Combined Stimulation of STN and SNr for Dysphagia in Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
20 patients with idiopathic Parkinson's disease and dysphagia will be included into this 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]. Both groups receive additional swallowing therapy as standard of care.

Detailed Description
-----------------
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 8 weeks on dysphagia. The Trial is designed as superiority study with an 81% power to detect a clinically relevant mean improvement of 2 points on the Penetration Aspiration Scale for fluids (two-tailed p < 0.05). To this end 20 patients will be randomized. After a common baseline assessment in [standardSTN], patients will be randomized to either [standardSTN] or [STN+SNr] in 1:1 ratio (10 per arm). The primary endpoint assessment is scheduled 8 weeks from baseline assessment (V2). Both treatment arms will receive swallowing therapy as standard of care. The rationale for this study comes from the association of swallowing and oral transport to neuronal integration upon the substantial nigra pars reticulate (SNr)-superior colliculus (SC) pathway (Rossi et al., 2016). Deep brain stimulation of the SNr has been put forward to modulate brainstem circuitry through its monosynaptic brainstem projections to the SC and to the pedunculopontine nucleus (PPN) (Chastan et al., 2009, Weiss et al., 2013, Rossi et al., 2016). Secondary outcome measures include anamnestic assessments on dysphagia, clinical global impression, freezing of gait and falls, balance, quality of life, neuropsychiatric symptoms and suicidality. Secondary outcome measures also include clinical assessment of dysphagia (Site of Swallow Reflex Initiation, Test of Mastication and Swallowing solids, pharyngeal residue) as well as motor symptoms with MDS-UPDRS III, Capsit-PD and Freezing of Gait Assessment Course.

Official Title
-----------------
Combined Stimulation of Subthalamic Nucleus and Substantia Nigra Pars Reticulata for Dysphagia: A Randomized Controlled Multicenter Trial

Conditions
-----------------
Parkinson's Disease, Dysphagia

Intervention / Treatment
-----------------
* Device: [standard STN]
* Device: [STN+SNr]
* Behavioral: Swallowing therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: cognitive competence to consent 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 sub thalamic 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 Penetration-Aspiration-Scale ≥ 3 or more than 20% utilization of vallecular space and/or pyriform sinuses post swallowing Disease duration ≥ 5 years Age: between 18 and 80 years Dopaminergic medication constant for at least two weeks prior to study enrollment Written informed consent Exclusion Criteria: Participation in other clinical trials within the past three months and during study enrolment Cognitive impairment (Mini Mental State Exam < 20) Severe depressive episode with or without psychotic symptoms and suicidality (ICD-10: F32.2, F32.3), psychosis (ICD-10: F23.-) Other severe pathological chronic condition that might confound treatment effects or interpretation of the data Pregnancy Infection and pneumonia at the time of study enrollment Other competing cause for dysphagia (e.g. stroke, operation, radiotherapy)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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] + swallowing therapy<br>standard stimulation on subthalamic (STN) contacts plus swallowing therapy | Device: [standard STN]<br>* standard stimulation on subthalamic (STN) contacts High frequency deep brain stimulation with variable (best individual) stimulation on subthalamic contacts<br>* Other names: subthalamic deep brain stimulation;Behavioral: Swallowing therapy<br>* Swallowing therapy with speech therapist<br>|
| Experimental: [STN+SNr] + swallowing therapy<br>Combined stimulation of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) plus swallowing therapy | Device: [STN+SNr]<br>* Combined stimulation of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) high frequency deep brain stimulation of combined (best individual) subthalamic and nigral stimulation<br>* Other names: combined subthalamic and nigral stimulation;Behavioral: Swallowing therapy<br>* Swallowing therapy with speech therapist<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Penetration Aspiration Scale | 8-point interval scale (range 1 - 8) to describe penetration and aspiration events . Scores are determined primarily by the depth to which material passes in the airway and by whether or not material entering the airway is expelled. (Rosenbek et al, 1996). The score is obtained in swallowing of fluids | Outcome after eight weeks (V2) with reference to baseline (V1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MDS-UPDRS parts I, II, III and IV | Rating Scale for symptoms of Parkinson's Disease: I Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Capsit-PD | Walking distance of 7m. Patient has to walk that distance back and forth. The time is measured as well as the number of steps needed for each way. Also, freezing episodes are counted. | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Freezing of Gait Assessment Course (FOG-AC) | Patients were asked to sit down on a chair, then stand up and walk to a floor mark .Within the mark they performed two 360° turns, clockwise (cw) and counter-clockwise (ccw). Then: open and walk through the door, turn outside, and come back to their chair. Four situations were rated: The start to walk, the turning (cw and ccw), and the passing through the door. 0 points: no festination and no FOG , 1 point: festination or any hastening steps. 2 points: FOG (trembling-in-place or total akinesia), which the patient could overcome himself. 3points: abortion of the task or need of interference by the examiner. Three levels of multiple tasking were applied: First passage;: no additional task (walking). Second passage: carrying a tray with a plastic cup full of water. Third passage: motor task and a mental task (carrying and calculation). (Ziegler et al. 2010) | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| PDQ-39 | The 39-item Parkinson's Disease Questionnaire is a widely used patient-reported clinical trial endpoint, where patients are asked about their health-related quality of life related to Parkinson's disease. | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Dysphagia-related Quality of Life (SWAL-QoL) | 48-item quality-of-life outcomes tool for dysphagia researchers and clinicians | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Clinical global impression self | (self-reporting, caregiver-reporting) | Outcome after eight weeks (V2) | 
| Diary on swallowing an related complications | complications (cough, suffocation, bronchitis, aspiration pneumonia) | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Site of Swallow reflex initiation | Two FEES outcome variables-delayed initiation of the pharyngeal reflex and postswallow pyriform sinus pooling(Scott et al 1998) | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Test of Mastication and Swallowing solids (TOMASS) | The Test of Masticating and Swallowing Solids (TOMASS) was developed as a quantitative assessment of solid bolus ingestion. For each study the test required participants to ingest a commercially available cracker with instructions to 'eat this as quickly as is comfortably possible'. Further averaged measures were derived including the number of masticatory cycles and swallows per bite, and time per bite, masticatory cycle and swallow. | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Pharyngeal Residue Visual Analogue Scale (VAS) | With FEES the pharyngeal residue (Sinus piriformis and vallecular) are rated on a visual analogue scale | Outcome after eight weeks (V2) with reference to baseline (V1) | 
| Functional oral intake scale (FOIS) | Scale to assess oral intake (7 points indicate full oral intake without restrictions, 1 points indicates no oral intake possible, 1-3 tube dependent) (Crary et al. 2005) | Outcome after eight weeks (V2) with reference to baseline (V1) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parkinson's disease, Dysphagia, Parkinsonian Disorders, Neurodegenerative Diseases, Movement Disorders, Nervous System Diseases, Basal Ganglia Diseases, Brain Diseases, Central Nervous System Diseases, Deep brain stimulation, substantia nigra pars reticulata, subthalamic nucleus