title: Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00334828.
authors.affiliation: Alpert Medical School of Brown University, Providence, Rhode Island, USA. Steven_Opal@brown.edu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
authors.forename: Pierre-Francois
authors.initials: PF
authors.lastname: Laterre
authors.forename: Bruno
authors.initials: B
authors.lastname: Francois
authors.forename: Steven P
authors.initials: SP
authors.lastname: LaRosa
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
authors.forename: Xavier
authors.initials: X
authors.lastname: Wittebole
authors.forename: Thierry
authors.initials: T
authors.lastname: Dugernier
authors.forename: Dominique
authors.initials: D
authors.lastname: Perrotin
authors.forename: Mark
authors.initials: M
authors.lastname: Tidswell
authors.forename: Luis
authors.initials: L
authors.lastname: Jauregui
authors.forename: Kenneth
authors.initials: K
authors.lastname: Krell
authors.forename: Jan
authors.initials: J
authors.lastname: Pachl
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Claus
authors.initials: C
authors.lastname: Peckelsen
authors.forename: Edward
authors.initials: E
authors.lastname: Cordasco
authors.forename: Chia-Sheng
authors.initials: CS
authors.lastname: Chang
authors.forename: Sandra
authors.initials: S
authors.lastname: Oeyen
authors.forename: Naoki
authors.initials: N
authors.lastname: Aikawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Maruyama
authors.forename: Roland
authors.initials: R
authors.lastname: Schein
authors.forename: Andre C
authors.initials: AC
authors.lastname: Kalil
authors.forename: Marc
authors.initials: M
authors.lastname: Van Nuffelen
authors.forename: Melvyn
authors.initials: M
authors.lastname: Lynn
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Rossignol
authors.forename: Jogadish
authors.initials: J
authors.lastname: Gogate
authors.forename: Mary B
authors.initials: MB
authors.lastname: Roberts
authors.forename: Janice L
authors.initials: JL
authors.lastname: Wheeler
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004187:Disaccharides / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D063305:Organ Dysfunction Scores; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality*; D012720:Severity of Illness Index; D013403:Sugar Phosphates / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D004187:Disaccharides; D013403:Sugar Phosphates; D051197:Toll-Like Receptor 4; C512420:eritoran