CONFIRMATORY INTERLEUKIN-1 RECEPTOR ANTAGONIST TRIAL IN SEVERE SEPSIS- A PHASE-III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER TRIAL

Objective: To determine the therapeutic efficacy and safety of recombi nant human interleukin-l receptor antagonist (rhIL-1ra) in the treatme nt of patients with severe sepsis. Design: Prospective, randomized, do uble-blind, placebo-controlled, multicenter trial with a planned, mids tudy, interim analysis, Setting: Ninety-one academic medical center in tensive care units in North America and Europe, Patients: Patients wit h severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. Interventions: Patients were randomized to receive either rh IL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg /hr) or placebo. Measurements and Main Results: The study was terminat ed after an interim analysis found that it was unlikely that the prima ry efficacy end points would be met, The 28-day, all-cause mortality r ate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mor tality rate in the placebo group was 36.4% (126/346), yielding a 9% re duction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in sh ock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly di ffer between treatment groups when analyzed on the basis of site of in fection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entr y, No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study. Conclusions: A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstra te a statistically significant reduction in mortality when compared wi th standard therapy in this multicenter clinical trial. It rhIL-1ra tr eatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.