PMID- 37965347 OWN - NLM STAT- MEDLINE DCOM- 20231116 LR - 20240320 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial. PG - 1255292 LID - 10.3389/fimmu.2023.1255292 [doi] LID - 1255292 AB - BACKGROUND: Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation. METHODS: We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively. RESULTS: The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms (p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms (p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug. CONCLUSION: The study results do not support the use of ConA to prevent COVID-19 progression. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, identifier NCT04414631. CI - Copyright (c) 2023 Urwyler, Leimbacher, Charitos, Moser, Heijnen, Trendelenburg, Thoma, Sumer, Camacho-Ortiz, Bacci, Huber, Stussi-Helbling, Albrich, Sendi and Osthoff. FAU - Urwyler, Pascal AU - Urwyler P AD - Division of Internal Medicine, University Hospital Basel, Basel, Switzerland. FAU - Leimbacher, Marina AU - Leimbacher M AD - Division of Internal Medicine, University Hospital Basel, Basel, Switzerland. FAU - Charitos, Panteleimon AU - Charitos P AD - Division of Internal Medicine, University Hospital Basel, Basel, Switzerland. FAU - Moser, Stephan AU - Moser S AD - Division of Internal Medicine, University Hospital Basel, Basel, Switzerland. FAU - Heijnen, Ingmar A F M AU - Heijnen IAFM AD - Division of Medical Immunology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland. FAU - Trendelenburg, Marten AU - Trendelenburg M AD - Division of Internal Medicine, University Hospital Basel, Basel, Switzerland. AD - Department of Clinical Research, University of Basel, Basel, Switzerland. AD - Department of Biomedicine, University of Basel, Basel, Switzerland. FAU - Thoma, Reto AU - Thoma R AD - Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. FAU - Sumer, Johannes AU - Sumer J AD - Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. FAU - Camacho-Ortiz, Adrian AU - Camacho-Ortiz A AD - Servicio de Infectologia, Hospital Universitario Dr. Jose Eleuterio Gonzalez, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico. FAU - Bacci, Marcelo R AU - Bacci MR AD - Department of General Practice, Centro Universitario em Saude do ABC, Santo Andre, Brazil. FAU - Huber, Lars C AU - Huber LC AD - Clinic for Internal Medicine, City Hospital Triemli, Zurich, Switzerland. FAU - Stussi-Helbling, Melina AU - Stussi-Helbling M AD - Clinic for Internal Medicine, City Hospital Triemli, Zurich, Switzerland. FAU - Albrich, Werner C AU - Albrich WC AD - Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. FAU - Sendi, Parham AU - Sendi P AD - Institute for Infectious Diseases, University of Bern, Bern, Switzerland. FAU - Osthoff, Michael AU - Osthoff M AD - Division of Internal Medicine, University Hospital Basel, Basel, Switzerland. AD - Department of Clinical Research, University of Basel, Basel, Switzerland. AD - Department of Biomedicine, University of Basel, Basel, Switzerland. LA - eng SI - ClinicalTrials.gov/NCT04414631 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20231027 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 SB - IM MH - Adult MH - Humans MH - *COVID-19/prevention & control MH - SARS-CoV-2 MH - Endothelial Cells MH - Inflammation MH - *Thrombosis PMC - PMC10641758 OTO - NOTNLM OT - C1 esterase inhibitor OT - COVID-19 OT - complement system OT - contact activation system OT - kallikrein kinin system OT - randomized trial COIS- MT reports receiving grants from the Swiss National Science Foundation, and having research collaborations with Roche, Novartis, and Idorsia outside the submitted work. WA reports receiving fees and research grants from A. Vogel AG, Gilead, and OM Pharma and fees for attendance of advisory boards to Pfizer, MSD Vifor Pharma, GSK, Sanofi, OM Pharma, and Janssen that were paid to his institution outside the submitted work. MO reports receiving grants from the Swiss National Science Foundation, consulting fees from Pharming Biotechnologies B.V. during the conduct of the study and grants from Pharming Biotechnologies B.V. outside the submitted work. LH reports receiving consulting fees from GlaxoSmithKline and Novartis during the conduct of the study but unrelated to this trial. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Pharming Biotechnologies B.V. The funder was involved in the design of the study at an initial stage and in the trial organization of the study in Brazil and Mexico (e.g., shipment of study drug). EDAT- 2023/11/15 06:42 MHDA- 2023/11/16 06:44 PMCR- 2023/01/01 CRDT- 2023/11/15 04:25 PHST- 2023/07/08 00:00 [received] PHST- 2023/10/12 00:00 [accepted] PHST- 2023/11/16 06:44 [medline] PHST- 2023/11/15 06:42 [pubmed] PHST- 2023/11/15 04:25 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1255292 [doi] PST - epublish SO - Front Immunol. 2023 Oct 27;14:1255292. doi: 10.3389/fimmu.2023.1255292. eCollection 2023.