The failure of Eisai's eritoran to improve survival in a Phase III trial in patients with severe sepsis (JAMA 309, 1154-1162; 2013) adds to the long list of ineffective experimental treatments for such patients. It also suggests that a complete rethink is needed in the strategies to evaluate novel agents for sepsis.

The trial tested the hypothesis that administering the synthetic Toll-like receptor 4 (TLR4) antagonist eritoran to block the interaction of lipopolysaccharide (LPS)--a component of the cell wall of Gram-negative bacteria and a potent inducer of immune responses--with its receptor MD2-TLR4 could improve survival in patients with severe sepsis, in whom there is a systemic uncontrolled inflammatory response to infection. However, among the 1,961 patients evaluated, who were randomized and treated with either eritoran or placebo within 12 hours of onset of first organ dysfunction, there was no reduction in 28-day mortality in the group receiving eritoran.