Severe sepsis, a generalized inflammatory host ^ response to infection that results in coagulopathy, diffuse endovascular injury, and death, occurs in approximately 750,000 patients in the United States each year. Patients with severe sepsis often experience failures of multiple organ systems, and recent estimates suggest that between 36% and 60% of all cases are fatal. Despite technical advances in critical care, including new dialysis techniques and methods of mechanical ventilation, sophisticated nutritional support, and antimicrobial therapies, mortality from severe sepsis and its sequelae had remained largely unchanged until the recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.
In November 2001, drotrecogin alfa (activated) [Xigris; Eli Lilly and Company; Indianapolis, IN] was approved in the United States for the treatment of adult patients with severe sepsis who have a high risk of death. This approval followed the completion of a phase 3 clinical trial (1,690 patients) and a supporting US phase 2 trial (131 patients). The PROWESS trial was a double-blind, multicenter study that randomized adult patients with severe sepsis to receive a 96-h infusion of drotrecogin alfa (activated), 24 ^g/kg/h, or placebo in addition to usual care. The primary end point was 28-day all-cause mortality, and treatment with drotrecogin alfa (activated) was associated with a 19.4% relative risk reduction in death compared with placebo (p = 0.005). fully
The Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) trial was a global, single-arm, phase-3B clinical trial of drotrecogin alfa (activated) that was designed to gather additional mortality and safety data among patients with severe sepsis in a monitored clinical trial setting. For administrative and data management purposes, this study was conducted as three separate and independent studies, and the study conducted in the United States (including Puerto Rico) concluded in November 2001. While the global ENHANCE study enrolled adult and pediatric patients, this report contains data only from the adult patients enrolled in the ENHANCE US study. Efficacy and safety data from the ENHANCE US study were compared with those from two completed, double-blind, placebo-controlled clinical trials that used similarly defined patient cohorts from the United States.