title: Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.
abstract: OBJECTIVE
  To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome.
  
  
  METHODS
  Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra.
  
  
  METHODS
  Twelve academic medical center intensive care units in the United States.
  
  
  METHODS
  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 IL-1ra or placebo.
  
  
  METHODS
  Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality.
  
  
  RESULTS
  A dose-dependent, 28-day survival benefit was associated with IL-1ra 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-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra 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-1ra 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-1ra 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-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated.
  
  
  CONCLUSIONS
  This initial evaluation suggests that human recombinant IL-1ra 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.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, OH 44195.
authors.forename: C J
authors.initials: CJ
authors.lastname: Fisher
authors.forename: G J
authors.initials: GJ
authors.lastname: Slotman
authors.forename: S M
authors.initials: SM
authors.lastname: Opal
authors.forename: J P
authors.initials: JP
authors.lastname: Pribble
authors.forename: R C
authors.initials: RC
authors.lastname: Bone
authors.forename: G
authors.initials: G
authors.lastname: Emmanuel
authors.forename: D
authors.initials: D
authors.lastname: Ng
authors.forename: D C
authors.initials: DC
authors.lastname: Bloedow
authors.forename: M A
authors.initials: MA
authors.lastname: Catalano
mesh_terms: D000328:Adult; D000368:Aged; D001424:Bacterial Infections / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D012795:Sialoglycoproteins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins