A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome.
A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome.
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DOI：
10.1186/1471-2466-12-5
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发表时间：
2012-02-16
影响因子：
3.1
通讯作者：
Wong HC
中科院分区：
文献类型：
--
作者：
Morris PE;Steingrub JS;Huang BY;Tang S;Liu PM;Rhode PR;Wong HC
组织因子(TF)依赖的外源性途径是急性肺损伤和急性呼吸窘迫综合征(ALI/ARDS)患者肺内凝血级联反应被局部激活的中心机制，是治疗干预的重要靶点。本研究旨在确定ALI/ARDS患者应用抗转铁蛋白抗体ALT-836的药代动力学和安全性。这是一项前瞻性、随机、安慰剂对照、剂量递增的I期临床试验，研究对象为疑似或确诊感染、正在接受机械通气并患有ALI/ARDS(PaO2/FiO2≤300 mm)的成年患者。18名患者(每个队列6名)按5：1的比例随机接受ALT-836或安慰剂治疗，并在符合筛查标准的48小时内接受治疗。队列患者单次静脉注射0.06、0.08或0.1 mg/kg ALT-836或安慰剂。采集血样进行药代动力学和免疫原性测定。安全性通过不良事件、生命体征、心电图、实验室、凝血和肺功能参数进行评估。药代动力学分析显示，ALT-836在0.06至0.1 mg/kg的剂量范围内呈剂量依赖关系。在试验期间，在研究人群中没有观察到抗ALT-836抗体反应。在接受ALT-836治疗的患者中，没有重大出血事件的报道。最常见的不良事件是贫血，在安慰剂和ALT-836治疗的患者中都观察到了，以及ALT-836剂量依赖性的自我分解血尿，这表明在该患者群体中ALT-836的可接受剂量水平为0.08毫克/公斤。总体而言，这项研究表明ALT-836可以安全地用于脓毒症诱发的ALI/ARDS患者。ClinicalTrials.gov：NCT01438853
The tissue factor (TF)-dependent extrinsic pathway has been suggested to be a central mechanism by which the coagulation cascade is locally activated in the lungs of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) and thus represents an attractive target for therapeutic intervention. This study was designed to determine the pharmacokinetic and safety profiles of ALT-836, an anti-TF antibody, in patients with ALI/ARDS. This was a prospective, randomized, placebo-controlled, dose-escalation Phase I clinical trial in adult patients who had suspected or proven infection, were receiving mechanical ventilation and had ALI/ARDS (PaO2/FiO2 ≤ 300 mm). Eighteen patients (6 per cohort) were randomized in a 5:1 ratio to receive ALT-836 or placebo, and were treated within 48 hours after meeting screening criteria. Cohorts of patients were administered a single intravenously dose of 0.06, 0.08 or 0.1 mg/kg ALT-836 or placebo. Blood samples were taken for pharmacokinetic and immunogenicity measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory, coagulation and pulmonary function parameters. Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg. No anti-ALT-836 antibody response was observed in the study population during the trial. No major bleeding episodes were reported in the ALT-836 treated patients. The most frequent adverse events were anemia, observed in both placebo and ALT-836 treated patients, and ALT-836 dose dependent, self-resolved hematuria, which suggested 0.08 mg/kg as an acceptable dose level of ALT-836 in this patient population. Overall, this study showed that ALT-836 could be safely administered to patients with sepsis-induced ALI/ARDS. ClinicalTrials.gov: NCT01438853
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影响因子：
158.5
作者：
Abraham, E;Laterre, P;Macias, WL
通讯作者：
Macias, WL
影响因子：
15.9
作者：
Scotton, Chris J.;Krupiczojc, Malvina A.;Chambers, Rachel C.
通讯作者：
Chambers, Rachel C.
影响因子：
6
作者：
Howell, DCJ;Johns, RH;Chambers, RC
通讯作者：
Chambers, RC
DOI：
10.1111/j.1538-7836.2009.03368.x
发表时间：
2009-07
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Mackman N
通讯作者：
Mackman N
影响因子：
39.3
作者：
Morrow, DA;Murphy, SA;Antman, EM
通讯作者：
Antman, EM