E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis - A randomized controlled trial

Context Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not. Objective To assess the efficacy and safety of E5 in the treatment of patie nts with severe gram-negative sepsis. Design A multicenter, double-blind, randomized, placebo-controlled trial co nducted at 136 US medical centers from April 1993 to April 1997, designed w ith 90% power to detect a 25% relative risk reduction, incorporating 2 plan ned interim analyses. Setting Intensive care units at university medical centers, Veterans Affair s medical centers, and community hospitals. Patients Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection. Intervention Patients were assigned to receive 2 doses of either E5, a muri ne monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552), Main Outcome Measures The primary end point was mortality at day 14; second ary end points were mortality at day 28, adverse event rates, and 14-day an d 28-day mortality in the subgroup without shock at presentation. Results The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infectio n confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56), Patients presenting wi thout shock had a slightly lower mortality when treated with E5 but the dif ference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse e vent rates between E5 and placebo. Conclusions Despite adequate sample size and high enrollment of patients wi th confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before fur ther large-scale studies of patients with sepsis are conducted.