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 Edward Abraham, MD; Pierre-François Laterre, MD; Jorge Garbino, MD; Susan Pingleton, MD; Thomas Butler, MD; Thierry Dugernier, MD; Benjamin Margolis, MD; Kenneth Kudsk, MD; Werner Zimmerli, MD; Paula Anderson, MD; Marc Reynaert, MD; Daniel Lew, MD; Werner Lesslauer, MD, PRPN; Sharon Passe; Philip Cooper, PhD; Alex Burdeska, PhD; Marlene Modi, PhD; Anton Leighton, MD; Miklos Salgo, MD; Philippe Van der Auwera, MD; for the Lenercept Study Group S epsis is characterized by signs of infection and a systemic inflam- matory response syndrome (1). Much of the ensuing pathology is postulated to be brought about by host- derived mediators rather than by the direct toxic effects of microbial products (1). Ex- cess tumor necrosis factor (TNF) is thought to contribute to the overwhelming sys- temic inflammatory response in sepsis leading to organ dysfunction and death (re- viewed in references 2, 3). Various strategies have been devel- oped with the common aim of reducing or neutralizing the excess TNF response associated with overwhelming infection. One such approach has been to take ad- vantage of the ability of soluble TNF re- ceptors to neutralize TNF. There are at least two cell membrane-associated TNF receptors, termed the p55 and p75 TNF receptors (4, 5). The extracellular por- tions of TNF receptors may be shed by proteolytic cleavage; these so-called solu- ble TNF receptors bind free TNF in the circulation and prevent it from binding to and, hence, activating target cells. Lenercept is a recombinant protein that is constructed by fusing human sol- uble p55 TNF receptors (extracellular do- main) to an immunoglobulin G1 heavy chain fragment and is expressed as a dimeric molecule in Chinese hamster ovary cells (4, 5). Preclinical studies dem- onstrated that lenercept binds to and neutralizes TNF (6) and prevents death in a variety of animal models of sepsis and septic shock (7). Based on these findings, clinical trials in the treatment of sepsis and septic shock have been carried out (8, 9). Lenercept binds TNF with a higher 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 Cen- ter, Box C272, 4200 E. Ninth Avenue, Denver, CO 80262. Copyright © 2001 by Lippincott Williams & Wilkins 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-immuno- globulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. Design: Multicenter, double-blind, phase III, placebo-con- trolled, 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 mea- sure 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 physiol- ogy score II-predicted mortality, profiles of clinical site of infec- tion and microbiological documentation, number of dysfunction- ing 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  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 mor- tality (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. (Crit Care Med 2001; 29:503–510) KEY WORDS: severe sepsis; early septic shock; tumor necrosis factor; tumor necrosis factor p55 receptor; clinical trial; human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 fusion protein; lenercept 503 Crit Care Med 2001 Vol. 29, No. 3