Eritoran does not decrease mortality during severe sepsis [The ACCESS Trial]

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1. Previous phase I and phase II trials in severe sepsis patients show the lipopolysaccharide antagonist eritoran decreases mortality.  

2. In this phase III trial, eritoran is not shown to decrease 28-day or 1-year mortality in severe sepsis and septic shock patients.

Sepsis is the result of abnormal systemic inflammation, of which lipopolysaccharide (LPS) i.e. endotoxin is a major stimulator. The current standard of care for severe sepsis involves fluid resuscitation and antimicrobial therapy. Eritoran, a synthetic analog of lipid A, acts as a specific antagonist of LPS action. This randomized, double blind, placebo-controlled, phase III trial indicates eritoran does not decrease all cause mortality at 28 days or 1 year in severe sepsis and septic shock patients.

Published today, the authors of this study demonstrate LPS inhibitory agents such as eritoran may not be as promising as previously assumed. Limitations of this study include the heterogeneity in the administration of other concurrent supportive therapies contributing to survival. Also, eritoran was administered on average over 9 hours after signs of organ dysfunction so it is possible that an earlier eritoran administration may provide a better response. Regardless, given the lack of treatment options and its high mortality rate, future research should continue the investigation of targeted therapies in treating severe sepsis.

Click to read the study, published today in JAMA

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Image: PD

1. Previous phase I and phase II trials in severe sepsis patients show the lipopolysaccharide antagonist eritoran decreases mortality.  

2. In this phase III trial, eritoran is not shown to decrease 28-day or 1-year mortality in severe sepsis and septic shock patients. 

This [randomized, double blind, placebo-controlled, phase III] study: This trial evaluated 1,961 patients in severe sepsis or septic shock between June 2006 and September 2010. Patients were enrolled from North America, Europe, Asia, and Australia. 1304 patients received eritoran and 657 received a placebo. The primary treatment outcome of 28-day mortality was seen in 28.1% of patients in the eritoran group and 26.9% in the placebo group (p = 0.59) All-cause mortality at 1 year showed no differences in mortality (p = 0.79). Type of infection, e.g. gram-negative or gram-positive, did not have a significant effect on the treatment outcome.

In sum: Sepsis is the result of abnormal systemic inflammation, of which lipopolysaccharide (LPS) i.e. endotoxin is a major stimulator. The current standard of care for severe sepsis involves fluid resuscitation and antimicrobial therapy. Eritoran, a synthetic analog of lipid A, acts as a specific antagonist of LPS action. This randomized, double blind, placebo-controlled, phase III trial indicates eritoran does not decrease all cause mortality at 28 days or 1 year in severe sepsis and septic shock patients.

Published today, the authors of this study demonstrate LPS inhibitory agents such as eritoran may not be as promising as previously assumed. Limitations of this study include the heterogeneity in the administration of other concurrent supportive therapies contributing to survival. Also, eritoran was administered on average over 9 hours after signs of organ dysfunction so it is possible that an earlier eritoran administration may provide a better response. Regardless, given the lack of treatment options and its high mortality rate, future research should continue the investigation of targeted therapies in treating severe sepsis.

Click to read the study, published today in JAMA

By John Prendergass and Rif Rahman

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