Combined Stimulation of STN and SNr for Resistant Freezing of Gait in Parkinson's Disease

Study Overview
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Brief Summary
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54 patients with idiopathic Parkinson's disease and freezing of gait resistant to subthalamic nucleus stimulation and dopaminergic medication will be included into this multicentre randomised controlled double-blinded parallel group clinical trial. The treatment consists of two different stimulation settings using (i) conventional stimulation of the subthalamic nucleus [standard STN] as active comparator and (ii) combined stimulation of active electrode contacts located in both the subthalamic nucleus and substantia nigra pars reticulata [STN+SNr].

Detailed Description
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The primary endpoint of this study is to investigate the efficacy and safety of combined [STN+SNr] stimulation by interleaving stimulation as compared to [standardSTN] after 3 months on refractory freezing of gait (FOG). The Trial is designed as superiority study with an 80% power to detect a mean improvement of 4.7 points on the Freezing of Gait Assessment Course (Ziegler et al., 2010) with one-tailed P < 0.2. To this end 54 patients will be studied. After a common baseline assessment in [standardSTN], patients will be randomized to either [standardSTN] or [STN+SNr] in 1:1 ratio (27 per arm). The primary endpoint assessment is scheduled 90 days from baseline assessment (V6). Additional interim visits are scheduled for secondary purpose from baseline at day 2 (V2), day 8 (V3), day 21 (V4), day 42 (V5). The rationale for this study comes from our previous phase II trial (Weiss et al., 2013) in which we have observed an improvement of freezing of gait from combined STN+SNr stimulation as secondary endpoint compared with standard STN stimulation at three-week follow-up. Secondary outcome measures include anamnestic assessments on freezing of gait and falls, balance, quality of life, neuropsychiatric symptoms and suicidality.

Official Title
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Combined Stimulation of Subthalamic Nucleus and Substantia Nigra Pars Reticulata for Resistant Freezing of Gait in Parkinson's Disease: A Randomized Controlled Multicenter Trial

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Procedure: [standard STN]
* Procedure: [STN+SNr]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Idiopathic Parkinson's disease (according to the British Brain Bank criteria (Hughes, 1992) including genetic forms Therapy with STN-DBS (deep brain stimulation) (ACTIVA pulse generators) at least six months from surgery Activa PC (Primary Cell) or Activa RC (Rechargeable Cell) as implanted pulse generator with Interleaving programming option Localization of an active electrode contact in the subthalamic nucleus Localization of the caudal electrode contacts in the substantia nigra pars reticulata area (coordinates relative to midcommisural Point (MCP): left: -7mm ≤ x ≤ -12mm; -2mm ≤ y ≤ -6mm; -6mm ≤ z ≤ -10mm right: 7mm ≤ x ≤ 12mm; -2mm ≤ y ≤ -6mm; -6mm ≤ z ≤ -10mm (x = medio-lateral, y = anterio-posterior, z = rostro-caudal) ≥ 30% improvement in UPDRS III with 'standard STN' compared to 'stimulation off' in dopaminergic off Freezing of Gait Assessment Course ≥10 and ≤33 Patient not wheelchair-bound and possible to move self-dependently outside a freezing episode. Disease duration ≥ 5 years Age: between 18 and 80 years Dopaminergic medication constant for at least four weeks prior to study enrolment Written informed consent Exclusion Criteria: Participation in other clinical trials within the past three months and during enrolment in our study Cognitive impairment (Mini Mental State Exam < 20) Suicidality, Psychosis Other severe pathological chronic condition that might confound treatment effects or interpretation of the data Pregnancy Paradoxical levodopa-induced on state freezing (Espay et al., 2012)

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: [standard STN]<br>Device: standard stimulation on subthalamic (STN) contacts | Procedure: [standard STN]<br>* High frequency deep brain stimulation with variable (best individual) stimulation on subthalamic contacts<br>* Other names: subthalamic deep brain stimulation;|
| Experimental: [STN+SNr]<br>Device: Combined stimulation of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) | Procedure: [STN+SNr]<br>* high frequency deep brain stimulation of combined (best individual) subthalamic and nigral stimulation<br>* Other names: combined subthalamic and nigral stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freezing of Gait Assessment Course (FOG-AC) |  | Outcome at day 90 (V6) with reference to baseline (V1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Timed Walking test from Core Assessment Program for Surgical Interventions in Parkinson's disease (CAPSIT-PD) |  | At baseline, day 2, 8, 21, 42 and 90, respectively | 
| Berg Balance Scale |  | At baseline, day 42 and 90, respectively | 
| Parkinson's disease questionnaire (PDQ-39) |  | At baseline, day 42 and 90, respectively | 
| Freezing of gait questionnaire |  | At baseline, day 42 and 90, respectively | 
| Beck's depression Inventory |  | At baseline, day 42 and 90, respectively | 
| Columbia-Suicide Severity Rating Scale |  | At baseline, day 42 and 90, respectively | 
| Clinical global impression scale |  | At day 42 and 90, respectively | 
| Falls diary |  | At baseline, day 2, 8, 21, 42 and 90, respectively | 
| Movement Disorders Society Unified Parkinson's disease Rating Scale (MDS-UPDRS III) |  | At baseline, day 2, 8, 21, 42 and 90, respectively | 
| Movement Disorders Society Unified Parkinson's disease Rating Scale (MDS-UPDRS II) |  | At baseline, day 42 and 90, respectively | 
| Movement Disorders Society Unified Parkinson's disease Rating Scale (MDS-UPDRS IV) |  | At baseline, day 42 and 90, respectively | 
| Freezing of Gait Assessment Course (FOG-AC) | To determine treatment kinematics | At baseline, day 2, 8, 21, 42 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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Parkinson's disease, freezing of gait, deep brain stimulation, substantia nigra pars reticulata, subthalamic nucleus