Automation of Extracorporeal Filtration of Subarachnoid Hemorrhage via Spinal Catheter

摘要 动脉瘤性蛛网膜下腔出血（SAH）是一种破坏性的神经系统疾病， 脑动脉瘤破裂平均发病率为每10万人11人， 美国每年有3万例。在破裂的动脉瘤固定后，密切观察患者， 住院14天，监测脑血管痉挛、水肿、脑积水，身体慢慢恢复 清除蛛网膜下腔残留的血液由于这些并发症的普遍存在， 仍然是改善这些患者的结果的显著未满足的需求。早期清除血液和血液 产物（如血红蛋白、氧合血红蛋白和下游炎症蛋白） 已证明脑脊液（CSF）可降低血管痉挛、中风、脑积水的发生率， 永久性分流安置，并缩短住院时间。目前可用的工具，如被动 然而，心室或腰椎引流不足以加速血液排出。我们的核心假设 来自CSF的血液和血液分解产物可以直接靶向并快速减少， 新的介入方法。Minnetronix是一家医疗设备开发和制造公司， 开发了一个自动化脑脊液处理和过滤平台。闭环装置提取“污染” 从腰大池排出脑脊液，并将“清洁的”脑脊液重新引入颈胸蛛网膜下腔 空间（称为神经单采术的过程），以高达2 ml/min的速度处理CSF。神经单采术治疗是一种 创新，新的治疗选择，旨在补充，而不是取代标准的 对SAH患者进行护理干预。首次人体试验（PILLAR研究-15例患者研究，初步 本申请中的数据）由DSMB进行了审查，并一致支持安全性和扩展 临床研究初步研究表明，在15：07过滤小时内处理的平均CSF为632.0 mL 初始升高的平均CSF总蛋白和RBC分别降低71.0%和57.9%。的 PILLAR扩展方案（称为PILLAR XT），在这项授权中提出，由FDA审查和批准 和中央IRB本研究将直接测量CSF流量算法的性能， 器械安全性评价，增加了自动化和更长的治疗时间。该研究将进一步 探索使用神经单采术治疗持续减少颅内和脊髓蛛网膜下腔的血液。 在PILLAR XT中，样本量更大（30例患者）和持续时间更长（I期最长36小时的泵时间 II期仅受导管留置时间72小时的限制）将允许更多的疗效数据支持 未来的关键研究这些数据将有助于系统的优化，协议的细化和选择 未来关键研究的适当终点。长期目标是开发一种自动化、成本低廉的 有效的平台与床旁导管放置，快速清除血液从脑脊液，并转化为 降低蛛网膜下腔出血的发病率和死亡率。

ABSTRACT Aneurysmal subarachnoid hemorrhage (SAH) is a devastating neurological condition occurring as the result of a ruptured cerebral aneurysm. The mean incidence is 11 people per 100,000 population and an estimated 30,000 cases annually in the US. After securement of a ruptured aneurysm, patients are closely observed in the hospital for 14 days to monitor for cerebral vasospasm, edema, hydrocephalus and for the body to slowly clear any remaining blood from the subarachnoid space. Due to the prevalence of these complications, there remains a significant unmet need to improve outcomes for these patients. Early removal of blood and blood products (e.g. hemoglobin, oxyhemoglobin, and downstream inflammatory proteins) from the cerebrospinal fluid (CSF) has been shown to reduce the incidence of vasospasm, stroke, hydrocephalus, the need for permanent shunt placement, and result in a shorter hospital course. Currently available tools, such as passive ventricular or lumbar drains, however, are not sufficient for expedited blood removal. Our central hypothesis is that blood and blood breakdown products from the CSF can be directly targeted and rapidly reduced, using a novel, interventional approach. Minnetronix, a medical device development and manufacturing company, has developed an automated CSF treatment and filtration platform. The closed-loop device extracts “contaminated” CSF from the lumbar cistern and reintroduces “cleaned” CSF back into the cervico-thoracic subarachnoid space (a process termed Neurapheresis), processing CSF at up to 2 ml/min. Neurapheresis therapy is an innovative, new therapeutic option that is intended to be complementary, and does not replace standard of care interventions, for patients with SAH. The first-in-human trial (PILLAR study- 15 patient study, preliminary data in this application) was reviewed by the DSMB and had unanimous support for safety and an expanded clinical study. The pilot study demonstrated a mean of 632.0 mL of CSF processed in 15:07 hours of filtration and initially elevated mean CSF total protein and RBCs were reduced by 71.0% and 57.9%, respectively. The PILLAR Extension protocol (termed PILLAR XT), proposed in this grant, was reviewed and approved by FDA and the central IRB. This study will directly measure performance of a CSF flow algorithm alongside continued evaluation of the device safety, with the addition of automation and longer therapy time. The study will further explore continued reduction of blood in the cranial and spinal subarachnoid space with Neurapheresis therapy. In PILLAR XT, the larger sample size (30 patients) and longer duration (up to 36 hours of pump time in Phase I and limited only by catheter indwelling time of 72 hours in Phase II) will allow more efficacy data to power a future pivotal study. This data will contribute to system optimization, refinement of the protocol and selection of the appropriate endpoints for a future pivotal study. The long-term goal is to develop an automated, cost- effective platform with bedside catheter placement that rapidly removes blood from CSF and translates to reduced morbidity and mortality for aneurysmal SAH.