Article (Scientific journals)
Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial.
De Leeuw, Elisabeth; Van Damme, Karel F A; Declercq, Jozefien et al.
2022In Respiratory Research, 23 (202), p. 1-11
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Keywords :
COVID-19; Complement 5; Complement system; Systemic inflammation; Anti-Infective Agents; Complement C5; Complement Inactivating Agents; Peptides, Cyclic; zilucoplan; Complement Inactivating Agents/adverse effects; Female; Humans; Male; Middle Aged; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment; Pulmonary and Respiratory Medicine
Abstract :
[en] BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear. METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) - 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified. CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.
Disciplines :
Immunology & infectious disease
Author, co-author :
De Leeuw, Elisabeth ;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
Van Damme, Karel F A ;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
Declercq, Jozefien ;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
Bosteels, Cedric ;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
Maes, Bastiaan;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
Tavernier, Simon J;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Primary Immunodeficiency Research Lab, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Detalle, Laurent;  UCB Biopharma SRL, Braine-l'Alleud, Belgium
Smart, Trevor;  UCB Pharma, Slough, UK
Glatt, Sophie;  UCB Pharma, Slough, UK
Debeuf, Nincy;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Deckers, Julie;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Lameire, Sahine;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Vandecasteele, Stefaan J;  Department of Infectious Diseases, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium
De Neve, Nikolaas;  Department of Anesthesiology and Intensive Care Medicine, OLV Hospital, Aalst, Belgium
Demedts, Ingel K;  Department of Respiratory Medicine, AZ Delta Roeselare-Menen, Roeselare, Belgium
Govaerts, Elke;  Department of Pulmonary Medicine, AZ Sint-Lucas Gent, Ghent, Belgium
Knoop, Christiane;  Department of Pulmonary Medicine, CHU Erasme Université Libre de Bruxelles, Brussels, Belgium
Vanhove, Karolien;  Department of Pneumology and Respiratory Oncology, AZ Vesalius, Tongeren, Belgium
Moutschen, Michel  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service des maladies infectieuses - médecine interne
Terryn, Wim;  Department of General Internal Medicine and Nephrology, Jan Yperman Hospital, Ieper, Belgium
Depuydt, Pieter;  Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Intensive Care Unit, Ghent University Hospital, Ghent, Belgium
Van Braeckel, Eva;  Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
Haerynck, Filomeen;  Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium ; Primary Immunodeficiency Research Lab, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
Hendrickx, Tine C J;  Clinical Trial Center, Pharmacy Department, AZ Sint-Lucas Gent, Ghent, Belgium
Parrein, Vanessa;  Sillar Clinical NV, Sint-Martens-Latem, Belgium
Lalla, Marianna;  UCB Pharma, Slough, UK
Brittain, Claire;  UCB Pharma, Slough, UK
Lambrecht, Bart N;  Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Technologiepark-Zwijnaarde 71, 9052, Ghent, Belgium. bart.lambrecht@ugent.be ; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. bart.lambrecht@ugent.be ; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. bart.lambrecht@ugent.be
More authors (18 more) Less
 These authors have contributed equally to this work.
Language :
English
Title :
Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial.
Publication date :
09 August 2022
Journal title :
Respiratory Research
ISSN :
1465-9921
eISSN :
1465-993X
Publisher :
BioMed Central Ltd, England
Volume :
23
Issue :
202
Pages :
1-11
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
UCB Pharma [BE]
Funding text :
We are grateful to the patients, their families and the health care providers for participating in this trial, during extremely challenging circumstances. We thank all study staff of the enrolling hospitals, and especially Stefanie Vermeersch, Anja Delporte, Bénédicte Demeyere, Jolien Buyle, Elise Haemerlynck, Ans Vandecouter, Mieke Denys, Evy Doolaege, Karlien Claes, Veronique Debacker and the staff of HIRUZ Health Innovation and Research Institute and Helena Aegerter, Ursula Smole, Leen Seys and Manon Vanheerswynghels of VIB for help with blood storage and analysis. We thank the entire UCB clinical study team and study reporting team with special thanks to Mark Vanderkelen, Johannes Streffer, Ann Cleverly, Anna Kirkley, Ellie Crompton-Brown, Gustaf Rydevik and Jemma Greenin. We want to acknowledge all members of the data safety monitoring board.CeB, EDL, JoD, BM, KVD have received an FWO PhD Fellowship. ND, JuD, SJT have received an FWO Postdoctoral Grant. ClB, LD, SG, ML, TS are employed by UCB. VP is employed by Sillar Clinical N.V. ClB, LD, ML, TS hold stock or stock options from UCB. LD holds stock or stock options from Sanofi. TS holds stock or stock options from Pfizer and Lilly. ClB, BNL, EVB have contributed or participated on a DSMB or Advisory Board. BNL has received a grant from Partner Therapeutics, Inc., has received consulting fees and payments from Sanofi and GSK and holds stock options from Argenx. EVB has received a grant from Ghent University, is principal investigator in a trial sponsored by Exevir Bio and has received consulting fees or payments from GSK, MDS and Gilead. ID, NDN, PD, EG, FH, TH, CK, SL, MM, WT, SV report no competing interests.We conducted a proof-of-concept phase 2, prospective, randomized, open-label study across 9 hospitals in Belgium. The trial was approved by the Ethical Committee of Ghent University Hospital and conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Study design, coordination, monitoring and data management was performed under the responsibility of the Health Innovation and Research Institute UZ Gent (HIRUZ). UCB provided study medication and assistance with data analysis and funded the study. Long-term follow-up of the patients was funded with the ClinicalTrials.COV grant (BOFCOV2020000801) from University Hospital Ghent. An independent data safety monitoring board monitored participant safety. Every patient or their legal representative provided informed consent before participation. All authors take responsibility for the integrity of the trial and the publication.
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