Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis

Abstract

EVERE SEPSIS, A SYNDROME OF acute infection complicated by organ dysfunction, is caused by a dysregulated systemic inflammatory response. Sepsis can progress to systemic hypotension (septic shock), Importance Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. Objective To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. Design, Setting, and Participants We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. Interventions Patients with severe sepsis (n=1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n=1304 and n=657 patients, respectively. Main Outcome Measures The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. Results Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P=.59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, Ϫ1.1; 95% CI, Ϫ5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P=.79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. Conclusions and Relevance Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality.

Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5

“…This suggests that at this time, general or specific interventions can be implemented to avert SIRS. Although targeted therapies such as specific TLR4 inhibitors did not alter outcomes in patients with severe sepsis, 26,27 this may be due to the fact that patients were already critically unwell and at advanced stages of SIRS when given a TLR4 antagonist. We hypothesise that treating patients with TLR4 inhibitors or agents that impair signalling through TLR5 or NF-kB may provide therapeutic benefit before the clinical manifestations of SIRS or sepsis become apparent.…”

Mechanisms of Pain in Sickle Cell Disease

“…"dditionally, TLR4 inhibitors such as T"K-242 and eritoran showed promising responses in animal studies for severe sepsis, but failed to show any eicacy in reducing 28-day mortality in phase III clinical trials [114, 11 ]. Though these molecules are still being evaluated for other pathologic conditions such as obesity in type 2 diabetic subjects [116], no clinical trials have been undertaken using these compounds to ameliorate chronic pain conditions.…”

“…However, in a separate study acute doses of aprepitant were shown to signiicantly increase the magnitude of mu agonist signs and symptoms in response to oxycodone [113]. Considering the role of SP in sickle pain and neurogenic inlammation, NK-1 receptor antagonists require further examination in preclinical models of SCD as co-drugs."dditionally, TLR4 inhibitors such as T"K-242 and eritoran showed promising responses in animal studies for severe sepsis, but failed to show any eicacy in reducing 28-day mortality in phase III clinical trials [114, 11 ]. Though these molecules are still being evaluated for other pathologic conditions such as obesity in type 2 diabetic subjects [116], no clinical trials have been undertaken using these compounds to ameliorate chronic pain conditions.…”

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

“…A previous study indicated that, among 235 patients who succumbed to sepsis or septic shock-associated mortality, those exhibiting cardiovascular system failure accounted for 35.3% (5). As the inflammatory reaction is important in sepsis, previous studies have attempted to use monoclonal antibodies raised against specific inflammatory factor receptors to inhibit the inflammatory reaction (2,6). However, sepsis results from interactions among various inflammatory factors and, as a result, treatments based on monoclonal antibodies lose their therapeutic potential due to the targeting of a single receptor (2).…”