A pilot Study To Determine the Safety of Argatroban Injection in Combination with

描述(由申请人提供)：阿加曲班是一种凝血酶抑制剂，已经在冠状动脉灌注和急性缺血性中风的环境中进行了研究。由于大多数缺血性卒中患者可能无法单独从rt-PA中获益，溶栓剂和抗凝剂的结合为再通提供了一种新的策略。主要目的：评价rt-PA联合阿加曲班治疗急性缺血性卒中的安全性。具体地说，大动脉(近端)闭塞的患者将被包括在内，这些患者可以通过CT血管造影(CTA)或经颅多普勒(TCD)超声识别。假设：联合应用rt-PA和阿加曲班治疗急性缺血性卒中是安全的。理论基础：溶栓剂和抗凝血剂的结合已被证明在其他疾病治疗(如心血管疾病)中有效。临床前工作表明，使用阿加曲班可以改善微循环，减少再闭塞，并在使用溶栓剂时提高再通率。然而，这两种治疗方法在急性缺血性中风患者中的联合应用尚未被研究。方法：安全性将通过SICH或PH-2的发生率来评估。安全性的主要衡量标准是在48小时内不能耐受超过10%的SICH或PH-2。共有65名患者将在症状出现后3小时内接受标准护理静脉注射rtPA。每个患者还将在rt-PA输注期间开始接受阿加曲班(100g/kg静脉滴注，然后L/g/kg/min输注)48小时。这项研究将是一项多中心、前瞻性、开放标签、单臂、安全性和活性的临床试验。次要目的：探讨联合应用rt-PA和阿加曲班治疗缺血性卒中患者的早期动脉再通率和临床恢复率。假设：联合应用rt-PA和阿加曲班将导致更高的血管再通率。此外，这一组合将带来更高的临床恢复率。理论基础：根据现有的缺血性卒中文献，仅静脉注射rt-PA治疗可在2小时内以15%的比率产生完全再通。此外，再通的速度和完整性很可能是 公共卫生相关性：在这项第二阶段研究中产生的数据将评估对急性中风患者潜在有效的联合治疗的安全性，并提供初步证据，表明联合治疗可能产生更完全的再通。

DESCRIPTION (provided by applicant): Argatroban, a thrombin inhibitor, has been studied in the setting of both coronary perfusion as well as acute ischemic stroke. Since the majority of ischemic stroke patients may not benefit from rt-PA alone, the combination of thrombolytics with anticoagulants present a novel strategy for reperfusion. Primary specific aim: To assess the safety of combination rt-PA and Argatroban in acute ischemic stroke patients. Specifically, patients with large artery (proximal) occlusions will be included which can be identified on either CT-angiogram (CTA) or transcranial Doppler (TCD) ultrasound. Hypothesis: The combination of rt-PA and Argatroban will be safe in acute ischemic stroke. Rationale: The combination of thrombolytics and anticoagulation has proven efficacious in other disease treatments (e.g., cardiovascular disease). Pre-clinical work has shown improved microcirculation flow with Argatroban, reduced re-occlusion and increased rates of recanalization when delivered with thrombolytics. However, the combination ofthese two treatments have not been studied in acute ischemic stroke patients. Approach: Safety will be assessed by theincidence of sICH or PH-2. The primary measure of safety will be to not tolerate greater than a 10% rate of sICH or PH-2 within 48 hours. A total of 65 patients will receive standard-of-care intravenous IV-rtPA within 3 hours of symptom onset. Each patient will also receive Argatroban (100¿g/kg bolus followed by l¿g/kg/min infusion) for 48 hours started during the rt-PA infusion. The study will be a multi-center, prospective, open-label, single-arm, safety and activity clinical trial. Secondary aims: To explore the rates of early arterial recanalization and clinical recovery in ischemic stroke patients treated with combination intravenous rt-PA and Argatroban. Hypothesis: Combination rt-PA and Argatroban will result in greater rates of vessel recanalization. In addition, the combination will result in greater rates of clinical recovery. Rationale: Based on available ischemic stroke literature, IV rt-PA treatment alone produces complete recanalization at 2 hours at a rate of <15%. In addition, speed and completeness of recanalization is likely the PUBLIC HEALTH RELEVANCE: Data generated during this phase II study will evaluate the safety of a potentially effective combination treatment for acute stroke patients and provide preliminary evidence that the combination may produce more complete recanalization.