A second large controlled clinical study of E5, a... : Critical Care Medicine (original) (raw)

Feature Article

A second large controlled clinical study of E5, a monoclonal antibody to endotoxin

Results of a prospective, multicenter, randomized, controlled trial

Bone, Roger C. MD FCCM; Balk, Robert A. MD FCCM; Fein, Alan M. MD FCCM; Perl, Trish M. MD; Wenzel, Richard P. MD; Reines, H. David MD FCCM; Quenzer, Ronald W. MD; Iberti, Thomas J. MD FCCM*; Macintyre, Neil MD; Schein, Roland M. H. MD FCCM

**The E5 Sepsis Study Group; From Rush-Presbyterian-St. Luke's Medical Center (Drs. Bone and Balk), Chicago, IL; Winthrop University Hospital (Dr. Fein), Mineola, NY; the University of Iowa College of Medicine and Iowa City VA Medical Center (Drs. Perl and Wenzel), Iowa City, IA; the Medical College of Virginia (Dr. Reines), Richmond, VA; the University of New Mexico (Dr. Quenzer), Albuquerque, NM; Mount Sinai Medical Center (Dr. Iberti*), New York, NY; Duke University Medical Center (Dr. MacIntyre), Durham, NC; and the University of Miami VA Medical Center, Jackson Memorial Hospital (Dr. Schein), Miami, FL.

This study was supported by Xoma Corporation and Pfizer Inc.

*Deceased.

**Members of the E5 Sepsis Study Group were: Roger C. Bone, MD; Robert Balk, MD; Gordon Trenholme, MD; Alan M. Fein, MD; Michael Niederman, MD; Donald Chalfin, MD; Trish M. Perl, MD, MSc; Richard P. Wenzel, MD, MSc; Peter Jebson, MD; H. David Reines, MD; Ronald Quenzer, MD; Thomas J. Iberti, MD*; Amy Abalos, RN; John Oropello, MD; Neil MacIntyre, MD; Patricia Empson, RN; Stephanie Caminitii, MD; Roland Schein, MD; Richard Greenman, MD; Frank Booth, MD; Joseph Plouffe, MD; Janie Russell, RN; George Gianakopoulos, MD; Paul Iannini, MD; Robert Hindes, MD; Karen Coblens, MD; Richard Kohler, MD; Michael Martin, MD; Gordon Bernard, MD; John Edwards, MD; Mark Crislip, MD; Scott Filler, MD; Stanley A. Nasraway, MD; Pamela K. Sigel, RN; Frank D. Sottile, MD; David H. Martin, MD; Bennett P. deBoisblanc, MD; P.H. Chandrasekar, MD; William A. Broughton, MD; Robert M. Middleton, MD; Allan F. Seibert, MD; George Emmanuel, MD; Thiam H. Lie, MD; C. Lynn V. Anderson, MD; George A. Pankey, MD; Paula Anderson, MD; Keith Olsen, PharmD; Gerardo S. San Pedro, MD; Donald Graham, MD; Jeffrey Grossman, MD; Philip B. Wels, MD; Jerome Schentag, PharmD; Mary C. Birmingham, PharmD; Brian McGrath, MD; Carmelita Tuazon, MD; Kathleen Conry, RN; Erlaine Bello, MD; Jack McCue, MD; A. Gray Ellrodt, MD; Susan Stein, MD; Mary Riedinger; Herman Chmel, MD; John Toney, MD; Bienvenido Yangco, MD; Eric Rackow, MD; Mark E. Astiz, MD; Charles Carpati, MD; Richard Jacobs, MD; James Holcroft, MD; Margaret Bagley, BS; Mary J. Vassar, RN; Jonathan Gottlieb, MD; Janice Kubis, RN; Henry Chambers, MD; Janice Liebler, MD; Arthur Brown, MD; Robert McCaffree, MD; Nancy Wedel, MD (Xoma); John Hannigan, MS (Xoma); Betty J. Nelson, MA (Xoma); Elizabeth A. Saria, MD (Xoma); Heather Jones (Xoma); Samuel Ackerman, MD (Xoma); Patrick Scannon, MD (Xoma); and C. Douglas Webb, PhD (Pfizer).

Address requests for reprints to: Roger C. Bone, MD, The Medical College of Ohio, 3000 Arlington Avenue, P.O. Box 10008, Toledo, OH 10008.

Abstract

Objective

To evaluate the safety and efficacy of E5, a murine, monoclonal 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 Affairs Medical Centers, and community hospitals.

Patients

847 patients were randomized into this study. Enrolled patients met criteria for three conditions: a) known or suspected Gram-negative infection; b) clinical evidence of sepsis; and c) signs of end-organ dysfunction. Patients with refractory shock were excluded from the study.

Interventions

Two doses of E5 (2 mg/kg/day by intravenous infusion 24 hrs apart), or placebo that was identical in appearance were administered. In addition, all patients received standard supportive therapy and broad-spectrum antibiotics.

Measurements and Main Results

The primary end point was mortality over 30 days. Secondary outcome measures included the resolution and prevention of organ failure in the same two populations. Additionally, the safety of E5 was evaluated. There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo (n = 530; p = .21). In addition, E5 did not improve survival for patients with Gram-negative sepsis and organ failure (n = 139; p = .3). However, a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received 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, regardless 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 dysfunction (p = .050). Hypersensitivity reactions attributable to E5 occurred in 2.6% of patients. An asymptomatic antibody response occurred in 44% of the E5-treated patients and in 12% of the patients who received placebo.

Conclusions

In this study, E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure. However, E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis. This benefit extended to those patients with suspected Gram-negative etiology. This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results. In addition, E5 resulted in the prevention of adult respiratory distress syndrome and central nervous system organ failure. However, more studies are needed to determine if this result can be extended to organ failure in general. E5 is safe as a treatment for patients with Gram-negative sepsis.

(Crit Care Med 1995; 23:994-1006)