Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: A multicenter, randomized, placebo-controlled, single-blind, dose escalation study
Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: A multicenter, randomized, placebo-controlled, single-blind, dose escalation study
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DOI：
10.1097/00003246-200111000-00007
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发表时间：
2001-11-01
影响因子：
8.8
通讯作者：
Creasey, AA
中科院分区：
文献类型：
--
作者：
Abraham, E;Reinhart, K;Creasey, AA
目的：为了确定一个安全和潜在的有效的重组组织因子途径抑制剂（rTFPI）剂量，为进一步的临床评价在严重sepsis.Design患者：前瞻性，随机，单盲，安慰剂对照，剂量递增，多中心，多国II期临床试验。美国和欧洲的38个重症监护病房。患者：210名严重脓毒症受试者，接受标准支持治疗和抗菌治疗。受试者接受安慰剂或rTFPI以0.025或0.05 mg/kg/hr持续静脉输注4天（96小时）。在随机分配至安慰剂组或rTFPI任一剂量组的患者中，人口统计学、疾病严重程度或感染源均无显著失衡。当所有接受rTFPI治疗的患者与所有安慰剂患者相比时，观察到28天全因死亡率相对降低20%。在rTFPI治疗的患者中，还观察到肺器官功能障碍评分和复合重症监护病房评分（肺、心血管和凝血）的改善。Logistic回归模型表明，当模型中仅包含治疗和INR时（p = .037），以及当校正基线急性生理学和慢性健康状况评价（APACHE II）和log（10）白细胞介素6时（p = .026），治疗与基线实验室国际标准化比值（INR）的相互作用效应显著。这种相互作用效应表明，较高的基线INR与更明显的有益rTFPI效应相关。与安慰剂相比，接受任一剂量rTFPI治疗的受试者的死亡率均未增加。与接受安慰剂的患者相比，在所有接受rTFPI治疗的患者中均观察到生物活性（通过凝血酶-抗凝血酶复合物（TATc）的统计学显著性降低检测）。所有治疗组在安全性方面均无重大失衡。治疗组间不良事件（AE）和重度不良事件（SAE）的频率相似，0.05 mg/kg/hr rTFPI组中SAE和涉及出血的SAE略有增加。涉及出血的AE的总体发生率在所有安慰剂组中为28%的患者，在所有rTFPI治疗组中为23%的患者;与所有安慰剂组（13%; p = .39）相比，在所有rTFPI组（9%）中观察到涉及出血的SAE发生率轻微但统计学上不显著的增加。尽管该试验没有把握度显示疗效，但与所有安慰剂组相比，在所有rTFPI组中观察到28天全因死亡率降低的趋势。本研究表明，rTFPI剂量为0.025和0.05 mg/kg/hr可安全给予严重脓毒症患者。此外，rTFPI表现出生物活性，如TATc复合物和白细胞介素-6水平降低所示。这些发现证明了在一项充分把握度、安慰剂对照、随机试验中进一步评价rTFPI治疗严重脓毒症的价值。
Objective: To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis.Design: Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial.Setting. Thirty-eight intensive care units in the United States and Europe.Patients: Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy.Interventions., Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs).Measurements and Main Results. There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p = .037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log(10) interleukin 6 were adjusted for (p = .026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo, There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (13%; p = .39).Conclusions., Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.