p55 Tumor Necrosis Factor Receptor Fusion Protein in the Treatment of Patients With Severe Sepsis and Septic Shock. A Randomized Controlled Multicenter Trial. Ro 45-2081 Study Group

JAMA. 1997 May 21;277(19):1531-8.

Abstract

Objective: To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and IgG1 sequences (referred to as p55-IgG), in the treatment of patients with severe sepsis or septic shock.

Design: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.

Setting: Forty-four community and university-affiliated hospitals in the United States and Europe.

Patients: There were 498 patients enrolled in this clinical trial.

Intervention: Patients prospectively stratified within each site into refractory shock or severe sepsis groups were randomized to receive a single infusion of p55-IgG, 0.083 mg/kg, 0.042 mg/kg, or 0.008 mg/kg, or placebo. Patients received standard aggressive medical/surgical care during the 28-day postinfusion period.

Outcome measure: Twenty-eight-day all-cause mortality.

Results: The distribution of variables describing demographics, organ system dysfunction or failure, infecting microorganisms, predicted mortality, plasma interleukin 6 levels, and plasma tumor necrosis factor alpha (TNF-alpha) levels were similar among patients in the p55-IgG and placebo treatment arms. A planned interim analysis was performed after 201 patients were enrolled. Because a statistically nonsignificant trend toward increased mortality was present in patients who had received 0.008 mg/kg, this treatment arm was discontinued, and the study continued with 3 arms. Among all infused patients, there was a statistically nonsignificant trend toward reduced 28-day all-cause mortality in those who received p55-IgG compared with placebo-treated patients (5% reduction, 0.042 mg/kg vs placebo; 15% reduction, 0.083 mg/kg vs placebo; P=.30). However, in patients with severe sepsis and early septic shock (n=247), therapy with p55-IgG, 0.083 mg/kg, was associated with a 36% reduction in 28-day all-cause mortality compared with placebo (P=.07): 20 (23%) of 87 patients died among those treated with p55-IgG, 0.083 mg/kg; 30 (37%) of 82 among those treated with p55-IgG, 0.042 mg/kg; and 28 (36%) of 78 in the placebo group. A prospectively planned logistic regression analysis to assess treatment effect on 28-day all-cause mortality by means of predicted mortality and serum interleukin 6 levels as continuous covariates demonstrated a significant improvement in outcome for the patients with severe sepsis treated with p55-IgG, 0.083 mg/kg, compared with placebo (P=.01). Serious adverse events, including death and the development of new organ system dysfunction, were reported in 65% of patients infused with placebo, with no increased frequency (56%) present in the 2 p55-IgG treatment arms. There were no reports of immediate hypersensitivity reactions caused by p55-IgG.

Conclusions: In this dose-finding study, there was no decrease in mortality between placebo and p55-IgG in all infused patients. In the prospectively defined population of patients with severe sepsis who received p55-IgG, 0.083 mg/kg, there was a trend toward reduced mortality at day 28 that became significant when predicted mortality and plasma interleukin 6 levels were included in a logistic regression analysis.

Publication types

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

MeSH terms

  • APACHE
  • Adult
  • Aged
  • Double-Blind Method
  • Female
  • Humans
  • Immunoglobulin Heavy Chains* / therapeutic use*
  • Immunoglobulin gamma-Chains
  • Interleukin-6 / blood
  • Logistic Models
  • Male
  • Middle Aged
  • Multiple Organ Failure
  • Prospective Studies
  • Receptors, Tumor Necrosis Factor*
  • Recombinant Fusion Proteins / therapeutic use
  • Sepsis / drug therapy*
  • Sepsis / physiopathology
  • Shock, Septic / drug therapy
  • Shock, Septic / physiopathology
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / metabolism

Substances

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