Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels.

Abstract

OBJECTIVE:

To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6.

DESIGN:

Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial.

SETTING:

One hundred fifty-seven intensive care units in the United States and Canada.

PATIENTS:

Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels.

INTERVENTIONS:

Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result.

MEASUREMENTS AND MAIN RESULTS:

In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo.

CONCLUSIONS:

Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.

• Authors: Edward A Panacek, John C Marshall, Timothy E Albertson, David H Johnson, Steven Johnson, Rodger D MacArthur, Mark Miller, William T Barchuk, Steven Fischkoff, Martin Kaul, Leah Teoh, Lori Van Meter, Lothar Daum, Stanley Lemeshow, Gregory Hicklin, Christopher Doig, Monoclonal Anti-TNF: a Randomized Controlled Sepsis Study Investigators
• Journal: Critical care medicine (Crit Care Med) Vol. 32 Issue 11 Pg. 2173-82 (Nov 2004) ISSN: 0090-3493 [Print] United States
• PMID: 15640628 (Publication Type: Clinical Trial, Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Interleukin-6
• Tumor Necrosis Factors
• afelimomab

Topics

• APACHE
• Antibodies, Monoclonal (immunology, pharmacology, therapeutic use)
• Canada (epidemiology)
• Cause of Death
• Critical Care (methods)
• Double-Blind Method
• Female
• Humans
• Infusions, Intravenous
• Interleukin-6 (blood)
• Logistic Models
• Male
• Middle Aged
• Multiple Organ Failure (microbiology, prevention & control)
• Proportional Hazards Models
• Prospective Studies
• Risk Factors
• Safety
• Sepsis (drug therapy, immunology, metabolism, mortality)
• Survival Analysis
• Treatment Outcome
• Tumor Necrosis Factors (blood)
• United States (epidemiology)