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

描述(申请人提供)：脑出血是中风最致命的形式。对于脑内(ICH)和脑室(IVH)出血的患者，社区死亡率一直被报告为50%-80%，而没有经过验证的有效治疗。当血液从脑室快速取出时，动物模型显示出显著的生理和功能益处；我们的人体试验数据显示出与血液取出相似的死亡率和功能益处趋势。目前使用室外引流(EVD)的治疗方法既不能提高长期存活率，也不能改变血液对组织的影响。加入重组组织型纤溶酶原激活剂(rt-PA)可能是一种快速、有效、安全的取血手段的关键，它可以限制脑组织损伤，提高EVD的取血效果，甚至可能控制颅内压。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次临床指导干预。我们寻求使用EVD和rt-PA作为IVH治疗的III期随机对照试验的支持。新的人体安全性和剂量发现数据表明，IVH凝块的快速清除可以与临床上重要的发病率和死亡率的改善相关(&gt；45%MRS 0-3)。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，在意识水平、ICU治疗强度、存活率和降低神经发病率负担(以功能表现衡量)方面具有强大的益处。文献、我们的数据以及之前的NINDS脑出血和NINDS健康差异综述支持进行关键的III期试验的必要性，通过比较使用EVD加rt-PA和单独使用EVD来调查清除IVH凝块的益处。我们有可能挽救生命，改善脑出血幸存者的结局，因为脑出血现在给少数族裔、妇女和老年人带来了不成比例的负担。这项试验有很大的潜力使每个受试者平均增加1.7 Qualy‘s，从而使经济影响显著。一旦我们提供了关键证据，使用SPOTRIAS和较新的网络将在技术上直接推广到广泛的医院，因为实施这种疗法的干预措施和专业知识已经很普遍。规划拨款支持了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，并准备在2009年初毫不拖延地开展工作。

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.