Opal S M, Fisher C J, Dhainaut J F, Vincent J L, Brase R, Lowry S F, Sadoff J C, Slotman G J, Levy H, Balk R A, Shelly M P, Pribble J P, LaBrecque J F, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M
Department of Medicine, Brown University and Memorial Hospital of Rhode Island, Providence 02912, USA.
Crit Care Med. 1997 Jul;25(7):1115-24. doi: 10.1097/00003246-199707000-00010.
To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis.
Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis.
Ninety-one academic medical center intensive care units in North America and Europe.
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.
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.
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.
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.
确定重组人白细胞介素-1受体拮抗剂（rhIL-1ra）治疗严重脓毒症患者的疗效和安全性。
前瞻性、随机、双盲、安慰剂对照、多中心试验，并进行计划中的中期期中分析。
北美和欧洲的91个学术医疗中心重症监护病房。
严重脓毒症或脓毒性休克患者（n = 696），除接受rhIL-1ra或安慰剂治疗外，还接受脓毒症的标准支持治疗和抗菌治疗。
患者随机接受静脉推注rhIL-1ra（100 mg）或安慰剂（溶媒），随后连续72小时静脉输注rhIL-1ra（2.0 mg/kg/小时）或安慰剂。
中期分析发现不太可能达到主要疗效终点后，该研究提前终止。rhIL-1ra治疗组的28天全因死亡率为33.1%（116/350），而安慰剂组的死亡率为36.4%（126/346），死亡率降低了9%（p = 0.3）。研究入组时患者匹配良好；入组时，52.9%的安慰剂治疗患者处于休克状态，而50.9%的rhIL-1ra治疗患者处于休克状态（p = 0.3）。根据感染部位、感染微生物、菌血症的存在、休克、器官功能障碍或研究入组时预测的死亡风险进行分析时，各治疗组之间的死亡率无显著差异。本研究中，rhIL-1ra治疗未导致不良反应或微生物二重感染数量增加。
在这项多中心临床试验中，与标准治疗相比，连续72小时静脉输注rhIL-1ra未能显示出死亡率有统计学意义的降低。如果rhIL-1ra治疗在严重脓毒症中有任何治疗活性，其额外益处很小，且在本临床试验定义的患者群体中难以证明。
