Confirmatory platelet-activating factor receptor antagonist trial in patients with severe Gram-negative bacterial sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial

Objective: To determine the efficacy and safety of using natural platelet-a ctivating factor receptor antagonist (PAFra), BN 52021, to treat patients w ith severe Gram-negative bacterial sepsis. Design: A prospective, randomized, double blind, placebo-controlled, multic enter clinical trial. Setting: Fifty-nine academic medical center intensive care units in Europe. Patients: Six hundred nine patients with severe sepsis, suspected to be rel ated to Gram-negative bacterial infection, who received PAFra or placebo. Interventions: Patients were randomized to receive either a dose of PAFra ( 120 mg iv) every 12 hrs over a 4-day period or placebo over a 4-day period. Measurements and Main Results: The patients were well matched at study entr y for severity of illness and for risk factors known to influence the outco me of sepsis, Among all randomized patients, the 28-day, all-cause mortalit y rate was 49% (152/308) in the placebo group, and 47% (140/300) in the PAF ra group (p = .50). When analyzed on the basis of the previously defined ta rget population, the 28-day, all cause mortality rate was 50% (115/232) in the placebo group and 44% (94/212) in the PAFra group, yielding a 12% reduc tion in mortality rate (p = .29), In patients with documented infection inv olving other organisms, there was no difference be tween treated and placeb o groups. When the outcomes of organ dysfunctions were examined in the over all population and in the documented Gram negative bacterial infection popu lation, the number of patients who resolved hepatic dysfunction tended to b e higher in the treated group than in the placebo group (p = .06). The numb er of adverse events reported were not different between the two groups. Conclusions: A 4-day administration of the studied PAFra (BN 52021) failed to demonstrate a statistically significant reduction in the mortality rate of patients with severe sepsis suspected to be related to Gram-negative bac terial infection. If PAFra treatment has any therapeutic activity in severe Gram negative bacterial sepsis, the incremental benefits are small and wil l be difficult to demonstrate in a patient population as defined by this cl inical trial.