhishek ; Morozov, Evgeny ; Gounder, Senthil Kumar Mothu ; Krishnamurthy, Srikanth ; Rezende, Ederlon ; Mc Harry, Kirsten ; Sommer, Ulrike ; Kumar, Balbir ; Vishnevsky, Alexander Yurievich ; Vaidyanathan, Venkatraman ; Esze, Tamas ; Srikanth, Ambika ; Radchenko, Elena Nikolaevna ; Stadnik, Claudio Marcel Berdun ; Brigante, Jorge Alejandro ; Lammens, Martine ; Panhuis, Esther ; Kotov, Mikhail E. ; Sayehli, Cyrus Michael ; Tiwari, Pawan ; Tidemandsen, Casper ; Katagarov, Dmitry Nikolaevich ; Benfield, Thomas ; Vishneva, Elena Mikhailovna ; Bagu, Ana Maria ; Hanses, Frank ; Soriano, Joan ; Lubnow, Matthias ; Budhraja, Akshay ; Jaoude, Caio Vinicius Gouvea ; Ratre, Brajesh Kumar ; Garkavi, Dmitriy Andreevich ; Iharos, Dora ; Madurka, Ildiko ; Nalin, Sabrina ; Boom, Lisenka ; Rendon, Adrian ; Toth, Krisztina Kormosoi ; Weismann, Dirk ; del Pino, Ramon Mendoza ; Ortiz, Adrian Camacho ; Messnikov, Oleg ; Bustios, Enrique Renzo Morello ; Hakansson, Kjell ; Abramov, Vladislav Gennadievich ; Meiser, Karin ; Orihuela, Boris Galin ; Klinker, Hartwig ; Frey, Anna ; Blinova, Elena Vladimirovna ; Hinovker, Vladimir Vladimirovich ; Zykov, Vladislav Anatolievich ; Stoll, Mathias ; Kharlamova, Svetlana ; Malacize, Vania Quinato ; Schulze, Petra ; Medina, Miguel Angel Jandete ; Gatalsky, Konstantin Konstantinovich ; Alferov, Sergey Petrovich ; Garcia, Felipe ; Moncivais, Berenice Soto ; Pedersen, Karen Brorup Heje ; Vig, Saurabh ; Boeve-Epping, Nancy ; Antonov, Vladimir Nikolaevich ; Scharf, Natascha ; Martynenko, Tatiana Ivanovna ; Trufanov, Konstantin Vasilievich ; Bondareva, Yulia Andereevna ; Snyman, Elizma ; Junge, Guido ; Isakova, Anna Pavlovna ; Ulrik, Charlotte S. ; Ignatova, Galina Lvovna ; McHarry, Kirsten ; Rudikh, Oleg Vladimirovich ; Franco, Gaston ; Viladomiu, Alex Soriano ; Hupf, Julian ; Ahmed, Nadia Johanna ; Filik, Henrique ; Hejja, Maria ; Ragognete, Henrique Gitti ; Welte, Tobias ; Ulrik, Charlotte Suppli ; Mohan, Anant ; Soriano, Joan B. ; Grebneva, Irina Viktorovna ; Egorova, Ekaterina Aleksandrovna ; Bhan, Swati
BACKGROUNDCoronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm.METHODSThis randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety.FINDINGSBetween May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals.INTERPRETATIONDFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS.TRIAL REGISTRATIONClinicalTrials.gov, NCT04382053.