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. 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

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia : a randomized trial.

RATIONALE: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS: A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity

Efficacy and Safety of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) in Severe Sepsis: A Randomized Controlled Trial

Context: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. Objectives: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. Design and Setting: A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. Patients: The primary efficacy population consisted of 1754 patients (≥18 years) with severe sepsis and a high INR (≥1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n=880) or placebo (arginine citrate buffer, n=874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo. Main Outcome Measure: All-cause 28-day mortality. Results: Overall mortality at 28 days in the tifacogin-treated group (n=880) vs the placebo group (n=874) for high INR was 34.2% vs 33.9%, respectively (P=.88, Pearson χ2 test; P=.75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P=.006, Pearson χ2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n=83) vs placebo (22.9%; n=118) (P=.051, Pearson χ2 test; P=.03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). Conclusions: Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR