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.

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.

• Authors: E Abraham, M P Glauser, T Butler, J Garbino, D Gelmont, P F Laterre, K Kudsk, H A Bruining, C Otto, E Tobin, C Zwingelstein, W Lesslauer, A Leighton
• Journal: JAMA (JAMA) Vol. 277 Issue 19 Pg. 1531-8 (May 21 1997) ISSN: 0098-7484 [Print] United States
• PMID: 9153367 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, physiopathology)
• Shock, Septic (drug therapy, physiopathology)
• Survival Analysis
• Tumor Necrosis Factor-alpha (metabolism)