Feasibility of Objective Measures and Outpatient Washout in Disease-Modifying Trials for Parkinson's Disease

帕金森病疾病修饰试验中客观措施和门诊冲洗的可行性

• 批准号: 10647638
• 负责人: Mallory L. Hacker
• 金额: $ 12.02万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647638
• 关键词: Acceleration; Activities of Daily Living; Address; Affect; Aging; American; Animal Model; Area; Biochemical Pathway; Bradykinesia; Brain scan; Care given by nurses; Clinical; Clinical Trials; Clinical assessments; Communities; Data; Deep Brain Stimulation; Disease; Disease Progression; Distress; Dyskinetic syndrome; Early treatment; Elderly; Enrollment; Environment; FDA approved; Funding; Future; Goals; Healthcare; Idiopathic Parkinson Disease; Inpatients; Intervention; Investigation; Knowledge; Measurement; Measures; Medical; Mentorship; Metabolic; Methods; Modification; Motor; Neurodegenerative Disorders; Neurons; Outpatients; Parkinson Disease; Patients; Pharmaceutical Preparations; Placebo Effect; Positron; Positron-Emission Tomography; Protocols documentation; Quality of life; Randomized; Research; Rest Tremor; Risk; Safety; Scanning; Scientist; Severities; Severity of illness; Single-Blind Study; Symptoms; Testing; Therapeutic; Training; Tremor; Uncertainty; Universities; age related; age related neurodegeneration; aged; aging population; career; career development; cost effective; electron tomography; experience; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; improved; motor symptom; multidisciplinary; nervous system disorder; neural network; neuroimaging; novel therapeutics; patient population; phase III trial; pilot trial; preclinical study; preservation; prospective test; randomized, clinical trials; side effect; standard care; wearable device; wearable sensor technology

PROJECT SUMMARY AND CAREER DEVELOPMENT ABSTRACT There is no therapy that slows the progression of any symptom of Parkinson’s disease (PD), a progressive, age-related neurodegenerative disorder that affects more than one million Americans. Although reserved for later PD stages as an alternative when medications fail, deep brain stimulation (DBS) therapy has strong evidence that it protects nigral neurons when applied in animal models of early-stage PD. Those promising preclinical studies motivated the first randomized clinical trial evaluating DBS in early-stage PD. Recent findings from that pilot trial provided class II evidence that early DBS slows the progression of rest tremor, a common and often distressing cardinal motor symptom for early-stage patients. This landmark finding must now be prospectively tested, and a multicenter, randomized phase 3 trial is approved by the FDA. Similar to the pilot, the phase 3 trial will evaluate underlying motor symptom progression using week-long therapeutic washouts. Since the original investigation completed, new objective measures to evaluate PD have emerged, including PD-specific metabolic networks identified from 18F-fluorodeoxyglucose (FDG) positron electron tomography (PET) scans and wearable biosensors that evaluate motor symptoms and dyskinesia. Including these unbiased measures alongside standard clinical assessments after a week-long therapeutic washout offers the opportunity to objectively evaluate whether early DBS slows PD progression compared to standard medical therapy. Additionally, there were no safety issues during 147 washout experiences in the pilot, and early-stage PD patients preserved their independence in activities of daily living throughout the washouts. Given the mild symptomology of early-stage PD, conducting the washouts in the ambulatory setting may offer a less burdensome and more cost-effective alternative. Before proceeding to a phase 3 trial, the feasibility of making changes to the week-long washout protocol to add objective FDG-PET neuroimaging (Aim 1) and wearable biosensors (Aim 2) while being conducted in the ambulatory setting (Aim 3) must first be tested. This study will fill critical knowledge gaps concerning use of new objective measures during an outpatient washout in 20 early-stage PD patients. This new information will be used to finalize the protocol of a phase 3 trial to determine if early DBS slows Parkinson’s disease motor symptom progression compared to standard care. My career goal is to become an independent scientist who investigates new therapies for early-stage Parkinson’s disease. I have identified four gaps in my training that, once filled, will accelerate my progress toward that goal. These four areas are: 1) PD neural networks, 2) objective PD measurements, 3) health care needs for older adults with neurological disorders, and 4) leading multidisciplinary clinical trials teams. I have developed a training plan to overcome these barriers that integrates formal didactic training with one-on-one, multidisciplinary mentorship in an outstanding research environment at Vanderbilt University. Completing the proposed research and training plan will help me successfully compete for R01-level funding.

项目摘要和职业发展摘要 目前还没有任何疗法可以减缓帕金森病 (PD) 任何症状的进展，帕金森病是一种 影响超过一百万美国人的进行性、与年龄相关的神经退行性疾病。 深部脑刺激 (DBS) 疗法是为晚期 PD 阶段保留的，作为药物治疗失败时的替代方案。 有强有力的证据表明，当应用于早期帕金森病动物模型时，它可以保护黑质神经元。 临床前研究激发了第一个评估 DBS 在早期 PD 中的随机临床试验的前景。 该试点试验的最新结果提供了 II 类证据，表明早期 DBS 会减慢休息进程 震颤是早期患者常见且常常令人痛苦的主要运动症状，这一里程碑式的发现。 现在必须进行前瞻性测试，并且 FDA 批准了一项多中心、随机 3 期试验。 对于试点项目，第三阶段试验将使用为期一周的治疗来评估潜在的运动症状进展 自最初的调查完成以来，评估 PD 的新的客观措施已经出现， 包括从 18F-氟脱氧葡萄糖 (FDG) 正电子中识别出的 PD 特异性代谢网络 断层扫描 (PET) 扫描和评估运动症状和运动障碍的可穿戴生物传感器。 经过一周的治疗清除后，这些公正的措施与标准临床评估一起进行 与标准相比，提供了客观评估早期 DBS 是否能减缓 PD 进展的机会 此外，在试点的 147 次冲洗过程中没有出现任何安全问题。 早期帕金森病患者在整个治疗过程中保持了日常生活活动的独立性。 鉴于早期 PD 的轻微症状，在门诊环境中进行冲洗可能会提供以下效果： 在进行第三阶段试验之前，需要考虑一种负担更轻且更具成本效益的替代方案。 更改为期一周的清除方案以添加客观 FDG-PET 神经影像（目标 1）和 可穿戴生物传感器（目标 2）在流动环境（目标 3）中进行时必须首先进行测试。 研究将填补关于在门诊冲洗期间使用新的客观措施的关键知识空白 该新信息将用于最终确定 20 名早期 PD 患者的 3 期试验方案。 确定与标准治疗相比，早期 DBS 是否可以减缓帕金森病运动症状的进展。 我的职业目标是成为一名独立科学家，研究早期阶段的新疗法 我发现了帕金森病训练中的四个空白，一旦填补，将加速我的进步。 这四个领域是：1) 局部放电神经网络，2) 客观局部放电测量，3) 医疗保健。 患有神经系统疾病的老年人的需求，以及 4) 领先的多学科临床试验团队。 制定了一项培训计划来克服这些障碍，将正式的教学培训与一对一的培训相结合， 在范德比尔特大学出色的研究环境中获得多学科指导。 提出的研究和培训计划将帮助我成功竞争R01级资助。