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, Jozefienet al.
[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
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
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
✱ 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.
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.
Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N Engl J Med. 2020;383:120–8. DOI: 10.1056/NEJMoa2015432
Carvelli J, Demaria O, Vely F, et al. Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature. 2020;588:146–50. DOI: 10.1038/s41586-020-2600-6
Ma L, Sahu SK, Cano M, et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol. 2021. 10.1126/sciimmunol.abh2259. DOI: 10.1126/sciimmunol.abh2259
Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020;220:1–13. DOI: 10.1016/j.trsl.2020.04.007
Satyam A, Tsokos MG, Brook OR, Hecht JL, Moulton VR, Tsokos GC. Activation of classical and alternative complement pathways in the pathogenesis of lung injury in COVID-19. Clin Immunol. 2021;226: 108716. DOI: 10.1016/j.clim.2021.108716
Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol. 2021;17:46–64. DOI: 10.1038/s41581-020-00357-4
Lo MW, Kemper C, Woodruff TM. COVID-19: complement, coagulation, and collateral damage. J Immunol. 2020;205:1488–95. DOI: 10.4049/jimmunol.2000644
Java A, Apicelli AJ, Liszewski MK, et al. The complement system in COVID-19: friend and foe? JCI Insight. 2020. 10.1172/jci.insight.140711. DOI: 10.1172/jci.insight.140711
Yan B, Freiwald T, Chauss D, et al. SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation. Sci Immunol. 2021. 10.1126/sciimmunol.abg0833. DOI: 10.1126/sciimmunol.abg0833
Skendros P, Mitsios A, Chrysanthopoulou A, et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest. 2020;130:6151–7. DOI: 10.1172/JCI141374
Risitano AM, Mastellos DC, Huber-Lang M, et al. Complement as a target in COVID-19? Nat Rev Immunol. 2020;20:343–4. DOI: 10.1038/s41577-020-0320-7
Afzali B, Noris M, Lambrecht BN, Kemper C. The state of complement in COVID-19. Nat Rev Immunol. 2021. 10.1038/s41577-021-00665-1. DOI: 10.1038/s41577-021-00665-1
Wang EY, Mao T, Klein J, et al. Diverse functional autoantibodies in patients with COVID-19. Nature. 2021;595:283–8. DOI: 10.1038/s41586-021-03631-y
Lam LKM, Reilly JP, Rux AH, et al. Erythrocytes identify complement activation in patients with COVID-19. Am J Physiol Lung Cell Mol Physiol. 2021;321:L485–9. DOI: 10.1152/ajplung.00231.2021
Holter JC, Pischke SE, de Boer E, et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci U S A. 2020;117:25018–25. DOI: 10.1073/pnas.2010540117
Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood. 2020;136:2080–9. DOI: 10.1182/blood.2020008248
Ali YM, Ferrari M, Lynch NJ, et al. Lectin pathway mediates complement activation by SARS-CoV-2 proteins. Front Immunol. 2021;12: 714511. DOI: 10.3389/fimmu.2021.714511
Jiang Y, Zhao G, Song N, et al. Blockade of the C5a–C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV. Emerg Microbes Infect. 2018;7:77.
Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. MBio. 2018. 10.1128/mBio.01753-18. DOI: 10.1128/mBio.01753-18
Zinellu A, Mangoni AA. Serum complement C3 and C4 and COVID-19 severity and mortality: a systematic review and meta-analysis with meta-regression. Front Immunol. 2021;12: 696085. DOI: 10.3389/fimmu.2021.696085
Marcos-Jimenez A, Sanchez-Alonso S, Alcaraz-Serna A, et al. Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients. Eur J Immunol. 2021;51:634–47. DOI: 10.1002/eji.202048858
Lin P, Chen W, Huang H, et al. Delayed discharge is associated with higher complement C3 levels and a longer nucleic acid-negative conversion time in patients with COVID-19. Sci Rep. 2021;11:1233. DOI: 10.1038/s41598-021-81010-3
Henry BM, Szergyuk I, de Oliveira MHS, et al. Complement levels at admission as a reflection of coronavirus disease 2019 (COVID-19) severity state. J Med Virol. 2021;93:5515–22. DOI: 10.1002/jmv.27077
Cugno M, Meroni PL, Gualtierotti R, et al. Complement activation and endothelial perturbation parallel COVID-19 severity and activity. J Autoimmun. 2021;116: 102560. DOI: 10.1016/j.jaut.2020.102560
Alosaimi B, Mubarak A, Hamed ME, et al. Complement anaphylatoxins and inflammatory cytokines as prognostic markers for COVID-19 severity and in-hospital mortality. Front Immunol. 2021;12: 668725. DOI: 10.3389/fimmu.2021.668725
Ramlall V, Thangaraj PM, Meydan C, et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med. 2020;26:1609–15. DOI: 10.1038/s41591-020-1021-2
Shen B, Yi X, Sun Y, et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell. 2020;182(59–72): e15.
Valenti L, Griffini S, Lamorte G, et al. Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19. J Autoimmun. 2021;117: 102595. DOI: 10.1016/j.jaut.2021.102595
Polycarpou A, Howard M, Farrar CA, et al. Rationale for targeting complement in COVID-19. EMBO Mol Med. 2020;12: e12642. DOI: 10.15252/emmm.202012642
Zelek WM, Cole J, Ponsford MJ, et al. Complement inhibition with the C5 blocker LFG316 in severe COVID-19. Am J Respir Crit Care Med. 2020;202:1304–8. DOI: 10.1164/rccm.202007-2778LE
Urwyler P, Moser S, Charitos P, et al. Treatment of COVID-19 with Conestat Alfa, a regulator of the complement, contact activation and Kallikrein-Kinin system. Front Immunol. 2020;11:2072. DOI: 10.3389/fimmu.2020.02072
Mastellos DC, Pires da Silva BGP, Fonseca BAL, et al. Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy. Clin Immunol. 2020;220: 108598. DOI: 10.1016/j.clim.2020.108598
Mastaglio S, Ruggeri A, Risitano AM, et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin Immunol. 2020;215: 108450. DOI: 10.1016/j.clim.2020.108450
Laurence J, Mulvey JJ, Seshadri M, et al. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin Immunol. 2020;219: 108555. DOI: 10.1016/j.clim.2020.108555
Kulasekararaj AG, Lazana I, Large J, et al. Terminal complement inhibition dampens the inflammation during COVID-19. Br J Haematol. 2020;190:e141–3. DOI: 10.1111/bjh.16641
Annane D, Heming N, Grimaldi-Bensouda L, et al. Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study. EClinicalMedicine. 2020;28: 100590. DOI: 10.1016/j.eclinm.2020.100590
Howard JF Jr, Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial. JAMA Neurol. 2020;77:582–92. DOI: 10.1001/jamaneurol.2019.5125
Declercq J, Van Damme KFA, De Leeuw E, et al. Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial. Lancet Respir Med. 2021;9:1427–38. DOI: 10.1016/S2213-2600(21)00377-5
Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173:489–95. DOI: 10.1503/cmaj.050051
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81. DOI: 10.1016/j.jbi.2008.08.010
Mastellos DC, Ricklin D, Lambris JD. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov. 2019;18:707–29. DOI: 10.1038/s41573-019-0031-6
Georg P, Astaburuaga-Garcia R, Bonaguro L, et al. Complement activation induces excessive T cell cytotoxicity in severe COVID-19. Cell. 2021. 10.1016/j.cell.2021.12.040. DOI: 10.1016/j.cell.2021.12.040
Vlaar APJ, de Bruin S, Busch M, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2020;2:e764–73. DOI: 10.1016/S2665-9913(20)30341-6
