Cited by 794Sepsis Diagnosis and TreatmentInflammation biomarkers and pathwaysAntibiotics Pharmacokinetics and Efficacy

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Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of Patients With Sepsis Syndrome: Results From a Randomized, Double-blind, Placebo-Controlled Trial

Fisher, Charles J.·1994·JAMA

DOI 10.1001/jama.1994.03510470040032

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Abstract

Objective. —To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. Study Design. —Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. Population. —A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. Outcome Measure. —Twenty-eight—day all-cause mortality. Results. —There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n=893; generalized Wilcoxon statistic,P=.22) or among patients with shock at study entry (n=713; generalized Wilcoxon statistic,P=.23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n=563; linear dose-response,P=.009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n=580; linear dose-response,P=.005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n=411; linear dose-response,P=.002). Conclusions. —There was not a statistically significant increase in survivial time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater. (JAMA. 1994;271:1836-1843)

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Narain, S., Stefanov, D. G., Chau, A. S., Weber, A. G., Marder, G. S., Kaplan, B. M., Malhotra, P., Bloom, O., Liu, A., LESSER, M. L., et al. (2020) · SSRN Electronic Journal · doi:10.1101/2020.06.16.20126714 · Cited by 17
Innate immune response to peritoneal bacterial infection
Català, C., Andrés, M. V., Casadó‐Llombart, S., Leyton-Pereira, A., Carrillo‐Serradell, L., Isamat, M., & Lozano, F. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.04.014 · Cited by 13
Study of the role of tumor necrosis factor-α (–308 G/A) and interleukin-10 (–1082 G/A) polymorphisms as potential risk factors to acute kidney injury in patients with severe sepsis using high-resolution melting curve analysis
Hashad, D. I., Elsayed, E. T., Helmy, T. A., et al. (2016) · Renal Failure · doi:10.1080/0886022x.2016.1244081 · Cited by 13
“Therefore, several trials were done to inhibit TNF-a and IL-1b in order to prevent organ damage and improve survival, but anti-TNF-a failed to show any clinical significance.(18,19) Based on these findings, new concepts regarding the pathogenesis of organ damage in sepsis have been suggested.”
Method
Feasibility randomised multicentre, double-blind, double-dummy controlled trial of anakinra, an interleukin-1 receptor antagonist versus intramuscular methylprednisolone for acute gout attacks in patients with chronic kidney disease (ASGARD): protocol study
Balasubramaniam, G. S., Parker, T. C., Turner, D. A., et al. (2017) · BMJ Open · doi:10.1136/bmjopen-2017-017121 · Cited by 13
Targeting Endothelial Barrier Dysfunction Caused by Circulating Bacterial and Mitochondrial N-Formyl Peptides With Deformylase
Quinones, P. M., Komic, A., McCarthy, C. G., Webb, R. C., & Wenceslau, C. F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01270 · Cited by 13
“Additionally, use of a recombinant, non-glycosylated human IL-1 receptor antagonist also showed no improvement in patients with severe sepsis and septic shock (29, 30).”
Background
Re-Evaluating Biologic Pharmacotherapies That Target the Host Response during Sepsis
Tuttle, K., McDonald, M. D., & Anderson, E. J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236049 · Cited by 13
Interleukin 1 receptor antagonist (IL1RA) in acute leukaemia: IL1RA is both secreted spontaneously by myelogenous leukaemia blasts and is a part of the acute phase reaction in patients with chemotherapy‐ induced leucopenia
Bruserud, Ø., Aasen, I., Akselsen, P. E., Bergheim, J., Rasmussen, G., & Nesthus, I. (1996) · European Journal Of Haematology · doi:10.1111/j.1600-0609.1996.tb00495.x · Cited by 13
“In leukaemia patients in vivo modulation of the cytokine network may become a therapeutic approach for inhibition of potentially harmful proinflammatory effects or for enhancement of antileukaemic effects (1,4, 11-14), and the cytokines and their antagonists have then been suggested as possible targets for in vivo mod…”
Background
Prospectively validated prediction of physiologic variables and organ failure in septic patients: The Systemic Mediator Associated Response Test (SMART)
Slotman, G. J. (2002) · Critical Care Medicine · doi:10.1097/00003246-200205000-00014 · Cited by 13
Endogenous Mechanisms Regulating TNF and IL-1 during Sepsis
van der Poll, T., & Lowry, S. F. (1995) · Yearbook of intensive care and emergency medicine · doi:10.1007/978-3-642-79154-3_31 · Cited by 13
Inhibition of interleukin-1 type I receptor expression in human cell-lines by an antisense phosphorothioate oligodeoxynucleotide
Miraglia, L. J., Geiger, T. M., Bennett, C. F., et al. (1996) · International Journal of Immunopharmacology · doi:10.1016/0192-0561(96)84502-4 · Cited by 13
When Sleeping Beauty Turns Ugly
Warnholtz, A., Wendt, M., & Münzel, T. F. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000014220.78856.97 · Cited by 12

Authors: Fisher, C. J.
Corresponding author: Fisher, Charles J.
ORCID: Fisher, Charles J.
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 1994-06-15
Volume: 271
Issue: 23
Pages: 1836
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.1994.03510470040032
OpenAlex: W4322697531
Cited by: 790
References: 0
Citations by year: 2026: 11 · 2025: 23 · 2024: 18 · 2023: 28 · 2022: 15 · 2021: 18 · 2020: 32 · 2019: 23 · 2018: 24 · 2017: 22 · 2016: 19 · 2015: 18 · 2014: 30 · 2013: 20 · 2012: 22
FWCI: 37.99
Type: journal article
Language: en
Open access: closed
Locations: JAMA (publishedVersion)
Topics: Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Health Sciences › Medicine › Pharmacology (medical) › Antibiotics Pharmacokinetics and Efficacy
Keywords: sepsis, septic shock, survival, organ dysfunction, mortality risk, dose-response relationship, drug safety, cytokine inhibition

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Recombinant Human Interleukin 1 Receptor Antagonist in the Treatment of Patients With Sepsis Syndrome: Results From a Randomized, Double-blind, Placebo-Controlled Trial

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