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Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients

Abraham, E.
Laterre, P. F.
Pingleton, S.
Butler, T.
Dugernier, T.
Margolis, B.
Kudsk, K.
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Published in Critical Care Medicine. 2001, vol. 29, no. 3, p. 503-510
Abstract OBJECTIVE: Phase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DESIGN: Multicenter, double-blind, phase III, placebo-controlled, randomized study. SETTING: A total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PATIENTS: A total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. INTERVENTION: After randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17-96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor alpha concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of.141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. CONCLUSION: Lenercept had no significant effect on mortality in the study population.
Keywords ApacheAdolescentAdultAgedAged, 80 and overCanada/epidemiologyDouble-Blind MethodDrug MonitoringEurope/epidemiologyFemaleHumansImmunoglobulin G/immunology/pharmacology/ therapeutic useImmunoglobulin Heavy ChainsImmunoglobulin gamma-ChainsInterleukin-6/bloodMaleMiddle AgedMultiple Organ Failure/microbiologyReceptors, Tumor Necrosis Factor/immunology/ therapeutic useRecombinant Fusion Proteins/immunology/pharmacology/ therapeutic useSepsis/blood/complications/ drug therapy/immunology/mortalitySeverity of Illness IndexShock, Septic/blood/complications/ drug therapy/immunology/mortalityUnited States/epidemiology
PMID: 11373411
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ABRAHAM, E. et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. In: Critical Care Medicine, 2001, vol. 29, n° 3, p. 503-510. doi: 10.1097/00003246-200103000-00006 https://archive-ouverte.unige.ch/unige:7066

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Deposited on : 2010-06-21

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