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.

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.

• Authors: E Abraham, P F Laterre, J Garbino, S Pingleton, T Butler, T Dugernier, B Margolis, K Kudsk, W Zimmerli, P Anderson, M Reynaert, D Lew, W Lesslauer, S Passe, P Cooper, A Burdeska, M Modi, A Leighton, M Salgo, P Van der Auwera, Lenercept Study Group
• Journal: Critical care medicine (Crit Care Med) Vol. 29 Issue 3 Pg. 503-10 (Mar 2001) ISSN: 0090-3493 [Print] United States
• PMID: 11373411 (Publication Type: Clinical Trial, Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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