Background. A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human tumor necrosis factor (TNF) receptor and the Fc portion of IgG1 (TNFR:Fc) binds and neutralizes TNF-α and prevents death in animal models of bacteremia and endotoxemia. Methods. To evaluate the safety and efficacy of TNFR:Fc in the treatment of septic shock, we conducted a randomized, double-blind, placebo-controlled, multicenter trial. A total of 141 patients were randomly assigned to receive either placebo or a single intravenous infusion of one of three doses of TNFR:Fc (0.15, 0.45, or 1.5 mg per kilogram of body weight). The primary end point was mortality from all causes at 28 days. Results. There were 10 deaths among the 33 patients in the placebo group (30 percent mortality), 9 deaths among the 30 patients receiving the low dose of TNFR:Fc (30 percent mortality), 14 deaths among the 29 receiving the middle dose (48 percent mortality), and 26 deaths among the 49 receiving the high dose (53 percent mortality) (P=0.02 for the dose- response relation). Baseline differences in the severity of illness did not account for the increased mortality in the groups receiving the higher doses of TNFR:Fc. Conclusions. In patients with septic shock, treatment with the TNFR:Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality.
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