Simultaneous DBS of the GPi and the NBM in Patients With Parkinson's Disease and Mild Cognitive Impairment

Study Overview
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Brief Summary
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Phase 1 study evaluating the safety of combined bilateral globus pallidus internus (GPi) and nucleus basalis of Meynert (NBM) stimulation in treating levodopa responsive motor symptoms of Parkinsonism and cognitive dysfunction, respectively, in patients with moderate to advanced Parkinson's disease having mild cognitive impairment.

Detailed Description
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This study aims to provide a proof of safety of combined bilateral Globus Pallidus internus (GPi) and Nucleus Basalis of Meynert (NBM) stimulation in patients with moderate to advanced Parkinson's disease having mild cognitive impairment. GPi stimulation with high-frequency ameliorates the cardinal motor symptoms and motor complications in Parkinson's disease patients, and this present study also wants to determine if additional NBM stimulation, with low-frequency stimulation, improves or slows progression of cognitive decline in patients with moderate to advanced Parkinson's disease having mild cognitive impairment, and to evaluate the effect of NBM stimulation on gait and balance impairment. Study Design: Prospective single center Phase 1 study with double-blind randomized delayed activation of basal nucleus of Meynert neurostimulation (staggered onset design). Planned Number of Subjects: 10 patients. Planned Number of Sites / Countries: Single center in Brazil. Study schedule: Presurgical baseline evaluation (motor on and off medication state; cognitive testing in best motor on state). DBS Implant Procedure. Postsurgical baseline evaluation (motor off state; cognitive testing in best motor on state) at 3±1 weeks after surgery and activation of globus pallidus internus neurostimulation using individualized stimulation parameters after a standard monopolar review. Regular adjustments of the GPi stimulation parameters aiming at the best motor improvement. Visit 1 (16 weeks after activation of GPi neurostimulation): motor off medication + GPi stimulation state, cognitive testing in on medication + GPi stimulation state. Randomization and blinded activation of NBM neurostimulation according to a 1:1 scheme. Visit 2 (16 weeks after randomization): motor off and on medication + stimulation state (GPi stimulation ± NBM stimulation); cognitive testing in motor on medication + stimulation state (GPi stimulation ± NBM stimulation). Activation of NBM neurostimulation in all patients. Visit 3 (16 weeks after activation of NBM stimulation in all patients): motor off and on medication + GPi and NBM stimulation state; cognitive testing in motor on medication + GPi and NBM stimulation state. Annual follow-up visit for up to 5 years after activation of NBM stimulation.

Official Title
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Simultaneous Deep Brain Stimulation of the Globus Pallidus Internus and the Nucleus Basalis of Meynert in Patients With Parkinson's Disease and Mild Cognitive Impairment

Conditions
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Parkinson Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Device: Deep brain stimulation implantation of a Vercise neurostimulation system in GPi and NBM.
* Device: GPi stimulation
* Device: NBM stimulation
* Device: Sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at the time of enrollment: 50 - 75 years. Diagnosis of idiopathic PD according to Movement Disorders Society (MDS) criteria (Albanese et al., 2017). Mild cognitive impairment (MCI) related to Parkinson's disease according to MDS criteria. (Livtan et al. 2012). Duration of bilateral idiopathic PD: ≥ 5 years of motor symptoms. Modified Hoehn and Yahr stage ≥ 2 on off medication state. UPDRS subset III (motor) ≥ 30 points on off medication state. Levodopa must improve PD symptoms by ≥ 30% in a levodopa challenge test, as measured by UPDRS subset III score. Presence of motor complications related to Parkinson's disease. Be willing and able to comply with all visits and study related procedures Able to understand the study requirements and the treatment procedures and to provide written informed consent before any study-specific tests or procedures are performed. Exclusion Criteria: Alcohol or drug abuse. Any significant psychiatric problems, including acute confusional state (delirium), ongoing psychosis, or clinically significant depression. Contraindications for deep brain stimulation (DBS) surgery. Heart failure, heart disease or any condition that contraindicates surgical procedures. Pacemaker or other active implanted stimulators. Clearly established Parkinson's disease dementia according to Movement Disorders Criteria. Participation in another drug, device, or biologics trial concurrently.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GPi stimulation + NBM stimulation<br>effective neurostimulation of the Nucleus basalis Meynert combined with globus pallidus internus (GPi) stimulation using Vercise deep brain stimulation | Device: Deep brain stimulation implantation of a Vercise neurostimulation system in GPi and NBM.<br>* Deep brain stimulation implantation of a Vercise neurostimulation system in GPi and NBM, at the same trajectory.<br>Device: GPi stimulation<br>* Bilateral high-frequency neurostimulation of the GPi using a Vercise neurostimulation system<br>Device: NBM stimulation<br>* Bilateral low-frequency neurostimulation of the NBM using a Vercise neurostimulation system<br>|
| Sham Comparator: GPi stimulation + sham stimulation<br>ineffective neurostimulation of the Nucleus basalis Meynert combined with subthalamic nucleus (STN) stimulation using Vercise deep brain stimulation | Device: Deep brain stimulation implantation of a Vercise neurostimulation system in GPi and NBM.<br>* Deep brain stimulation implantation of a Vercise neurostimulation system in GPi and NBM, at the same trajectory.<br>Device: GPi stimulation<br>* Bilateral high-frequency neurostimulation of the GPi using a Vercise neurostimulation system<br>Device: Sham stimulation<br>* Ineffective neurostimulation by setting 0mA output at the Vercise neurostimulation system<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of combined bilateral Globus Pallidus internus (GPi) and Nucleus Basalis of Meynert (NBM) stimulation in patients with moderate to advanced Parkinson's disease with mild cognitive impairment as determined by reported adverse events. | Safety of combined bilateral GPi and NBM stimulation in patients with moderate to advanced Parkinson's disease having mild cognitive impairment as determined by reported adverse events. | 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Parkinson's Disease - Cognitive Rating Scale (PD-CRS). | This scale can range from 0 to 134, and higher scores mean a better outcome. | 36 weeks | 
| Change in Mattis Dementia Rating Scale. | This scale can range from 0 to 144, and higher scores mean a better outcome. | 36 weeks | 
| Change in Verbal Fluency Battery. | FAS and animals | 36 weeks | 
| Change in Trail Making Task. | Trail Making Task Part A + B. | 36 weeks | 
| Change in Stroop Test. | Stroop Test (Victoria Version). | 36 weeks | 
| Change in Symbol Digit Modalities Test. | Digit symbol coding - WAIS. | 36 weeks | 
| Change in Parkinson's Disease Questionnaire for quality of life (PDQ-39). | This questionnaire can range from 0 to 100%, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Questionnaire of the EuroQol-group (EQ-5D-5L). | This questionnaire can range from 0 to 25, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Unified Parkinson's Disease Rating Scale section I (UPDRS I). | This scale can range from 0 to 52, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Unified Parkinson's Disease Rating Scale section II (UPDRS II). | This scale can range from 0 to 52, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Unified Parkinson's Disease Rating Scale section III (UPDRS III). | This scale can range from 0 to 132, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Unified Parkinson's Disease Rating Scale section IV (UPDRS IV). | This scale can range from 0 to 24, and higher scores mean a worse outcome. | 36 weeks | 
| Change in objective assessment of gait measured by a sensor (MobilityLab) that assess step speed. |  | 36 weeks | 
| Change in objective assessment of gait measured by a sensor (MobilityLab) that assess number of steps per minute. |  | 36 weeks | 
| Change in objective assessment of gait measured by a sensor (MobilityLab) that assess distance between heels. |  | 36 weeks | 
| Change in objective assessment of gait measured by a sensor (MobilityLab) that assess balance. |  | 36 weeks | 
| Change in objective assessment of gait measured by Time Up and Go - Test 3 meters (TUG test 3M). |  | 36 weeks | 
| Change in objective assessment of gait measured by Time Up and Go dual task - Test 3 meters (TUG dual task - test 3M). |  | 36 weeks | 
| Change in objective assessment of gait measured by freezing of gait score (FOG score). |  | 36 weeks | 
| Change in New Freezing of Gait Questionnaire (N-FOG). | This questionnaire can range from 0 to 28, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Falls Efficacy Scale International (FES-I). | This questionnaire can range from 0 to 64, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Activities-Specific Balance Confidence Scale (ABC scale). | This scale can range from 0 to 100%, and higher scores mean a better outcome. | 36 weeks | 
| Change in Beck Depression Inventory (BDI). | This inventory can range from 0 to 63, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Beck Anxiety Inventory (BAI). | This inventory can range from 0 to 63, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Starkstein Apathy Scale. | This scale can range from 0 to 42, and higher scores mean a worse outcome. | 36 weeks | 
| Change in Neuropsychiatric Inventory (NPI). |  | 36 weeks | 
| Change in Ardouin Scale of Behavior in Parkinson's Disease. | This scale can range from 0 to 84, and higher scores mean a worse outcome. | 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, Mild cognitive impairment, Globus Pallidus internus (GPi) Stimulation, Nucleus basalis of Meynert (NBM) Stimulation, Deep Brain Stimulation (DBS)