Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: A randomized, open-label, placebocontrolled multicenter trial

Objectives: To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-lra) in the treatment of patients with sepsis syndrome. Design: Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant ILlra. Setting: Twelve academic medical center intensive care units in the United States. Patients: Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of ILlra or placebo. Interventions: Patients received an intravenous loading dose of either human recombinant IL-lra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of BL-lra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality. Measurements and Main Results: A dosedependent, 28-day survival benefit was associated with IL-lra treatment (p= .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-lra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-lra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-lra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-lra in patients with septic shock at study entry (n = 65;p= .002) and in patients with Gram-negative infection (n = 45;p= .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of >100 pg/ mL at study entry demonstrated a dose-related survival benefit with IL-lra treatment (p= .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-lra treatment dose (p= .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p= .038). A renal elimination mechanism for IL-lra was suggested by the positive correlation between IL-lra plasma clearance and estimated creatinine clearance (p= .001; r2 = .51). Human recombinant IL-lra was well tolerated. Conclusions: This initial evaluation suggests that human recombinant IL-lra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings. (Crit Care Med 1994; 22:12-21)