TREATMENT OF SEPTIC SHOCK WITH THE TUMOR-NECROSIS-FACTOR RECEPTOR-FC FUSION PROTEIN

Background, A recombinant, soluble fusion protein that is a dimer of a n extracellular portion of the human tumor necrosis factor (TNF) recep tor and the Fc portion of IgG1 (TNFR:Fc) binds and neutralizes TNF-alp ha and prevents death in animal models of bacteremia and endotoxemia. Methods. To evaluate the safety and efficacy of TNFR:Fc in the treatme nt of septic shock, we conducted a randomized, double-blind, placebo-c ontrolled, multicenter trial. A total of 141 patients were randomly as signed to receive either placebo or a single intravenous infusion of o ne of three doses of TNFR:Fc (0.15, 0.45, or 1.5 mg per kilogram of bo dy weight). The primary end point was mortality from all causes at 28 days. Results. There were 10 deaths among the 33 patients in the place bo group (30 percent mortality), 9 deaths among the 30 patients receiv ing the low dose of TNFR:Fc (30 percent mortality), 14 deaths among th e 29 receiving the middle dose (48 percent mortality), and 26 deaths a mong 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 rece iving the higher doses of TNFR:Fc. Conclusions. In patients with septi c shock, treatment with the TNFR:Fc fusion protein does not reduce mor tality, and higher doses appear to be associated with increased mortal ity. (C) 1996, Massachusetts Medical Society.