TY - JOUR
T1 - Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis
T2 - The ACCESS randomized trial
AU - Opal, Steven M.
AU - Laterre, Pierre Francois
AU - Francois, Bruno
AU - LaRosa, Steven P.
AU - Angus, Derek C.
AU - Mira, Jean Paul
AU - Wittebole, Xavier
AU - Dugernier, Thierry
AU - Perrotin, Dominique
AU - Tidswell, Mark
AU - Jauregui, Luis
AU - Krell, Kenneth
AU - Pachl, Jan
AU - Peckelsen, Takeshi Takahashi Claus
AU - Cordasco, Edward
AU - Chang, Chia Sheng
AU - Oeyen, Sandra
AU - Aikawa, Naoki
AU - Maruyama, Tatsuya
AU - Schein, Roland
AU - Kalil, Andre C.
AU - Van Nuffelen, Marc
AU - Lynn, Melvyn
AU - Rossignol, Daniel P.
AU - Gogate, Jogadish
AU - Roberts, Mary B.
AU - Wheeler, Janice L.
AU - Vincent, Jean Louis
PY - 2013/3/20
Y1 - 2013/3/20
N2 - 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; 0.85-1.13). 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. Trial Registration: clinicaltrials.gov Identifier: NCT00334828
AB - 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; 0.85-1.13). 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. Trial Registration: clinicaltrials.gov Identifier: NCT00334828
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U2 - 10.1001/jama.2013.2194
DO - 10.1001/jama.2013.2194
M3 - Article
C2 - 23512062
AN - SCOPUS:84875124740
SN - 0098-7484
VL - 309
SP - 1154
EP - 1162
JO - JAMA
JF - JAMA
IS - 11
ER -