April 3, 2013
Despite Preliminary Promise, Eritoran Doesn’t Reduce Sepsis Mortality Rate
Providence, RI—Despite potentially promising results in some preliminary studies, a large phase 3 clinical trial found that use of the drug eritoran had no significant effect on reducing all-cause 28-day mortality or 1-year mortality in patients with severe sepsis and septic shock.
Background in the article, published recently in the Journal of the American Medical Association, notes that “lipopolysaccharide (LPS) or endotoxin, the major component of the outer membrane of gram-negative bacteria, is a potent stimulator of the inflammatory response,” triggering inflammation in gram-negative sepsis. Eritoran, a synthetic analog of lipid A, is a potent and specific antagonist of LPS action, and appeared to produce lower mortality (although not statistically significant) in an earlier phase 2 trial.
Steven M. Opal, MD, of Brown University in Providence, RI, and colleagues conducted the phase 3 trial to determine the safety and effectiveness of eritoran in reducing mortality in patients with severe sepsis.
For the randomized, multinational trial, conducted in 197 intensive care units from June 2006 to September 2010,1,961 patients with severe sepsis 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) (1,304 patients) or placebo (657 patients).
With the final follow-up completed in September 2011, the study’s primary endpoint was 28-day all-cause mortality with secondary end points of all-cause mortality at 3, 6, and 12 months after treatment initiation.
Treatment with eritoran did not result in significant reductions in the primary study end point of 28-day mortality among randomized patients who received at least one dose. Researchers reported that 28.1% (366) of patients in the eritoran group died compared to 26.9% percent (177) of patients in the placebo group.
Nor was a significant difference noted in the secondary end point of 1-year all-cause mortality: 44.1% (290) patients in the eritoran group died versus 43.3% (565) in the placebo group.
“These findings are in contrast with several preclinical studies and in phase 1 clinical trials in which eritoran terminated lipopolysaccharide-associated molecular and clinical events when administered in adequate doses. Despite these promising early results, no evidence of significant benefit was observed with eritoran in this large phase 3 trial,” the authors write. “Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients.”
Adverse events were no greater in the eritoran group than in the placebo group, according to the industry-funded study.
|U.S. Pharmacist Social Connect