1. 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
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Gottlieb RL, Clement M, Cook P, Deveikis A, Foong KS, Robinson P, Slim J, Spak CW, Buelens A, Callewaert K, De Meyer S, Mo WL, Verbrugge I, Van Wesenbeeck L, Zhuang Y, Chien JW, Opsomer M, and Van Landuyt E
- Subjects
- Humans, Male, Double-Blind Method, Female, Middle Aged, Aged, Adult, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Severity of Illness Index, Interleukin-6 antagonists & inhibitors, Interleukin-6 blood, Antibodies, Monoclonal, Humanized therapeutic use, COVID-19 Drug Treatment, COVID-19 immunology, COVID-19 mortality, SARS-CoV-2 immunology
- 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., Competing Interests: Declaration of Competing Interest Robert L. Gottlieb served as coordinating national principal investigator and as a consultant for this trial. He reports service on scientific advisory boards for AbbVie, AstraZeneca, Eli Lilly, Gilead Sciences, GSK, and Roche, and consulting via his institution for Kinevant Sciences, also related to COVID-19. Service on speakers bureau with Alnylam Pharmaceuticals and Pfizer, consultancy to Alnylam, research support from CareDx, and a gift-in-kind to his institution from Gilead Sciences to support NCT03383419 are also reported, all outside the submitted work. Meredith Clement has received research support (grants to institution) from Gilead Sciences and ViiV Healthcare, has served on advisory boards for Roche Diagnostics Corporation and ViiV Healthcare. Paul Cook is a PI for the following: NIH, Janssen, Gilead, ViiV, Seres, and Finch. Audra Deveikis, Kap Sum Foong, Philip Robinson, and Cedric W. Spak have nothing to declare. Jihad Slim serves on speakers bureaus for Gilead, ViiV, Merck, Janssen, AbbVie, and Thera. Katleen Callewaert is an employee of Janssen Pharmaceutica NV. Annemie Buelens, Sandra De Meyer, Liesbeth Van Wesenbeeck, and Erika Van Landuyt are employees of Janssen Pharmaceutica NV and own stock in Johnson & Johnson. Wai Ling Mo is an employee of Janssen-Cilag Limited. Inge Verbrugge and Magda Opsomer were employees of Janssen Pharmaceutica NV at the time of the study. Yanli Zhuang and Jacon Chien were employees of Janssen Research & Development, LLC at the time of the study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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