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

Crit Care Med. 2001 Mar;29(3):503-10. doi: 10.1097/00003246-200103000-00006.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • APACHE
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Canada / epidemiology
  • Double-Blind Method
  • Drug Monitoring
  • Europe / epidemiology
  • Female
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G / pharmacology
  • Immunoglobulin G / therapeutic use*
  • Immunoglobulin Heavy Chains*
  • Immunoglobulin gamma-Chains
  • Interleukin-6 / blood
  • Male
  • Middle Aged
  • Multiple Organ Failure / microbiology
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology
  • Recombinant Fusion Proteins / therapeutic use*
  • Sepsis / blood
  • Sepsis / complications
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Sepsis / mortality
  • Severity of Illness Index
  • Shock, Septic / blood
  • Shock, Septic / complications
  • Shock, Septic / drug therapy*
  • Shock, Septic / immunology
  • Shock, Septic / mortality
  • United States / epidemiology

Substances

  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Immunoglobulin gamma-Chains
  • Interleukin-6
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • Ro 45-2081