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-Francois 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
Critical Care Medicine.
29(3):503-510, March 2001.
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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.
(C) 2001 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins