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: 8291888
• 负责人: DANIEL F HANLEY
• 金额: $ 492.76万
• 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/8291888
• 关键词: Adverse event; Aftercare; Alteplase; Animal Model; Blood; Blood Clot; Blood coagulation; Brain hemorrhage; Caring; Categories; Cerebral hemisphere hemorrhage; Clinical; Clinical Trials; Coagulation Process; Communities; Conscious; Creation of ventriculo-peritoneal shunt; Critical Care; Cytolysis; Data; Disease; Dose; Drainage procedure; Effectiveness; Elderly woman; Excision; Funding; Glasgow Outcome Scale; Goals; Grant; Hemorrhage; Home environment; Hospitalization; Hospitals; Hour; Human; Injury; Intervention; Intracranial Pressure; Intraventricular; Length of Stay; Literature; Location; Measures; Minority; Morbidity - disease rate; Movement; National Institute of Neurological Disorders and Stroke; Neurologic; Obstruction; Odds Ratio; Outcome; Outcome Measure; Patients; Performance; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Physiological; Placebos; Population; Positioning Attribute; Quality of life; Randomized Clinical Trials; Reporting; Request for Applications; Research; Residual state; Resolution; Safety; Signal Transduction; Stroke; Survivors; Time; Tissues; Translating; brain tissue; clinical practice; demographics; economic impact; functional outcomes; health disparity; health related quality of life; improved; indexing; intraventricular hemorrhage; mortality; public health relevance; theories; treatment duration; trend; trial comparing

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血块可能与发病率和死亡率的临床重要改善相关（> - 45% mRS 0-3）。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。该试验具有强大的潜力，平均每个受试者增加1.7个质量，使经济影响显著。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。计划拨款支持我们从已完成的II期试验顺利过渡到最终的III期试验。我们现在已经完全投入运营，并将在2009年初毫不拖延地投入运营。