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CRITICAL CARE AND TRAUMA

A Phase II, Double-Blind, Placebo-Controlled, Ascending-Dose Study of Eritoran (E5564), a Lipid A Antagonist, in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass

Elliott Bennett-Guerrero, MD^*, Hilary P. Grocott, MD^*, Jerrold H. Levy, MD, Kevin A. Stierer, MD, Charles W. Hogue, MD, Albert T. Cheung, MD^||, Mark F. Newman, MD^*, Alison A. Carter, PhD^¶, Daniel P. Rossignol, PhD^¶, and Charles D. Collard, MD^#

From the *Department of Anesthesiology, Duke University Medical Center, Durham, NC (EBG, HPG, MFN); Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA (JHL); The Heart Institute at St. Joseph Medical Center, Towson, MD (KAS); Johns Hopkins University Medical School, Baltimore, MD (CWH); ||Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA (ATC); ¶Eisai Medical Research, Ridgefield Park, NJ (AAC, DPR); #Division of Cardiovascular Anesthesiology, Baylor College of Medicine, Texas Heart® Institute, St. Luke's Episcopal Hospital, Houston, TX (CDC).

BACKGROUND: Lipid A, the toxic moiety of endotoxin, is linked to multiple complications after cardiac surgery, including fever, vasodilation, and pulmonary and renal dysfunction. The lipid A antagonist eritoran (or E5564) prevents endotoxin-induced systemic inflammation in animals and humans. In this study we assessed the safety of eritoran administration in patients undergoing cardiac surgery and obtained preliminary efficacy data for the prophylaxis of endotoxin-mediated surgical complications.

METHODS: A double-blind, randomized, ascending-dose, placebo-controlled study was conducted at nine hospitals. Patients undergoing coronary artery bypass graft and/or cardiac valvular surgery with cardiopulmonary bypass were enrolled. Patients received a 4-h infusion of placebo (n = 78) vs 2 mg (n = 24), 12 mg (n = 26), or 28 mg (n = 24) of eritoran initiated approximately 1 h before cardiopulmonary bypass.

RESULTS: No significant safety concerns were identified with continuous safety monitoring, and enrollment continued to the highest prespecified dose (28 mg). No statistically significant differences were observed in most variables related to systemic inflammation or organ dysfunction/injury.

CONCLUSIONS: This Phase II safety study suggests that the administration of the novel lipid A antagonist, eritoran, is not associated with overt toxicity in cardiac surgical patients. Blocking lipid A with eritoran does not appear to confer any clear benefit to elective cardiac surgical patients.

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