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，已被研究用于冠状动脉灌注和急性缺血性卒中。由于大多数缺血性脑卒中患者可能无法仅从rt-PA中获益，溶栓剂与抗凝剂的联合应用为再灌注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脑卒中患者的安全性。具体来说，大动脉（近端）闭塞的患者可以通过ct血管造影（CTA）或经颅多普勒超声（TCD）识别。假设：rt-PA联合阿加曲班治疗急性缺血性脑卒中是安全的。理由：溶栓剂和抗凝剂联合应用已被证明对其他疾病（如心血管疾病）治疗有效。临床前研究表明，阿加曲班可改善微循环流量，减少再闭塞，并增加溶栓药物的再通率。然而，这两种治疗方法在急性缺血性脑卒中患者中的联合应用还没有研究。方法：安全性将通过siich或PH-2的发生率来评估。主要的安全措施是在48小时内不能容忍超过10%的siich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IV-rtPA。每位患者还将在rt-PA输注期间开始48小时接受阿加曲班（100 g/kg丸，随后1 g/kg/min输注）。该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：探讨联合静脉注射rt-PA和阿加曲班治疗缺血性脑卒中患者的早期动脉再通率和临床恢复情况。假设：rt-PA联合阿加曲班可提高血管再通率。此外，这种组合将导致更高的临床恢复率。理由：根据现有的缺血性卒中文献，单独静脉注射rt-PA治疗可在2小时内以<15%的速率实现完全再通。此外，再通化的速度和完整性可能是最重要的

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.