Clot Lysis: Evaluating Accelerated Resolution of IVH Phase III (CLEAR III)

凝块溶解：评估 IVH III 期加速溶解 (CLEAR III)

• 批准号: 8084084
• 负责人: DANIEL F HANLEY
• 金额: $ 550.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084084
• 关键词: Clot; Lysis; Evaluating; Accelerated; Resolution

DESCRIPTION (provided by applicant): Brain hemorrhage is the most fatal form of stroke. For patients with both intracerebral (ICH) and intraventricular (IVH) hemorrhages, community mortality is consistently reported at 50-80% with no validated, efficacious treatment. Animal models demonstrate substantial physiologic and functional benefit when blood is removed rapidly from the ventricle; our human trial data show similar mortality and functional benefit trends with blood removal. Current therapy which uses extraventricular drainage (EVD) neither improves long-term survival nor alters the effect of blood on tissue. Adding recombinant tissue plasminogen activator (rt-PA) may be the key to a rapid, effective, and safe means for blood removal that limits brain tissue injury, increasing the effectiveness of EVD's in removing blood and perhaps controlling ICP. If validated by a clinical trial, our therapy would offer the first-ever clinically directive intervention for this lethal disease. We seek support for a Phase III RCT trial using EVD and rt-PA as IVH treatment. New human safety and dose-finding data demonstrate the concept that rapid removal of IVH clot can be associated with clinically important improvements in morbidity and mortality (>45% mRS 0-3). This is a strong signal that we can translate IVH animal models to human treatment with robust beneficial effects on level of consciousness, ICU treatment intensity, survival, and lowered neurologic morbidity burden as measured by functional performance. The literature, our data, and prior NINDS ICH and NINDS health disparities reviews, support the need for a pivotal Phase III trial, investigating the benefits of removal of IVH clot by comparing use of EVD plus rt-PA vs. EVD alone. We can potentially save lives and improve outcome of brain hemorrhage survivors which now disproportionally burdens minorities, women and the elderly. This trial has robust potential to add an average of 1.7 Qualy's per subject treated making the economic impact substantial. Once we provide critical evidence, generalization to a wide range of hospitals, using SPOTRIAS and newer networks, would be technically straightforward as the interventions and expertise to perform this therapy are already widespread. The planning grant has supported a smooth transition from our completed Phase II trials to the definitive Phase III trial. We are now fully operational and in position to perform without delay in early 2009. PUBLIC HEALTH RELEVANCE: Brain hemorrhage is the most fatal form of stroke with a 50-80% mortality rate in patients with both ICH and IVH hemorrhage extension. This disease disproportionately burdens minorities, women and the elderly. Dose finding and human safety data demonstrate that when a clot is removed rapidly from the ventricle using an EVD and rt-PA administration as treatment, functional and physiologic benefits can be seen (good mRS 0-3 >45%). If the clinical trial we propose validates our theory it would offer the first-ever clinically directive intervention for this lethal disease, potentially saving lives and improving the functional outcomes of brain hemorrhage survivors including their quality of life.

描述（由申请人提供）：脑出血是最致命的中风形式。对于脑内（ICH）和脑室内（IVH）脑出血患者，社区死亡率一直报告为50-80%，无经验证的有效治疗。动物模型表明，当血液从心室快速移除时，具有显著的生理和功能益处;我们的人体试验数据显示，血液移除的死亡率和功能益处趋势相似。目前使用脑室外引流（EVD）的治疗既不能提高长期生存率，也不能改变血液对组织的影响。添加重组组织纤溶酶原激活剂（rt-PA）可能是快速、有效和安全的血液清除方法的关键，该方法限制了脑组织损伤，增加了EVD清除血液的有效性，并可能控制ICP。如果通过临床试验验证，我们的疗法将为这种致命疾病提供有史以来第一个临床指导性干预。我们寻求对使用EVD和rt-PA作为IVH治疗的III期RCT试验的支持。新的人体安全性和剂量探索数据证明了快速清除IVH凝块可能与发病率和死亡率（>45% mRS 0-3）的临床重要改善相关的概念。这是一个强烈的信号，表明我们可以将IVH动物模型转化为人类治疗，对意识水平、ICU治疗强度、生存率和降低的神经系统发病率负担（通过功能表现测量）具有强大的有益作用。文献、我们的数据和既往NINDS ICH和NINDS健康差异审查支持进行关键III期试验的必要性，通过比较使用EVD + rt-PA与单独使用EVD来研究清除IVH凝块的获益。我们有可能挽救生命，改善脑出血幸存者的预后，这些幸存者现在给少数民族、妇女和老年人带来了沉重的负担。该试验具有强大的潜力，每例受试者平均增加1.7例Qualys，从而产生巨大的经济影响。一旦我们提供关键证据，使用SPOTRIAS和更新的网络推广到广泛的医院，在技术上将是简单的，因为进行这种治疗的干预措施和专业知识已经很普遍。规划补助金支持我们从已完成的第二阶段试验顺利过渡到最终的第三阶段试验。我们现在已全面投入运作，能够毫不拖延地在2009年初开展工作。 公共卫生关系：脑出血是最致命的卒中形式，在ICH和IVH出血扩展患者中死亡率为50-80%。这一疾病给少数民族、妇女和老年人造成不成比例的负担。剂量探索和人体安全性数据表明，当使用EVD和rt-PA给药作为治疗从心室快速清除凝块时，可以看到功能和生理益处（良好mRS 0-3 >45%）。如果我们提出的临床试验验证了我们的理论，它将为这种致命疾病提供有史以来第一次临床指导性干预，可能挽救生命并改善脑出血幸存者的功能结果，包括他们的生活质量。