title: Influence of severity of illness on the effects of eritoran tetrasodium (E5564) and on other therapies for severe sepsis.
abstract: Disease severity varies widely in patients with severe sepsis. Eritoran tetrasodium (E5564), a TLR4 antagonist, blocks the binding of endotoxin and is being evaluated as a novel therapy for severe sepsis. This analysis aimed to assess the efficacy of eritoran based on severity of illness and similar effects in other recent sepsis trials. Prospective covariates from a randomized, double-blind, placebo-controlled, phase 2 trial were analyzed for treatment interaction measured by 28-day mortality. Five statistical interaction methodologies were used. The modified intent-to-treat population (n = 292), all-cause 28-day mortality was as follows: placebo, 33.3% (32/96); eritoran 45 mg/105 mg, 29.6% (58/196). Logistic regression analysis identified Acute Physiology and Chronic Health Evaluation II scores, predicted-risk-of-mortality scores, IL-6, age, sex, race, and eritoran use as associated with survival. Significant treatment interactions were observed (eritoran vs. placebo) for baseline covariates: Acute Physiology and Chronic Health Evaluation II (P = 0.035), predicted-risk-of-mortality scores (P = 0.008), number of organ failures (P = 0.079), international normalized ratio (P = 0.05), and acute physiology score (P = 0.039). I analysis showed that 38% of the total eritoran treatment variance was explained by the severity-of-illness heterogeneity rather than by chance. No interactions observed with other variables. Consistent with the finding in this eritoran trial, other sepsis trials (IL-1 receptor antagonist, TNFsr-p55, antithrombin, drotrecogin alfa-activated) also demonstrated significant treatment by severity interaction. Potential survival benefits of eritoran in severe sepsis patients were associated with high severity of illness. These findings were used to design a phase 3 trial. Similar treatment by severity-of-illness interaction was found in most recent sepsis trials.
authors.affiliation: University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 68198,USA. akalil@unmc.edu
authors.forename: Andre C
authors.initials: AC
authors.lastname: Kalil
authors.forename: Steven P
authors.initials: SP
authors.lastname: LaRosa
authors.forename: Jagadish
authors.initials: J
authors.lastname: Gogate
authors.forename: Melvyn
authors.initials: M
authors.lastname: Lynn
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
mesh_terms: D004187:Disaccharides / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D013403:Sugar Phosphates / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D004187:Disaccharides; D015850:Interleukin-6; D013403:Sugar Phosphates; C512420:eritoran