A 2ND LARGE CONTROLLED CLINICAL-STUDY OF E5, A MONOCLONAL-ANTIBODY TOENDOTOXIN - RESULTS OF A PROSPECTIVE, MULTICENTER, RANDOMIZED, CONTROLLED TRIAL

Objective: To evaluate the safety and efficacy of E5, a murine, monocl onal antibody directed against endotoxin, in the treatment of patients with Gram-negative sepsis, Design: A multicenter, randomized, double- blind, placebo-controlled trial. Setting: Fifty-three hospitals across the United States, including university medical centers, Veterans Aff airs Medical Centers, and community hospitals. Patients: 847 patients were randomized into this study. Enrolled patients met criteria for th ree conditions: a) known or suspected Gramnegative infection; b) clini cal evidence of sepsis; and c) signs of end-organ dysfunction. Patient s with refractory shock were excluded from the study. Interventions: T wo doses of E5 (2 mg/kg/day by intravenous infusion 24 hrs apart), or pIacebo that was identical in appearance were administered. In additio n, all patients received standard supportive therapy and broad-spectru m antibiotics. Measurements and Main Results: The primary end point wa s mortality over 30 days. Secondary outcome measures included the reso lution and prevention of organ failure in the same two populations. Ad ditionally, the safety of E5 was evaluated, There was no significant i mprovement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received place bo (n = 530;p = .21). In addition, E5 did not improve survival for pat ients with Gram-negative sepsis and organ failure (n = 139; p = .3). H owever, a significantly greater percentage of patients with Gram-negat ive sepsis experienced resolution of major organ failure if they recei ved E5, compared with those patients who received placebo (n = 139; 48 % E5 vs. 25% placebo; p = .005). This result extended to all patients who entered the study with one or more major organ failures, regardles s of the etiology of the infection (n = 225; 41% E5 vs. 27% placebo; p = .024). E5 also provided protection against the development of some organ failures, but significant prevention was only observed for adult respiratory distress syndrome (p = .007) and central nervous system d ysfunction (p = .050). Hypersensitivity reactions attributable to E5 o ccurred in 2.6% of patients. An asymptomatic antibody response occurre d in 44% of the E5-treated patients and in 12% of the patients who rec eived placebo. Conclusions: In this study, E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those p atients also had organ failure. However, E5 did result in greater reso lution of organ failure in patients with Gram-negative sepsis. This be nefit extended to those patients with suspected Gram-negative etiology . This finding is important because patients with suspected Gram-negat ive sepsis and organ failure can be identified without waiting for cul ture results. In addition, E5 resulted in the prevention of adult resp iratory distress syndrome and central nervous system organ failure. Ho wever, more studies are needed to determine if this result can be exte nded to organ failure in general. E5 is safe as a treatment for patien ts with Gram-negative sepsis.