Phase 2 trial of eritoran tetrasodium ( E 5564 ) , a Toll-like receptor 4 antagonist , in patients with severe sepsis *

Endotoxin (lipopolysaccharide) is the major constituent of the outer membrane of both Gram-negative pathogenic bacteria and normal enteric Gramnegative flora. Endotoxin, when administered intravenously to healthy volunteers, stimulates proinflammatory and thrombotic responses observed in severe sepsis patients (1, 2). Patients with severe sepsis initiated by Gram-negative organisms, Gram-positive organisms, and fungi have high plasma levels of endotoxin (3). Release of endogenous endotoxin from the gut and liver due to splanchnic hypoperfusion is thought to explain this phenomenon (3). Sepsis patients with high levels of plasma endotoxin activity have an increased mortality rate (1). Although the immune response initiated by endotoxin may be protective and act as an early warning sign of microbial invasion, the adverse effects of widespread inflammation, coagulopathy, and vascular compromise seen in severe sepsis are often detrimental. Endotoxin is transferred from the bacterial cell wall by a human lipopolysaccharide binding protein to membrane-bound CD-14 found on the cell surface of myeloid cells of the innate immune system. A signaling complex forms, consisting of endotoxin, an adaptor protein (MD-2), and a transmembrane protein known as Toll-like receptor 4 (TLR4) (4–7). The lipid A portion of endotoxin binds to a complex of TLR4 and MD-2 via hydrophobic and electrostatic forces (8, 9). Subsequent dimerization of these complexes of endotoxin bound to TLR4-MD-2 leads to intracellular signaling, production of nuclear factorB, and ultimately proinflammatory cytokines. In the past, therapies designed to interfere with endotoxin did not improve outcome (10–21). However, new therapeutic targets are suggested by recent discoveries that reveal how endotoxin Objectives: Endotoxin is a potent stimulus of proinflammatory response and systemic coagulation in patients with severe sepsis. Endotoxin is a component of Gram-negative bacteria that triggers an innate immune response through Toll-like receptor 4 signaling pathways in myeloid cells. We evaluated safety and tolerability of two dose regimens of eritoran tetrasodium (E5564), a synthetic Toll-like receptor 4 antagonist, and explored whether it decreases 28-day mortality rate in subjects with severe sepsis. Design: Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial. Setting: Adult intensive care units in the United States and Canada. Patients: Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80%. Interventions: Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days. Measurements and Main Results: Prevalence of adverse events was similar among subjects treated with 45 mg or 105 mg of eritoran tetrasodium or with placebo. For modified intent-to-treat subjects, 28-day all-cause mortality rates were 26.6% (eritoran tetrasodium 105 mg), 32.0% (eritoran tetrasodium 45 mg), and 33.3% in the placebo group. Mortality rate in the eritoran tetrasodium 105-mg group was not significantly different from placebo (p .335). In prespecified subgroups, subjects at highest risk of mortality by APACHE II score quartile had a trend toward lower mortality rate in the eritoran tetrasodium 105-mg group (33.3% vs. 56.3% placebo group, p .105). A trend toward a higher mortality rate was observed in subjects in the lowest APACHE II score quartile for the eritoran 105-mg group (12.0% vs. 0.0% placebo group, p .083). Conclusions: Eritoran tetrasodium treatment appears well tolerated. The observed trend toward a lower mortality rate at the 105-mg dose, in subjects with severe sepsis and high predicted risk of mortality, should be further investigated. (Crit Care Med 2010; 38:72–83)