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.
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.


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


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


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


METHODS
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.


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.
Panacek
Edward A
EA
Department of Medicine, University of California-Davis Medical Center, Sacramento, CA, USA.
Marshall
John C
JC
Albertson
Timothy E
TE
Johnson
David H
DH
Johnson
Steven
S
MacArthur
Rodger D
RD
Miller
Mark
M
Barchuk
William T
WT
Fischkoff
Steven
S
Kaul
Martin
M
Teoh
Leah
L
Van Meter
Lori
L
Daum
Lothar
L
Lemeshow
Stanley
S
Hicklin
Gregory
G
Doig
Christopher
C
D018806:APACHE; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D002170:Canada / Q000453:epidemiology; D002423:Cause of Death; D003422:Critical Care / Q000379:methods; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000097:blood*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000382:microbiology / Q000517:prevention & control; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012449:Safety; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D016019:Survival Analysis; D016896:Treatment Outcome; D048069:Tumor Necrosis Factors / Q000097:blood; D014481:United States / Q000453:epidemiology
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D048069:Tumor Necrosis Factors; C427683:afelimomab