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

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.