CARING FOR THE CRITICALLY ILL PATIENT Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis The ACCESS Randomized Trial

Steven M. Opal, MD Pierre-Francois Laterre, MD Bruno Francois, MD Steven P. LaRosa, MD Derek C. Angus, MD, MPH Jean-Paul Mira, MD, PhD Xavier Wittebole, MD Thierry Dugernier, MD Dominique Perrotin, MD Mark Tidswell, MD Luis Jauregui, MD Kenneth Krell, MD Jan Pachl, MD Takeshi Takahashi, MD Claus Peckelsen, MD Edward Cordasco, DO Chia-Sheng Chang, MD Sandra Oeyen, MD Naoki Aikawa, MD, PhD Tatsuya Maruyama, MD, PhD Roland Schein, MD Andre C. Kalil, MD, MPH Marc Van Nuffelen, MD Melvyn Lynn, PhD Daniel P. Rossignol, PhD Jogadish Gogate, PhD Mary B. Roberts, MS Janice L. Wheeler, BS, RN Jean-Louis Vincent, MD, PhD for the ACCESS Study Group SEVERE 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, 1.1; 95% CI, 5.3 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; 0.851.13). 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. Trial Registration clinicaltrials.gov Identifier: NCT00334828 JAMA. 2013;309(11):1154-1162 www.jama.com