TY - JOUR
T1 - p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock
T2 - A randomized controlled multicenter trial
AU - Abraham, Edward
AU - Glauser, Michel P.
AU - Butler, Thomas
AU - Garbino, Jorge
AU - Gelmont, David
AU - Laterre, Pierre F.
AU - Kudsk, Kenneth
AU - Bruining, Hajo A.
AU - Otto, Charles
AU - Tobin, Ellis
AU - Zwingelstein, Christian
AU - Lesslauer, Werner
AU - Leighton, Anton
N1 - Funding Information:
Manuscript received Apr. 25, 2006; revised Oct. 26, 2006. This research was supported as a Brain Neuroinformatics research program by the Korean Ministry of Commerce, Industry, and Energy. Jae-Sung Kong (phone: + 82 53 940 8631, email: kongjs@ee.knu.ac.kr), Sang-Heon Kim (email: myobfdc@ee.knu.ac.kr), Dong-Kyu Sung (email: dksung@ee.knu.ac.kr), and Jang-Kyoo Shin (phone: + 82 53 950 5531, email: jkshin@ee.knu.ac.kr) are with Department of Electronics, Kyungpook National University, Daegu, Korea.
PY - 1997/5/21
Y1 - 1997/5/21
N2 - 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 α (TNF-α) 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.
AB - 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 α (TNF-α) 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.
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U2 - 10.1001/jama.277.19.1531
DO - 10.1001/jama.277.19.1531
M3 - Article
C2 - 9153367
AN - SCOPUS:8244235133
SN - 0002-9955
VL - 277
SP - 1531
EP - 1538
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 19
ER -