Clinical trial NCT02588144: Combined Stimulation of STN and SNr for Resistant Freezing of Gait in Parkinson's Disease
Official title: Combined Stimulation of Subthalamic Nucleus and Substantia Nigra Pars Reticulata for Resistant Freezing of Gait in Parkinson's Disease: A Randomized Controlled Multicenter Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Parkinson's Disease
Keywords: Parkinson's disease
freezing of gait
deep brain stimulation
substantia nigra pars reticulata
subthalamic nucleus
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: Medtronic
First posted: 2015-10-27
Enrollment: 54
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: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Freezing of Gait Assessment Course (FOG-AC)
timeFrame: Outcome at day 90 (V6) with reference to baseline (V1)
Secondary outcomes:
measure: Timed Walking test from Core Assessment Program for Surgical Interventions in Parkinson's disease (CAPSIT-PD)
timeFrame: At baseline, day 2, 8, 21, 42 and 90, respectively
measure: Berg Balance Scale
timeFrame: At baseline, day 42 and 90, respectively
measure: Parkinson's disease questionnaire (PDQ-39)
timeFrame: At baseline, day 42 and 90, respectively
measure: Freezing of gait questionnaire
timeFrame: At baseline, day 42 and 90, respectively
measure: Beck's depression Inventory
timeFrame: At baseline, day 42 and 90, respectively
measure: Columbia-Suicide Severity Rating Scale
timeFrame: At baseline, day 42 and 90, respectively
measure: Clinical global impression scale
timeFrame: At day 42 and 90, respectively
measure: Falls diary
timeFrame: At baseline, day 2, 8, 21, 42 and 90, respectively
measure: Movement Disorders Society Unified Parkinson's disease Rating Scale (MDS-UPDRS III)
timeFrame: At baseline, day 2, 8, 21, 42 and 90, respectively
measure: Movement Disorders Society Unified Parkinson's disease Rating Scale (MDS-UPDRS II)
timeFrame: At baseline, day 42 and 90, respectively
measure: Movement Disorders Society Unified Parkinson's disease Rating Scale (MDS-UPDRS IV)
timeFrame: At baseline, day 42 and 90, respectively
measure: Freezing of Gait Assessment Course (FOG-AC)
timeFrame: At baseline, day 2, 8, 21, 42 after active treatment (STN vs. STN+SNr), respectively
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: Center of Neurology and Hertie Institute for Clinical Brain Research, Department for Neurodegenerative Diseases and Neurosurgery University of Tübingen
state: Baden-Württemberg
city: Munich
country: Germany
facility: Ludwig-Maximilians-University Munich, Klinikum Großhadern, Department for Neurology and Neurosurgery
state: Bayern
city: Regensburg
country: Germany
facility: University Hospital Regensburg , Department for Neurology and Neurosurgery
state: Bayern
city: Düsseldorf
country: Germany
facility: University Hospital of Düsseldorf, Departments for Neurology and Neurosurgery
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: University Hospital Köln, Department for Neurology and Neurosurgery
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: University Hospital Leipzig, Department for Neurology and Neurosurgery
state: Sachsen
city: Kiel
country: Germany
facility: University Hospital Kiel, Department for Neurology and Neurosurgery
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Charite- University Hospital Berlin, Departments for Neurology and Neurosurgery
city: Hamburg
country: Germany
facility: University Hospital Hamburg-Eppendorf, Department for Neurology and Neurosurgery
city: Luxembourg
country: Luxembourg
facility: University Hospital Luxembourg, Department for Neurology and Neurosurgery
Study officials:
affiliation: Department for Neurodegenerative Diseases, Centre for Neurology, Tübingen, Germany, and Hertie-Institute for Clinical Brain Research
name: Daniel Weiss, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, Tübingen, Germany, and Center for Integrative Neuroscience, Tübingen, Germany
name: Alireza Gharabaghi, 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.