Asymmetric Subthalamic Deep Brain Stimulation for Axial Motor Dysfunction in Parkinson's Disease

Study Overview
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Brief Summary
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This single-center, randomized, quadruple-blinded, double-crossover comparative efficacy trial will study the effects of unilateral 50% voltage reduction in axial motor dysfunction for patients with Parkinson's disease that develop treatment-resistant postural stability gait dysfunction after bilateral subthalamic nucleus deep brain stimulation surgery.

Official Title
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A Single-center, Randomized, Double-blinded, Double-crossover Trial of Asymmetric Subthalamic Deep Brain Stimulation for Axial Motor Dysfunction in Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Other: Asymmetric STN-DBS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Parkinson's disease (PD) (previously diagnosed according to the UK brain bank criteria) who develop treatment-resistant postural instability gait dysfunction (PIGD) more than 6 months but less than 5 years after bilateral subthalamic nucleus deep brain stimulation (STN-DBS). Treatment-resistant PIGD will be defined as freezing of gait and UPDRS or MDS-UPDRS PIGD subscales of more than 6 points despite optimization of medications and bilateral STN-DBS programming. Exclusion Criteria: Treatment-resistant PIGD less than 6 months or more than 5 years after STN-DBS surgery. PIGD responsive to optimization of medications and/or bilateral STN-DBS programming. Cognitive impairment or psychiatric comorbidities (including substance abuse) that would interfere with the informed consent process, study adherence or outcome assessments. Advanced PD or any other neurological, cardiovascular or musculoskeletal co-morbidities that would preclude or require assistance to complete the 10-meter walking test. Patients not able to comply with 4-week interval evaluations following their potential enrollment due to personal reasons. Serious illness (requiring systemic treatment and/or hospitalization) until subject either completes therapy or is clinically-stable on therapy, in the opinion of the site investigator, for at least 30 days prior to study entry. Inability or unwillingness of subject or legal guardian/representative to give written informed consent.
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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Baseline STN-DBS<br>Maintenance of baseline bilateral STN-DBS settings. | |
| Experimental: Asymmetric STN-DBS 1<br>Unilateral 50% reduction of voltage (e.g. right side) | Other: Asymmetric STN-DBS<br>* Asymmetric deep brain stimulation<br>|
| Experimental: Asymmetric STN-DBS 2<br>Unilateral 50% reduction of voltage (e.g. left side) | Other: Asymmetric STN-DBS<br>* Asymmetric deep brain stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gait Velocity | As measured during the 10-meter walk test. In this test, participants walk at their usual, regular pace over a total distance of 10 meters. The middle 6-meters (between the 2-meter and 8-meter marks) are timed to measure gait velocity during steady-state gait. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Motor Function | As measured by the MDS-UPDRS (Movement Disorders Society Unified Parkinson's Disease Rating Scale), which is a clinical and research tool to measure symptoms and signs of Parkinson's disease. It has 4 parts: I (non-motor experiences of daily living), II (motor experiences of daily living), III (motor exam) and IV (motor complications). The MDS-UPDRS has 60 items, scored from 0-4 each. The minimum score is 0 and the maximum score is 240. The MDS-UPDRS (motor) is Part III and measures motor signs. It has 28 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 112. The MDS-UPDRS (axial motor) is composed of items 3.1 to 3.3a and 3.9 to 3.13 of Part III of the MDS-UPDRS and measures axial motor signs. It has 8 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 32. In the MDS-UPDRS total, motor and axial motor sub-scales, lower scores indicate better symptoms/signs and higher scores indicate worse symptoms/signs, respectively. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Axial Motor Function (1) | As measured by the Mini-BESTest. The Mini-BESTest is a shorter version of the BESTest (Balance Evaluation Systems Test). It is a clinical and research tool to measure balance control. The Mini-BESTest has 14 items, scored from 0-2 each, so the minimum score is 0 and the maximum score is 28. Lower scores indicate worse balance control and higher scores indicate better balance control. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Axial Motor Function (2) | As measured by the UPDRS-PIGD sub-scale. The UPDRS-PIGD is the Postural Instability Gait Dysfunction (PIGD) sub-scale of the Unified Parkinson's Disease Rating Scale (UPDRS). It is a clinical and research tool to measure PIGD. The UPDRS-PIGD has 5 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 20. Lower scores indicate better PIGD and higher scores indicate worse PIGD. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Axial Motor Function (3) | As measured by the Freezing of Gait Questionnaire. The Freezing of Gait Questionnaire is a clinical and research tool to measure freezing of gait. It has 6 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 24. Lower scores indicate better and higher scores indicate worse freezing of gait, respectively. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quantitative Gait Analysis (1) | Changes in gait velocity in m/s as measured by a quantitative gait analysis system (Zeno walkway). | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quantitative Gait Analysis (2) | Changes in step length in cm (mean, right, left) as measured by a quantitative gait analysis system (Zeno walkway). Step length difference = [right - left step length] | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quantitative Gait Analysis (3) | Step length ratio = [right step length] / [left step length] Step length symmetry = ([right - left step length] / [right + left step length]) | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quantitative Speech Analysis (1) | Changes in pitch in Hertz (Hz) as measured by the Praat software. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quantitative Speech Analysis (2) | Changes in loudness in decibels (dB) as measured by the Praat software. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quantitative Speech Analysis (3) | Changes in jitter measured in percentage by the Praat software. In this case, jitter is the percentage change in the stability of the frequency of speech tone (i.e. speech cycle-to-cycle frequency variation) | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quantitative Speech Analysis (4) | Changes in shimmer measured in percentage by the Praat software. In this case, shimmer is the percentage change in the stability of the amplitude of speech tone (i.e. speech cycle-to-cycle amplitude variation) | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Quality of Life | As measured by the Total Score of the 39-item Parkinson's Disease Quality of Life Questionnaire (PDQ-39). The PDQ-39 is a clinical and research tool to measure quality of life in Parkinson's disease. It has 39 questions, which patients score as never (0% of the time), occasionally (25% of the time), sometimes (50% of the time), often (75% of the time) or always (100% of the time). The PDQ-39 Total Score or Summary Index is the average of the 39 questions, expressed. The minimum score is 0% (never) and the maximum score is 100% (always). Lower scores indicate better quality of life and higher scores indicate worse quality of life. | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 
| Change in Select Cognitive Tasks | Left brain cognitive function: Hopkins Verbal Learning Test-Revised: Total recall trials 1-3 (0-36), delayed recall (0-12); Phonemic Verbal Fluency (0-no max); Semantic Verbal Fluency (Animal cue) (0-no max); Letter 1-back and 2-back working memory tasks (0-100%). Right brain cognitive function: Brief Visual Memory Test-Revised: Total recall trials 1-3 (0-36), delayed recall (0-12); Computerized landmark line bisection (-10 to 10); Spatial 1-back and 2-back working memory tasks (0-100%). Ranges in parentheses. Line bisection: closer to 0 is more accurate. For the rest: higher values are better | Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, axial motor dysfunction, asymmetric neuromodulation, subthalamic nucleus deep brain stimulation