Therapeutic Window for Acute Therapy (P50)

描述（申请人提供）：血管内冷却治疗脑卒中2/3试验（ICTuS 2/3）建立在ICTuS-L正在进行的低温研究轨道上，从证明血管内冷却结合溶栓的可行性和安全性发展到与休斯顿SPOTRIAS合作评估，在3小时窗口内出现的急性缺血性卒中患者中血管内诱导低温的有效性。我们招募了一个咨询委员会，所有这些人都将作为研究的进展，并修改了研究，包括低温和正常体温的武器在疗效设计。ICTuS 2/3是一项确定性的III期试验，1600例接受溶栓治疗的患者随机分为低温组和常温组。该试验将分2个阶段进行，一项由SPOTRIAS资助的2期研究，共有450名患者参加，随后是一项由R 01资助的试验，以完成研究。我们计划将450例II期患者纳入III期的1600例样本量中。SPOTRIAS第2阶段的目的是确认修订后的方案确实消除了ICTuS-L中观察到的肺炎风险升高;静脉注射4 º C生理盐水改善了冷却效果;招募可以维持在0.4例患者/部位/月。此外，将在400例患者后进行正式的无效性中期分析。在SPOTRIAS下为450例患者提供的资金将使我们能够在无效性中期分析期间继续研究中心活动（入组）。将根据里程碑的实现情况和无效性中期分析，决定是否继续进行III期研究。我们希望从SPOTRIAS资金到R 01资金的无缝过渡，并最终完成一项关键的1600例患者血管内低温3期研究。 公共卫生相关性：中风是美国成人残疾的主要原因。低温是临床前研究中确定的最有前途的脑卒中神经保护疗法之一。ICTuS 2/3将研究低温对临床结局的影响，并进一步描述联合溶栓的安全性。重要的是，我们将确定低温是否可以在广泛的临床试验场所部署。

DESCRIPTION (provided by applicant): The Intravascular Cooling in the Treatment of Stroke 2/3 trial (ICTuS 2/3) builds on the ongoing hypothermia research track of ICTuS-L, evolving from demonstration of the feasibility and safety of intravascular cooling in combination with thrombolysis to collaborative assessment, with Houston SPOTRIAS, of the efficacy of the endovascular induction of hypothermia in acute ischemic stroke patients presenting within the 3-hour window. We recruited an Advisory Committee, all of whom will serve as the study progresses, and revised the study to include hypothermia and normothermia arms in an efficacy design. ICTuS 2/3 is a definitive Phase 3 trial of 1600 patients who receive thrombolysis randomized to hypothermia vs normothermia. The trial will be run in 2 stages, a SPOTRIAS-funded Phase 2 study of 450 patients, followed by an R01 funded trial to complete the study. We plan that the 450 Phase 2 patients will be included in the 1600 sample size for phase 3. The purpose of Phase 2 under SPOTRIAS is to confirm that the revised protocol indeed eliminates the elevated risk of pneumonia seen in ICTuS-L; that intravenous 4¿C saline improves cooling effectiveness; and that recruitment can be sustained at 0.4 patients/site/month. In addition, a formal interim analysis for futility will occur after 400 patients. Funding for 450 patients under SPOTRIAS will allow us to continue site activity (enrollment) during the time of the interim analysis for futility. A go/no-go decision to proceed to Phase 3 will be made based on the achievement of the milestones and the interim analysis for futility. We hope to have a seamless transition from SPOTRIAS funding to R01 funding and end up with a pivotal 1600 patient Phase 3 study of endovascular hypothermia. PUBLIC HEALTH RELEVANCE: Stroke is the leading cause of adult disability in the US. Hypothermia is one of the most promising neuroprotective therapies identified in preclinical studies for stroke. ICTuS 2/3, will investigate the effect of hypothermia on clinical outcome and further delineate safety in combination with thrombolysis. Importantly, we will determine whether hypothermia can be deployed across a wide range of clinical trial sites.