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.
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.
Bennett-Guerrero
Elliott
E
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA. elliott.bennettguerrero@duke.edu
Grocott
Hilary P
HP
Levy
Jerrold H
JH
Stierer
Kevin A
KA
Hogue
Charles W
CW
Cheung
Albert T
AT
Newman
Mark F
MF
Carter
Alison A
AA
Rossignol
Daniel P
DP
Collard
Charles D
CD
D000368:Aged; D006348:Cardiac Surgical Procedures; D002315:Cardiopulmonary Bypass; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000097:blood; D008297:Male; D008875:Middle Aged; D011182:Postoperative Care; D011183:Postoperative Complications / Q000453:epidemiology / Q000517:prevention & control; D011446:Prospective Studies
C404742:E5564; D008050:Lipid A