CLEAR IVH Phase III Planning Grant

描述（由申请人提供）：脑出血是中风最致命的形式。对于脑内（ICH）和脑室内（IVH）出血的患者，社区死亡率一直报告为50-80%，没有经过验证的有效治疗。动物模型显示，当血液迅速从心室排出时，对生理和功能有实质性的好处；我们的人体试验数据显示，血液去除后死亡率和功能获益趋势相似。目前使用室外引流（EVD）的治疗既不能改善长期生存，也不能改变血液对组织的影响。添加重组组织型纤溶酶原激活剂（rt-PA）可能是一种快速、有效和安全的血液清除方法的关键，这种方法可以限制脑组织损伤，提高EVD的清除血液的有效性，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第一个临床指导干预。我们寻求支持使用EVD和rt-PA作为IVH治疗的III期RCT试验。新的人体安全性和剂量发现数据表明，快速清除IVH血块可能与临床上发病率和死亡率的重要改善有关。这是一个强有力的信号，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、生存率和通过功能表现衡量的降低神经系统发病率负担具有强大的有益影响。文献、我们的数据以及之前的NINDS ICH和NINDS健康差异评价支持进行关键的III期试验的必要性，通过比较使用EVD + rt-PA与单独使用EVD来研究去除IVH凝块的益处。我们有可能挽救生命，改善脑出血幸存者的预后，而脑出血目前给少数民族、妇女和老年人造成了不成比例的负担。一旦我们提供了关键的证据，推广到更大范围的医院，使用SPOTRIAS和更新的网络，在技术上将是直截了当的，因为实施这种治疗的干预措施和专业知识已经很普遍。计划拨款将支持我们从将于2007年秋季完成的第二阶段试验顺利过渡到最终的第三阶段试验，使我们能够全面运作并立即执行。

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, increases 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. 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 disproportionately burdens minorities, women and the elderly. 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 will support a smooth transition from our Phase II trials which will be completed in the fall of 2007, to the definitive Phase III trial making us fully operational and in position to perform without delay.