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

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To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-lra) in the treatment of patients with sepsis syndrome.


Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant ILlra.


Twelve academic medical center intensive care units in the United States.


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.


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.


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)

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