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.
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.


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


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


METHODS
There were 498 patients enrolled in this clinical trial.


METHODS
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.


METHODS
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.
Abraham
E
E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Glauser
M P
MP
Butler
T
T
Garbino
J
J
Gelmont
D
D
Laterre
P F
PF
Kudsk
K
K
Bruining
H A
HA
Otto
C
C
Tobin
E
E
Zwingelstein
C
C
Lesslauer
W
W
Leighton
A
A
D018806:APACHE; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000627:therapeutic use*; D007142:Immunoglobulin gamma-Chains; D015850:Interleukin-6 / Q000097:blood; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D012772:Shock, Septic / Q000188:drug therapy / Q000503:physiopathology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C099374:Ro 45-2081