Clinical trial NCT03470324: Combined Stimulation of STN and SNr for Dysphagia in Parkinson's Disease
Official title: Combined Stimulation of Subthalamic Nucleus and Substantia Nigra Pars Reticulata for Dysphagia: A Randomized Controlled Multicenter Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Parkinson's Disease
Dysphagia
Keywords: 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
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: Michael J. Fox Foundation for Parkinson's Research
First posted: 2018-03-19
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Penetration Aspiration Scale
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
Secondary outcomes:
measure: MDS-UPDRS parts I, II, III and IV
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Capsit-PD
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Freezing of Gait Assessment Course (FOG-AC)
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: PDQ-39
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Dysphagia-related Quality of Life (SWAL-QoL)
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Clinical global impression self
timeFrame: Outcome after eight weeks (V2)
measure: Diary on swallowing an related complications
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Site of Swallow reflex initiation
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Test of Mastication and Swallowing solids (TOMASS)
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Pharyngeal Residue Visual Analogue Scale (VAS)
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
measure: Functional oral intake scale (FOIS)
timeFrame: Outcome after eight weeks (V2) with reference to baseline (V1)
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: University of Tübingen
Study officials:
affiliation: University Hospital Tuebingen
name: Daniel Weiss, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Weiss D, Walach M, Meisner C, Fritz M, Scholten M, Breit S, Plewnia C, Bender B, Gharabaghi A, Wachter T, Kruger R. Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial. Brain. 2013 Jul;136(Pt 7):2098-108. doi: 10.1093/brain/awt122. Epub 2013 Jun 11.
citation: Rossi MA, Li HE, Lu D, Kim IH, Bartholomew RA, Gaidis E, Barter JW, Kim N, Cai MT, Soderling SH, Yin HH. A GABAergic nigrotectal pathway for coordination of drinking behavior. Nat Neurosci. 2016 May;19(5):742-748. doi: 10.1038/nn.4285. Epub 2016 Apr 4.
citation: Chastan N, Westby GW, Yelnik J, Bardinet E, Do MC, Agid Y, Welter ML. Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson's disease. Brain. 2009 Jan;132(Pt 1):172-84. doi: 10.1093/brain/awn294. Epub 2008 Nov 11.
citation: Scholten M, Klemt J, Heilbronn M, Plewnia C, Bloem BR, Bunjes F, Kruger R, Gharabaghi A, Weiss D. Effects of Subthalamic and Nigral Stimulation on Gait Kinematics in Parkinson's Disease. Front Neurol. 2017 Oct 17;8:543. doi: 10.3389/fneur.2017.00543. eCollection 2017.
citation: Hidding U, Gulberti A, Horn A, Buhmann C, Hamel W, Koeppen JA, Westphal M, Engel AK, Gerloff C, Weiss D, Moll CK, Potter-Nerger M. Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients. Parkinsons Dis. 2017;2017:7306192. doi: 10.1155/2017/7306192. Epub 2017 Jan 26.
citation: Weiss D, Breit S, Wachter T, Plewnia C, Gharabaghi A, Kruger R. Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson's disease. J Neurol. 2011 Jun;258(6):1183-5. doi: 10.1007/s00415-011-5906-3. Epub 2011 Feb 2. No abstract available.