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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, Edward MD; Laterre, Pierre-François MD; Garbino, Jorge MD; Pingleton, Susan MD; Butler, Thomas MD; Dugernier, Thierry MD; Margolis, Benjamin MD; Kudsk, Kenneth MD; Zimmerli, Werner MD; Anderson, Paula MD; Reynaert, Marc MD; Lew, Daniel MD; Lesslauer, Werner MD, PRPN; Cooper, Sharon Passe; Philip PhD; Burdeska, Alex PhD; Modi, Marlene PhD; Leighton, Anton MD; Salgo, Miklos MD; Van der Auwera, Philippe MD for the Lenercept Study Group

Clinical Investigations

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 α 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.

Lenercept had no significant effect on mortality in the study population.

Lenercept is produced by Genentech, South San Francisco, CA.

Supported, in part, by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Address requests for reprints to: Edward Abraham, MD, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Box C272, 4200 E. Ninth Avenue, Denver, CO 80262.

© 2001 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins