NYMC Faculty Publications
The IL-6 Hypothesis in COVID-19: A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Free IL-6 Sequestration by the Monoclonal Antibody Sirukumab in Severe and Critical COVID-19
Author Type(s)
Faculty
DOI
10.1016/j.jinf.2024.106241
Journal Title
The Journal of Infection
First Page
106241
Document Type
Article
Publication Date
10-1-2024
Department
Medicine
Abstract
BACKGROUND: Upregulation of IL-6 has been associated with worse prognosis in COVID-19 patients. Impact on IL-6 signalling has mostly been limited to clinical outcomes in IL-6 receptor antagonist trials. METHODS: We performed a phase 2, randomised, double-blind, placebo-controlled trial (NCT04380961) of US-based hospitalised adults (<85 years) with laboratory-confirmed SARS-CoV-2 infection and severe (low levels of supplemental oxygen) or critical disease (high levels of oxygen supplementation). Patients received sirukumab 5 mg/kg or placebo single dose IV on Day 1 plus standard of care. The primary endpoint was time to sustained clinical improvement up to Day 28 based on an ordinal scale. Secondary endpoints included clinical improvement, all-cause mortality, and safety. Following an interim analysis, the protocol was amended to only recruit patients with critical COVID-19. FINDINGS: From May 2020 to March 2021, 209 patients were randomised; 112 had critical disease (72 sirukumab, 40 placebo) at baseline. Median time to sustained clinical improvement in critical patients was 17 and 23 days in the sirukumab and placebo groups (HR, 1∙1; 95% CI, 0∙66-1∙88; p > 0∙05). At Day 28, 59∙4% versus 55∙0% of patients achieved clinical improvement with sirukumab versus placebo and rates of all-cause mortality were 24∙6% versus 30∙0%, respectively. Rates of grade ≥3 adverse events were comparable between the sirukumab and placebo groups (25∙9% vs 32∙9%; all patients). INTERPRETATION: In critical COVID-19 patients who received sirukumab, there was no statistically significant difference in time to sustained clinical improvement versus placebo despite objective sequestration of circulating IL-6, questioning IL-6 as a key therapeutic target in COVID-19.
Recommended Citation
Gottlieb, R. L., Clement, M., Cook, P., Deveikis, A., Foong, K. S., Robinson, P., Slim, J., Spak, C. W., Buelens, A., Callewaert, K., De Meyer, S., Mo, W. L., Verbrugge, I., Van Wesenbeeck, L., Zhuang, Y., Chien, J. W., Opsomer, M., & Van Landuyt, E. (2024). The IL-6 Hypothesis in COVID-19: A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Free IL-6 Sequestration by the Monoclonal Antibody Sirukumab in Severe and Critical COVID-19. The Journal of Infection, 89 (4), 106241. https://doi.org/10.1016/j.jinf.2024.106241
