Assessment of the safety of recombinant tissue factor pathway inhibitor in XXXX with severe @entity295 : a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

@entity1 @entity650 @entity295 @entity137 @entity6463 @entity548 @entity281
OBJECTIVE: To identify a safe and potentially effective recombinant tissue factor pathway inhibitor ( @entity6463 ) dose for further clinical evaluation in @entity1 with severe @entity295 . DESIGN: Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. SETTING: Thirty-eight intensive care units in the United States and Europe. @entity1 : Two hundred and ten subjects with severe @entity295 who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Subjects received a continuous intravenous infusion of placebo or @entity6463 at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). MEASUREMENTS AND MAIN RESULTS: There were no significant imbalances in demographics, severity of illness, or source of @entity281 in @entity1 randomized to placebo or either dose of @entity6463 . A 20% relative reduction in 28-day all-cause mortality was observed when all @entity6463 -treated @entity1 were compared with all placebo @entity1 . An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the @entity6463 -treated @entity1 . Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p =.037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p =.026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial @entity6463 effect. There was no increase in mortality in subjects treated with either dose of @entity6463 compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all @entity6463 -treated @entity1 compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and @entity137 ( @entity137 ) was similar among the treatment groups, with a slight increase in @entity137 and @entity137 involving @entity548 in the 0.05 mg/kg/hr @entity6463 group. The overall incidence of AEs involving @entity548 was 28% of @entity1 in the all placebo group and 23% of @entity1 in the all @entity6463 -treated group; a slight but statistically insignificant increase in incidence of @entity137 involving @entity548 was observed in the all @entity6463 group (9%) as compared with the all placebo group (6%; p =.39). CONCLUSIONS: Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all @entity6463 group compared with all placebo. This study demonstrates that @entity6463 doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe @entity295 @entity1 . Additionally, @entity6463 demonstrated bioactivity, as shown by reduction in TATc complexes and @entity650 levels. These findings warrant further evaluation of @entity6463 in an adequately powered, placebo controlled, randomized trial for the treatment of severe @entity295 .
