一项评估抗体组织因子拮抗剂在急性肺损伤或急性呼吸窘迫综合征患者中的药代动力学、安全性和耐受性的 I 期研究。
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.
机构信息
Altor BioScience Corp., Miramar, FL, USA.
出版信息
BMC Pulm Med. 2012 Feb 16;12:5. doi: 10.1186/1471-2466-12-5.
BACKGROUND
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.
METHODS
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 (PaO(2)/FiO(2) ≤ 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.
RESULTS
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.
CONCLUSIONS
Overall, this study showed that ALT-836 could be safely administered to patients with sepsis-induced ALI/ARDS.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT01438853.
背景
组织因子（TF）依赖性外源性途径已被认为是急性肺损伤和急性呼吸窘迫综合征（ALI/ARDS）患者肺部凝血级联局部激活的核心机制，因此代表了治疗干预的有吸引力的靶点。本研究旨在确定抗 TF 抗体 ALT-836 在 ALI/ARDS 患者中的药代动力学和安全性特征。
方法
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，纳入疑似或确诊感染、接受机械通气且患有 ALI/ARDS（PaO2/FiO2 ≤ 300mmHg）的成年患者。18 名患者（每组 6 名）按 5:1 的比例随机分为接受 ALT-836 或安慰剂组，并在符合筛选标准后 48 小时内接受治疗。患者队列单次静脉注射 0.06、0.08 或 0.1mg/kg 的 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、凝血和肺功能参数评估。
结果
药代动力学分析显示，在 0.06 至 0.1mg/kg 的输注范围内，ALT-836 的暴露呈剂量依赖性。在研究期间，研究人群中未观察到抗 ALT-836 抗体反应。接受 ALT-836 治疗的患者未报告重大出血事件。最常见的不良事件是贫血，在安慰剂和 ALT-836 治疗患者中均观察到，且与 ALT-836 剂量相关，为自限性血尿，提示 0.08mg/kg 为该患者人群中 ALT-836 的可接受剂量水平。
结论
总体而言，本研究表明 ALT-836 可安全用于脓毒症诱导的 ALI/ARDS 患者。
试验注册
ClinicalTrials.gov：NCT01438853。
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