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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Dubinsky, S., Hamadeh, A., Imburgia, C. E., McKnite, A. M., Hunt, J. P., Wong, K., Rice, C., Rower, J. E., Watt, K., & Edginton, A. N. (2024) · Clinical Pharmacokinetics · doi:10.1007/s40262-024-01424-w · Cited by 6
Endothelial cell responses in sepsis are attenuated by targeting truncated procalcitonin
Brabenec, L., Hellenthal, K. E. M., Kintrup, S., Cyran, L., Burkard, P., Nottebaum, A. F., Schughart, K., Wagner, S., Arnold, R. R., Rauschenberger, V., et al. (2026) · Nature Communications · doi:10.1038/s41467-025-68199-x · Cited by 5
Substantial heterogeneity of inflammatory cytokine production and its inhibition by a triple cocktail of toll-like receptor blockers in early sepsis
Buys, W., Bick, A., Madel, R. J., Westendorf, A. M., Buer, J., Herbstreit, F., Kirschning, C. J., & Peters, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1277033 · Cited by 5
shRNAs targeting high-mobility group box-1 inhibit E-selectin expression via homeobox A9 in human umbilical vein endothelial cells
Zhang, X., Luan, Z., & Ma, X. (2013) · Molecular Medicine Reports · doi:10.3892/mmr.2013.1314 · Cited by 5
Immune-modulating interventions in critically ill septic patients: pharmacological options
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Anti-ovine interleukin-1 β monoclonal antibody immunotherapy in an ovine model of Gram-negative septic shock
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“Although animal studies suggest a beneficial effect (8–12), clinical trials involving rhIL-1ra in patients with severe sepsis and septic shock have not reported comparable efficacy (13, 14).”
Background
The need for disruptive innovation in acute kidney injury
Doi, K. (2020) · Clinical and Experimental Nephrology · doi:10.1007/s10157-020-01920-w · Cited by 5
“However, these treatments failed to show any protection from human sepsis [50, 51].”
Background
Innate Immunity in Critical Care
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Is There NO Treatment For Severe Sepsis?
Bredan, A., & Cauwels, A. (2008) · Libyan Journal of Medicine · doi:10.3402/ljm.v3i1.4748 · Cited by 5

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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