Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.
OBJECTIVE
To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis.


METHODS
Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis.


METHODS
Ninety-one academic medical center intensive care units in North America and Europe.


METHODS
Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo.


METHODS
Patients were randomized to receive either rhIL-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.


RESULTS
The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock 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 differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. 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 demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment 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.
Opal
S M
SM
Department of Medicine, Brown University and Memorial Hospital of Rhode Island, Providence 02912, USA.
Fisher
C J
CJ
Dhainaut
J F
JF
Vincent
J L
JL
Brase
R
R
Lowry
S F
SF
Sadoff
J C
JC
Slotman
G J
GJ
Levy
H
H
Balk
R A
RA
Shelly
M P
MP
Pribble
J P
JP
LaBrecque
J F
JF
Lookabaugh
J
J
Donovan
H
H
Dubin
H
H
Baughman
R
R
Norman
J
J
DeMaria
E
E
Matzel
K
K
Abraham
E
E
Seneff
M
M
D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D008875:Middle Aged; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy*; D012772:Shock, Septic / Q000188:drug therapy; D012795:Sialoglycoproteins / Q000627:therapeutic use*; D016019:Survival Analysis
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins