Combined STN/SNr-DBS for the Treatment of Refractory Gait Disorders in Parkinson's Disease

Study Overview
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Brief Summary
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12 patients with idiopathic Parkinson's disease and refractory gait disturbances under best individual subthalamic nucleus stimulation and dopaminergic medication will be included into this randomised double-blind cross-over two-armed clinical trial. The treatment consists of two different stimulation settings using (i) conventional stimulation of the subthalamic nucleus [STNmono] and (ii) combined stimulation of distant electrode contacts located in the subthalamic nucleus and caudal border zone of STN and substantia nigra pars reticulata [STN+SNr].

Detailed Description
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A composite 'axial score' including the major clinical and anamnestic items on gait, posture and balance function from UPDRSII (items 13-15) and UPDRS III (items 27-31) constitutes the primary outcome measure. Secondary outcome measures include specified clinical and anamnestic assessments on freezing of gait, balance, quality of life, non-motor symptoms, impulsivity, impulse control and neuropsychiatric symptoms. The aim of the present trial is to investigate the efficacy and safety of combined stimulation on subthalamic and nigral electrode contacts [STN+SNr] in refractory hypokinetic gait disturbances compared with [STNmono] (active comparator). The results will clarify, whether the combined [STN+SNr] stimulation improves otherwise refractory gait disturbances in PD.

Official Title
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Combined STN/SNr-DBS for the Treatment of Refractory Gait Disorders in Parkinson's Disease: Design of a Two-armed Double-blind Cross-over Study

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Device: deep brain stimulation (ACTIVA PC, Medtronic)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age: between 18 and 80 years Idiopathic Parkinson's disease (according to the British Brain Bank criteria (Hughes, 1992) including genetic forms and therapy with STN-DBS (ACTIVA pulse generators) at least six months from surgery Optimized subthalamic stimulation at study enrolment (refer 'treatment' section) Gait disturbance refractory on best individual STN-DBS (STNmono) and dopaminergic therapy: 'gait score' in the best clinical [MedOn/STNmono] condition ≥ 12 Clinical and image-guided (and facultatively electrophysiological) confirmation of (i) one of the two rostral contacts of the quadripolar electrode localized in the STN area, and (ii) the caudal contacts in the border zone of STN and SNr. Dopaminergic medication constant for at least four weeks prior to study enrolment Disease duration ≥ 5 years Exclusion Criteria: Cognitive impairment (Mini Mental State Exam < 25) Participation in other clinical trials within the past three months and during enrolment in our study Suicidality, Psychosis Other severe pathological chronic condition that might confound treatment effects or interpretation of the data Pregnancy Acute adverse events from stimulation on contacts in the caudal STN / SNr border interfering with the intended stimulation protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: [STNmono]<br>Conventional stimulation on subthalamic contacts | Device: deep brain stimulation (ACTIVA PC, Medtronic)<br>* High frequent deep brain stimulation with variable (best individual) stimulation on subthalamic contacts and standard parameters on nigral contacts (125 Hz, 60µs, best individual amplitude)<br>* Other names: Neurostimulation with ACTIVA PC, Medtronic;|
| Experimental: [STN+SNr]<br>Combined subthalamic and nigral stimulation | Device: deep brain stimulation (ACTIVA PC, Medtronic)<br>* High frequent deep brain stimulation with variable (best individual) stimulation on subthalamic contacts and standard parameters on nigral contacts (125 Hz, 60µs, best individual amplitude)<br>* Other names: Neurostimulation with ACTIVA PC, Medtronic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 'Axial score' | The composite 'axial score' is built by 8 items from the UPDRS II and III, all 5-point rated (0 to 4) representing increasing levels of pathology. The 'axial score' will be scored by the sum of the ratings across the 8 items (Range 0 to 32). As change in UPDRS scores is a common primary efficacy outcome measure in Parkinson's disease and only items of the original UPDRS are required for the definition of the primary endpoint, the statistical evaluation methods should be based on the psychometric validation of the UPDRS and no own validation studies are necessary. Safety: falls | Three weeks after active treatment (STN vs. STN+SNr), respectively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAPSIT-PD |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Freezing of gait assessment course |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Freezing of gait questionnaire |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Berg Balance Scale |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Non-motor symptoms scale |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Non-motor symptoms quest |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Beck's depression scale index |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Minnesota Impulsive Disorders Interview |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| Barratt Impulsiveness Scale |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| UPDRS I-IV |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 
| PDQ-39 |  | At baseline and three weeks after active treatment (STN vs. STN+SNr), respectively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gait, Parkinson's disease, deep brain stimulation, substantia nigra pars reticulata, subthalamic nucleus