Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis.

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.