A Placebo-Controlled Effectiveness in INPH Shunting (PENS) Trial

特发性常压脑积水（iNPH）是一种可逆性痴呆和步态不平衡的老年人形式，已通过手术脑室-腹膜分流（VPS）治疗。虽然VPS已经实施了几十年，但VPS的有效性尚未在适当运行的安慰剂对照临床试验中进行测试。由于缺乏安慰剂对照试验的数据，对老年人VPS的怀疑大大限制了它的使用。本研究计划的主要目标是收集数据，以明确回答分流手术是否对iNPH患者有益的问题。我们将通过一项前瞻性、盲法、随机安慰剂对照临床试验来实现这一目标，该试验使用的是当代FDA批准的可调节分流系统。该瓣膜允许“虚拟关闭”设置，允许无创和可逆地分配患者接受功能（活性组）或无功能（安慰剂组）分流治疗。该试验将在20个地点招募100名iNPH患者。选择分流手术的参与者将根据标准和广泛使用的iNPH指南进行选择。该试验是一种延迟治疗模式，所有100名患者将接受相同的手术和设备，仅在初始瓣膜设置（活性或安慰剂）上有所不同。主要分析将是在植入后三个月的步态速度从基线变化的组比较。二次分析将测量平衡、认知和膀胱控制。植入后3个月，两组受试者均盲调至主动设置，随访9个月。该研究的第二个目标是在手术前评估临床、影像学和脑脊液生物标志物，以确定与后续分流反应的关联。分流术后也重复进行MR成像和扩展的神经心理学测试，以评估可能与步态变化相关的特定解剖和认知领域的变化。我们期望，如果我们证明了分流在iNPH中的有效性，我们将建立一种有效的治疗方法，并促进适当的iNPH分流。此外，对与成功结果相关的患者生物标志物的研究将允许未来测试更准确和有效的患者选择算法。还可以建议确定改善的iNPH患者的亚组。这项对照试验的数据最终将使美国30 - 70万iNPH患者获得有效的手术治疗。如果数据显示分流术在安慰剂组无效，老年患者将免于潜在的发病率和无效脑外科手术的费用。

Idiopathic Normal Pressure Hydrocephalus (iNPH) is a reversible form of dementia and gait imbalance in the elderly that has been treated with surgical ventriculoperitoneal shunting (VPS). Although VPS has been performed for decades, the effectiveness of VPS has not been tested in an appropriately run placebo-controlled clinical trial. Due to the lack of data from placebo-controlled trials, skepticism about VPS in the elderly has significantly limited its use. The primary goal of this research proposal is to gather data with the goal of a definitive answer on the question of whether shunt surgery offers a benefit to patients with iNPH. We will accomplish this through a prospective, blinded, randomized placebo-controlled clinical trial that uses a contemporary FDA approved adjustable shunt system. This valve allows a “virtual off” setting allowing for noninvasive and reversible assignment of patients to treatment with a functioning (active group) or non- functioning (placebo group) shunt. The trial will enroll 100 iNPH patients at 20 sites. Participants selected for shunt surgery will be chosen based on standard and widely used iNPH guidelines. The trial is a delayed treatment paradigm where all 100 patients will receive the same surgery and device, differing only in the initial valve setting (active or placebo). The Primary analysis will be a group comparison of change from baseline in gait velocity at three months after implantation. Secondary analysis will measure balance, cognition, and bladder control. Three months after implantation, all participants in both groups are blindly adjusted to the active setting and followed for 9 months. A secondary goal of the study is to evaluate clinical, imaging, and CSF biomarkers before surgery to identify associations with subsequent shunt response. MR imaging and extended neuropsychological testing are also repeated after shunting to evaluate specific anatomical and cognitive domain changes that may be associated with gait changes. We expect that if we demonstrate the effectiveness of shunting in iNPH we will establish an effective treatment and facilitate an increase in appropriate iNPH shunting. In addition, the study of patient biomarkers associated with successful outcomes will allow future testing of algorithms for more accurate and efficient patient selection. Identification of subgroups of iNPH patients with improvement may also be suggested. Data from this controlled trial can ultimately benefit the 300 to 700 thousand iNPH patients in the US to receive an effective surgical treatment. If data shows that shunting is found to be ineffective in the placebo group, elderly patients will be spared the potential morbidity and cost of an ineffective brain surgery.