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

INPH 分流 (PENS) 试验中安慰剂对照的有效性

• 批准号: 10279146
• 负责人: Richard Holubkov
• 金额: $ 305.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279146
• 关键词: Adult; Affect; Age-Years; Algorithms; Alzheimer' s Disease; Amyloid beta-42; Anatomy; Biological Markers; Bladder Control; Blinded; Blood Vessels; Brain; Cephalic; Cerebrospinal fluid shunts procedure; Clinical; Clinical effectiveness; Cognition; Cognitive; Collaborations; Controlled Clinical Trials; Creation of ventriculo-peritoneal shunt; Data; Data Collection; Dementia; Devices; Diagnosis; Disease; Effectiveness; Elderly; Enrollment; Equilibrium; Excision; FDA approved; Future; Gait; Goals; Guidelines; Health; Health Expenditures; Hydrocephalus; Image; Impaired cognition; Impairment; Lead; Liquid substance; Magnetic Resonance Imaging; Measures; Medical; Methods; Morbidity - disease rate; Neurologist; Neurology; Neuropsychological Tests; Neuropsychology; Neurosurgeon; Normal Pressure Hydrocephalus; Operative Surgical Procedures; Outcome; Outcome Assessment; Outcome Measure; Participant; Patient Selection; Patients; Pattern; Persons; Physiological; Placebo Control; Placebo Effect; Placebos; Population; Prevalence; Randomized; Randomized Clinical Trials; Reporting; Research; Research Proposals; Risk; Running; Shunt Device; Site; Subgroup; Surveys; Symptoms; System; Testing; Treatment Effectiveness; Uncertainty; Uncontrolled Study; Urinary Incontinence; Ventricular; Work; active method; aging population; base; biomarker identification; brain surgery; clinical outcome measures; comparison group; cost; disability; early experience; effective therapy; fluid flow; health care service; imaging biomarker; implantation; micturition urgency; neurodegenerative dementia; older patient; patient biomarkers; placebo controlled study; placebo controlled trial; placebo group; primary endpoint; primary outcome; programs; prospective; randomized placebo-controlled clinical trial; recruit; response; secondary analysis; secondary outcome; success; tau Proteins; treatment effect; virtual

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.

特发性正常压力脑积水（iNPH）是老年人痴呆和步态不平衡的一种可逆形式，已通过脑室腹腔分流术（VPS）进行治疗。虽然VPS已经进行了几十年，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的怀疑极大地限制了其使用。本研究提案的主要目标是收集数据，以明确回答分流手术是否为iNPH患者提供获益的问题。我们将通过一项前瞻性、设盲、随机安慰剂对照临床试验来实现这一目标，该试验使用了FDA批准的可调节分流系统。该阀允许“虚拟关闭”设置，允许无创和可逆地将患者分配至功能性（活性组）或非功能性（安慰剂组）分流管治疗。该试验将在20家研究中心入组100例iNPH患者。将根据标准和广泛使用的iNPH指南选择接受分流术的受试者。该试验是一种延迟治疗范式，所有100名患者将接受相同的手术和设备，仅初始阀门设置（活性或安慰剂）不同。主要分析将是植入后3个月时步态速度相对于基线变化的组比较。次要分析将测量平衡、认知和膀胱控制。植入后3个月，两组中的所有参与者均被盲调至活动设置，并随访9个月。本研究的次要目的是在手术前评价临床、影像学和CSF生物标志物，以确定与后续分流反应的相关性。分流后还重复进行MR成像和扩展神经心理学测试，以评估可能与步态变化相关的特定解剖和认知领域变化。我们预计，如果我们证明分流术在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iNPH分流的增加。此外，与成功结局相关的患者生物标志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。还建议识别改善的iNPH患者亚组。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，接受有效的手术治疗。如果数据显示分流术在安慰剂组中无效，老年患者将免于潜在的发病率和无效脑手术的费用。