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，已在冠状动脉灌注和急性缺血性卒中的背景下进行了研究。由于大多数缺血性卒中患者可能无法从单独的rt-PA中获益，因此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：评估rt-PA和阿加曲班联合治疗急性缺血性卒中患者的安全性。具体而言，将纳入可通过CT血管造影（CTA）或经颅多普勒（TCD）超声识别的大动脉（近端）闭塞患者。假设：rt-PA和阿加曲班联合治疗急性缺血性卒中是安全的。理由：溶栓和抗凝的组合已被证明在其他疾病治疗中有效（例如，心血管疾病）。临床前研究表明，阿加曲班可改善微循环流动，减少再闭塞，并增加溶栓剂给药时的再通率。然而，这两种治疗方法的联合应用尚未在急性缺血性卒中患者中进行过研究。方法：将通过sICH或PH-2的发生率评估安全性。安全性的主要指标是48小时内sICH或PH-2发生率不超过10%。共有65例患者将在症状发作后3小时内接受标准治疗静脉注射IV-rtPA。每例患者还将在rt-PA输注期间开始接受阿加曲班（100 μ g/kg推注，随后以l μ g/kg/min输注）48小时。本研究将是一项多中心、前瞻性、开放标签、单组、安全性和活性临床试验。次要目的：探讨静脉注射rt-PA和阿加曲班联合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：rt-PA和阿加曲班联合使用将导致更高的血管再通率。此外，该组合将导致更高的临床恢复率。依据：根据现有的缺血性卒中文献，单独IV rt-PA治疗在2小时时产生完全再通，再通率<15%。此外，再通的速度和完全性可能是 公共卫生相关性：本II期研究期间生成的数据将评价急性卒中患者潜在有效的联合治疗的安全性，并提供联合治疗可能产生更完全再通的初步证据。

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.