Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis
Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis
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DOI：
10.1097/ccm.0b013e3181b07b78
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发表时间：
2010-01-01
影响因子：
8.8
通讯作者：
Opal, Steven M.
中科院分区：
文献类型：
--
作者：
Tidswell, Mark;Tillis, William;Opal, Steven M.
目的：内毒素是严重脓毒症患者促炎反应和全身凝血的有力刺激因素。内毒素是革兰氏阴性细菌的一种成分，通过髓系细胞中的Toll样受体4信号通路触发先天免疫反应。我们评估了两种剂量的厄立特里亚四钠(E5564)的安全性和耐受性，E5564是一种合成的Toll样受体4拮抗剂，并探索它是否能降低严重脓毒症患者的28天死亡率。设计：前瞻性、随机、双盲、安慰剂对照、多中心、递增剂量II期试验。地点：美国和加拿大的成人重症监护病房。患者：在确诊严重脓毒症后12小时内300名成年人，使用急性生理学和慢性健康评估(APACHE)II-预测死亡风险在20%到80%之间。干预：静脉注射厄立特里亚四钠(总剂量为45毫克或105毫克)或安慰剂，每12小时服用一次，连续6天。测量和主要结果：服用45毫克或105毫克厄立特里亚四钠或服用安慰剂的受试者不良事件发生率相似。对于修改后的意向治疗受试者，28天全因死亡率分别为26.6%(厄立特里亚四钠105毫克)、32.0%(厄立特里亚四钠45毫克)和33.3%的安慰剂组。厄立特里亚四钠105毫克组的死亡率与安慰剂组没有显著差异(p=.335)。在预先指定的亚组中，按APACHE II评分四分位数计算，死亡率最高的受试者在厄立特里亚四钠105毫克组中有降低死亡率的趋势(33.3%对56.3%的安慰剂组，p=.105)。厄立特里亚105毫克组APACHE II评分最低四分位数的受试者有较高死亡率的趋势(12.0%vs.0.0%安慰剂组，p=0.083)。结论：厄立特里亚四钠治疗似乎耐受性良好。在严重脓毒症和高预测死亡风险的受试者中，观察到的105毫克剂量下死亡率降低的趋势应该进一步调查。(Crit Care Med 2010；38：72-83)
Objectives: Endotoxin is a potent stimulus of proinflammatory response and systemic coagulation in patients with severe sepsis. Endotoxin is a component of Gram-negative bacteria that triggers an innate immune response through Toll-like receptor 4 signaling pathways in myeloid cells. We evaluated safety and tolerability of two dose regimens of eritoran tetrasodium (E5564), a synthetic Toll-like receptor 4 antagonist, and explored whether it decreases 28-day mortality rate in subjects with severe sepsis.Design: Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial.Setting: Adult intensive care units in the United States and Canada.Patients: Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80%.Interventions: Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days.Measurements and Main Results: Prevalence of adverse events was similar among subjects treated with 45 mg or 105 mg of eritoran tetrasodium or with placebo. For modified intent-to-treat subjects, 28-day all-cause mortality rates were 26.6% (eritoran tetrasodium 105 mg), 32.0% (eritoran tetrasodium 45 mg), and 33.3% in the placebo group. Mortality rate in the eritoran tetrasodium 105-mg group was not significantly different from placebo (p = .335). In prespecified subgroups, subjects at highest risk of mortality by APACHE II score quartile had a trend toward lower mortality rate in the eritoran tetrasodium 105-mg group (33.3% vs. 56.3% placebo group, p = .105). A trend toward a higher mortality rate was observed in subjects in the lowest APACHE II score quartile for the eritoran 105-mg group (12.0% vs. 0.0% placebo group, p = .083).Conclusions: Eritoran tetrasodium treatment appears well tolerated. The observed trend toward a lower mortality rate at the 105-mg dose, in subjects with severe sepsis and high predicted risk of mortality, should be further investigated. (Crit Care Med 2010; 38:72-83)