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

特发性正常压力性脑积水(INPH)是接受脑室-腹膜分流术(VPS)治疗的老年痴呆和步态失衡的一种可逆性形式。虽然VPS已经进行了几十年，但VPS的有效性还没有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VPS在老年人中的怀疑大大限制了它的使用。这项研究提案的主要目的是收集数据，目的是对分流手术是否对INPH患者有好处的问题有一个明确的答案。我们将通过使用当代FDA批准的可调节分流系统的前瞻性、盲目、随机的安慰剂对照临床试验来实现这一点。这种瓣膜允许“虚拟关闭”设置，允许非侵入性和可逆性地将患者分配到功能分流(主动组)或无功能分流(安慰剂组)进行治疗。这项试验将在20个地点招募100名INPH患者。选择接受分流手术的患者将根据标准和广泛使用的INPH指南进行选择。这项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，只是在初始瓣膜设置(主动或安慰剂)方面有所不同。初步分析将对植入后三个月步态速度与基线的变化进行分组比较。二次分析将测量平衡、认知和膀胱控制。植入3个月后，两组受试者均盲目调整至活动环境，并随访9个月。这项研究的第二个目标是在手术前评估临床、影像和脑脊液生物标记物，以确定与随后分流反应的关系。分流术后还会重复进行磁共振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，如果我们证明分流术在INPH中的有效性，我们将建立有效的治疗方法，并促进适当的INPH分流术的增加。此外，对与成功结果相关的患者生物标记物的研究将允许未来测试算法，以更准确和有效地选择患者。也可以建议识别改善的INPH患者的亚组。这项对照试验的数据最终可以使美国30万至70万INPH患者受益，使他们接受有效的手术治疗。如果数据显示分流在安慰剂组中无效，老年患者将免除无效脑外科手术的潜在发病率和费用。

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.