A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis
A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis
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DOI：
10.1097/ccm.0b013e3181e7c5c9
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发表时间：
2010-08-01
影响因子：
8.8
通讯作者：
Cohen, Jon
中科院分区：
文献类型：
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作者：
Rice, Todd W.;Wheeler, Arthur P.;Cohen, Jon
目的：评价Toll样受体4介导的信号转导的小分子抑制剂TAK-242能否抑制细胞因子水平，提高严重脓毒症患者28天的全因死亡率。设计：随机、双盲、安慰剂对照试验。设置：全球93个重症监护病房。患者：274例严重脓毒症合并休克或呼吸衰竭患者。干预：患者被随机分配到30分钟的负荷剂量，然后96小时输注安慰剂，TAK-242 1.2 mg/kg/d，或TAK-242 2.4 mg/kg/天。测量和主要结果：主要药效学终点是血清白介素6水平相对于基线的变化，28天全因死亡率是主要临床终点。由于TAK-242在抑制血清白介素6水平方面缺乏作用，该试验被终止。共有274名受试者被随机分配和治疗。基线时的临床参数在三组中是平衡的。根据白介素6浓度曲线下的0到96.5小时的面积测量，Tak-242在任一剂量下都不抑制白介素6。具体地说，TAK-242 1.2和2.4 mg/kg/d组的效应曲线下面积分别增加了9%和26.9%，与安慰剂组没有统计学差异(p分别为0.63和0.15)。28天的死亡率在安慰剂组为24%，低剂量组为22%，高剂量组为17%(p=0.26，安慰剂组与高剂量组相比)。在同时患有休克和呼吸衰竭的患者中，观察到死亡率没有显著降低(安慰剂[n=51]，33%，与大剂量[n=52]，19%，p=.10)。用TAK-242治疗后，30.1%的患者高铁血红蛋白水平出现一过性的、剂量相关的升高。结论：TAK-242不能抑制脓毒症、休克或呼吸衰竭患者的细胞因子水平。TAK-242治疗导致血清高铁血红蛋白水平轻微升高，但其他方面耐受性良好。虽然每天2.4 mg/kg剂量的休克和呼吸衰竭患者的观察死亡率较低，但差异不显著。(Crit Care Med 2010；38：1685-1694)
Objective: To evaluate whether TAK-242, a small-molecule inhibitor of Toll-like receptor-4-mediated signaling, suppresses cytokine levels and improves 28-day all-cause mortality rates in patients with severe sepsis.Design: Randomized, double-blind, placebo-controlled trial.Setting: A total of 93 intensive care units worldwide.Patients: A total of 274 patients with severe sepsis and shock or respiratory failure.Interventions: Patients were randomly assigned to receive a 30-min loading dose followed by 96-hr infusions of placebo, TAK-242 1.2 mg/kg/day, or TAK-242 2.4 mg/kg/day.Measurements and Main Results: The primary pharmacodynamic end point was change in serum interleukin-6 levels relative to baseline, with 28-day all-cause mortality rate the primary clinical end point. The trial was terminated because of a lack of effect of TAK-242 in suppressing serum interleukin-6 levels. A total of 274 subjects were randomly assigned and treated. Clinical parameters at baseline were balanced across the three groups. TAK-242 did not suppress interleukin-6 as measured by 0- to 96.5-hr area under the interleukin-6 concentration curve at either dose. Specifically, the area under the effect curve increased by 9% and 26.9% in the TAK-242 1.2 and 2.4 mg/kg/day groups, respectively, which was not statistically different from placebo (p = .63 and .15, respectively). The 28-day mortality rate was 24% in the placebo, 22% in the low-dose, and 17% in the high-dose group (p = .26 for placebo vs. high dose). A nonsignificant reduction in mortality rate was observed in a subset of patients with both shock and respiratory failure (placebo [n = 51], 33%, vs. high dose [n = 52], 19%, p = .10). Transient, dose-related increases in methemoglobin levels were observed with TAK-242 treatment in 30.1% of the patients.Conclusions: TAK-242 failed to suppress cytokine levels in patients with sepsis and shock or respiratory failure. Treatment with TAK-242 resulted in mild increases in serum methemoglobin levels but was otherwise well tolerated. Although observed mortality rates in patients with both shock and respiratory failure were lower with the 2.4 mg/kg/day dose, differences were not significant. (Crit Care Med 2010; 38: 1685-1694)