Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial

• Published in: Respiratory research Vol. 23; no. 1; pp. 202 - 11
• Main Authors: De Leeuw, Elisabeth, Van Damme, Karel F. A., Declercq, Jozefien, Bosteels, Cedric, Maes, Bastiaan, Tavernier, Simon J., Detalle, Laurent, Smart, Trevor, Glatt, Sophie, Debeuf, Nincy, Deckers, Julie, Lameire, Sahine, Vandecasteele, Stefaan J., De Neve, Nikolaas, Demedts, Ingel K., Govaerts, Elke, Knoop, Christiane, Vanhove, Karolien, Moutschen, Michel, Terryn, Wim, Depuydt, Pieter, Van Braeckel, Eva, Haerynck, Filomeen, Hendrickx, Tine C. J., Parrein, Vanessa, Lalla, Marianna, Brittain, Claire, Lambrecht, Bart N.
• Format: Journal Article Web Resource
• Language: English
• Published: England BioMed Central Ltd 09.08.2022; BioMed Central; BMC
• Subjects: Anti-Infective Agents; Antibiotics; Biological response modifiers; Complement (Immunology); Complement 5; Complement C5; Complement component C5; Complement Inactivating Agents; Complement Inactivating Agents - adverse effects; Complement system; Coronaviruses; COVID-19; COVID-19 Drug Treatment; Drug therapy; Effectiveness; Female; Health aspects; Hospital patients; Hospitalization; Human health sciences; Humans; Hypoxemia; Immunologie & maladie infectieuse; Immunology & infectious disease; Inflammation; Inhibitors; Interleukin 8; Interleukins; Male; Mean; Middle Aged; Mortality; Nosocomial infections; Oxygenation; Patients; Peptides, Cyclic; Prophylaxis; Proteins; Pulmonary and Respiratory Medicine; Respiratory function; Safety; SARS-CoV-2; Sciences de la santé humaine; Severe acute respiratory syndrome coronavirus 2; Statistical analysis; Systemic inflammation; Testing; Treatment Outcome; Ventilators; zilucoplan; Belgium; COVID-19; Complement system; Complement 5; Systemic inflammation
• ISSN: 1465-993X; 1465-9921; 1465-993X
• DOI: 10.1186/s12931-022-02126-2

The efficacy and safety of complement inhibition in COVID-19 patients is unclear. A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO /FiO  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. 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 PaO /FiO  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. 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 (PaO /FiO ) 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.