A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients With Sepsis and Suspected Disseminated Intravascular Coagulation
A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients With Sepsis and Suspected Disseminated Intravascular Coagulation
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DOI：
10.1097/ccm.0b013e31828e9b03
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发表时间：
2013-09-01
影响因子：
8.8
通讯作者：
Kaul, Inder
中科院分区：
文献类型：
--
作者：
Vincent, Jean-Louis;Ramesh, Mayakonda K.;Kaul, Inder
目的：确定重组血栓调节蛋白（ART-123）治疗疑似脓毒症相关弥散性血管内凝血的安全性和有效性。设计：2b期，国际，多中心，双盲，随机，安慰剂对照，平行组，筛选试验。环境：在17个国家的233个icu。患者：所有因脓毒症和疑似弥散性血管内凝血而入院的成年患者，使用改良的国际血栓和止血学会评分进行评估。干预措施：除标准治疗外，患者随机接受静脉ART-123 （0.06 mg/kg/d）治疗6天或安慰剂。主要终点是死亡率的降低。次要终点包括明显弥散性血管内凝血的逆转和疾病严重程度的降低。测量和主要结果：共有750名患者被随机分组，其中9名患者未接受分配的治疗，371名患者接受ART-123治疗，370名患者接受安慰剂治疗。两组在任何基线变量上均无显著差异。ART-123组28天死亡率为17.8%，安慰剂组为21.6% （Cochran-Mantel-Haenszel双侧rho值为0.273，支持ART-123，符合预先设定的有效性证据统计检验）。两组患者的无事件天数和存活天数无统计学差异。ART-123组d -二聚体、凝血酶原片段F1.2和TATc浓度低于安慰剂组。两组在器官功能、炎症标志物、出血或血栓事件或新感染的发展方面没有差异。在事后分析中，ART-123的最大获益见于至少有一种器官系统功能障碍的患者，且基线时国际标准化比值大于1.4。结论：ART-123对于脓毒症合并疑似弥散性血管内凝血的危重患者是一种安全的干预措施。该研究提供的证据表明，该药物在脓毒症相关凝血病（包括弥散性血管内凝血）中的疗效支持进一步开发。未来的研究应侧重于在最有可能对该药物有反应的患者亚组中使用ART-123。
Objectives: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation.Design: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial.Setting: Two hundred and thirty-three ICUs in 17 countries.Patients: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score.Interventions: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity.Measurements and Main Results: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided rho value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. D-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline.Conclusions: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.