Eritoran, a highly active and specific lipopolysaccharide inhibitor, failed to improve 1-month or 1-year mortality in an international phase III clinical trial of nearly 2,000 patients with severe sepsis, according to a report published March 19 in JAMA.
Eritoran had appeared very promising in preclinical, phase I, and phase II trials, blocking cytokine responses, terminating lipopolysaccharide-associated inflammatory events, and ultimately reducing patient mortality. "Despite these promising early results, no evidence of significant benefit was observed with eritoran in this large phase III trial," said Dr. Steven M. Opal of the division of infectious diseases at Memorial Hospital of Rhode Island, Pawtucket, and his associates.
"Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients," they noted.
Eritoran is a synthetic analog of lipid A and a potent, specific antagonist against lipopolysaccharide activity, which drives the inflammatory response. In this 5-year double-blind study conducted at 197 ICUs throughout North America, Europe, South American, Africa, Asia, and Australia, 1,984 patients with severe sepsis or septic shock were randomly assigned to receive either intravenous eritoran (1,322 subjects) or matching placebo (662 subjects) and followed at 1 month, 3 months, 6 months, and 1 year.
The pathogens that most commonly caused sepsis in this study were Escherichia coli (22%), Staphylococcus aureus (12%), and Streptococcus pneumoniae (11%). The lung was the site of infection in approximately half of the patients in each group.
The incidence of bloodstream infection was similar between the two groups, affecting 38% of the eritoran group and 40% of the placebo group.
Both groups of patients received comparable supportive care, appropriate antimicrobial therapy, and timely infection control.
The primary outcome measure was 28-day mortality in these patients who were at high risk of dying. This rate was not significantly different between the group that received active drug (28%) and the group that received placebo (27%). Similarly, all-cause mortality at 1 year was comparable between the two groups, at 44% and 43%, respectively, the investigators said (JAMA 2013;309:1154-62).
In several subgroup analyses, eritoran also showed no beneficial effect on patient mortality. The rates were similar regardless of baseline APACHE score, baseline SOFA score, the presence or absence of septic shock, the site of the primary infection, or whether the infection was gram-negative or gram-positive.
"Our results ... call into question the role of an endotoxin-blocking agent in halting the inflammatory progression and organ dysfunction once sepsis is already underway," Dr. Opal and his associates said.
This study was supported by Eisai, developer of eritoran. Dr. Opal and his associates reported ties to numerous industry sources.