Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: The ACCESS randomized trial

Steven M. Opal, Pierre Francois Laterre, Bruno Francois, Steven P. LaRosa, Derek C. Angus, Jean Paul Mira, Xavier Wittebole, Thierry Dugernier, Dominique Perrotin, Mark Tidswell, Luis Jauregui, Kenneth Krell, Jan Pachl, Takeshi Takahashi Claus Peckelsen, Edward Cordasco, Chia Sheng Chang, Sandra Oeyen, Naoki Aikawa, Tatsuya Maruyama, Roland ScheinAndre C Kalil, Marc Van Nuffelen, Melvyn Lynn, Daniel P. Rossignol, Jogadish Gogate, Mary B. Roberts, Janice L. Wheeler, Jean Louis Vincent

Research output: Contribution to journalArticle

399 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)1154-1162
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume309
Issue number11
DOIs
StatePublished - Mar 20 2013

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Sepsis
Mortality
Placebos
Lipopolysaccharides
Lipid A
Toll-Like Receptor 4
Kaplan-Meier Estimate
eritoran
Gram-Negative Bacteria
Coinfection
Intensive Care Units
Outcome Assessment (Health Care)
Membranes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis : The ACCESS randomized trial. / Opal, Steven M.; Laterre, Pierre Francois; Francois, Bruno; LaRosa, Steven P.; Angus, Derek C.; Mira, Jean Paul; Wittebole, Xavier; Dugernier, Thierry; Perrotin, Dominique; Tidswell, Mark; Jauregui, Luis; Krell, Kenneth; Pachl, Jan; Peckelsen, Takeshi Takahashi Claus; Cordasco, Edward; Chang, Chia Sheng; Oeyen, Sandra; Aikawa, Naoki; Maruyama, Tatsuya; Schein, Roland; Kalil, Andre C; Van Nuffelen, Marc; Lynn, Melvyn; Rossignol, Daniel P.; Gogate, Jogadish; Roberts, Mary B.; Wheeler, Janice L.; Vincent, Jean Louis.

In: JAMA - Journal of the American Medical Association, Vol. 309, No. 11, 20.03.2013, p. 1154-1162.

Research output: Contribution to journalArticle

Opal, SM, Laterre, PF, Francois, B, LaRosa, SP, Angus, DC, Mira, JP, Wittebole, X, Dugernier, T, Perrotin, D, Tidswell, M, Jauregui, L, Krell, K, Pachl, J, Peckelsen, TTC, Cordasco, E, Chang, CS, Oeyen, S, Aikawa, N, Maruyama, T, Schein, R, Kalil, AC, Van Nuffelen, M, Lynn, M, Rossignol, DP, Gogate, J, Roberts, MB, Wheeler, JL & Vincent, JL 2013, 'Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: The ACCESS randomized trial', JAMA - Journal of the American Medical Association, vol. 309, no. 11, pp. 1154-1162. https://doi.org/10.1001/jama.2013.2194
Opal, Steven M. ; Laterre, Pierre Francois ; Francois, Bruno ; LaRosa, Steven P. ; Angus, Derek C. ; Mira, Jean Paul ; Wittebole, Xavier ; Dugernier, Thierry ; Perrotin, Dominique ; Tidswell, Mark ; Jauregui, Luis ; Krell, Kenneth ; Pachl, Jan ; Peckelsen, Takeshi Takahashi Claus ; Cordasco, Edward ; Chang, Chia Sheng ; Oeyen, Sandra ; Aikawa, Naoki ; Maruyama, Tatsuya ; Schein, Roland ; Kalil, Andre C ; Van Nuffelen, Marc ; Lynn, Melvyn ; Rossignol, Daniel P. ; Gogate, Jogadish ; Roberts, Mary B. ; Wheeler, Janice L. ; Vincent, Jean Louis. / Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis : The ACCESS randomized trial. In: JAMA - Journal of the American Medical Association. 2013 ; Vol. 309, No. 11. pp. 1154-1162.
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abstract = "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",
author = "Opal, {Steven M.} and Laterre, {Pierre Francois} and Bruno Francois and LaRosa, {Steven P.} and Angus, {Derek C.} and Mira, {Jean Paul} and Xavier Wittebole and Thierry Dugernier and Dominique Perrotin and Mark Tidswell and Luis Jauregui and Kenneth Krell and Jan Pachl and Peckelsen, {Takeshi Takahashi Claus} and Edward Cordasco and Chang, {Chia Sheng} and Sandra Oeyen and Naoki Aikawa and Tatsuya Maruyama and Roland Schein and Kalil, {Andre C} and {Van Nuffelen}, Marc and Melvyn Lynn and Rossignol, {Daniel P.} and Jogadish Gogate and Roberts, {Mary B.} and Wheeler, {Janice L.} and Vincent, {Jean Louis}",
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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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