One Pass thalamIc aNd subthalamIc stimulatiON

Study Overview
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Brief Summary
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Main part of the study: Randomised, active controlled, double blinded (patient and observer blinded), monocentric trial with three treatments, three periods and six treatment sequences allocated according to a Williams design Open Label Extension: After study treatment as described above, patients will be treated unblinded in their preferred stimulation mode until 36 months after implantation.

Detailed Description
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Tremor is the most salient symptom of Parkinson's disease (IPS=idiopathic Parkinson syndrome). Other symptoms are bradykinesia, rigidity and postural instability. As much as 75% of patients with IPS show resting tremor. Initially, tremor is typically unilateral and only visible in stress situation. In the later stage of the disease it becomes bilateral. The OPINION trial aims at the investigation of a combined approach to thalamic/subthalamic deep brain stimulation (DBS) for the treatment of patients with tremor dominant IPS or patients with equivalent type IPS who perceive tremor to be their dominant symptom. The planned approach will for the first time allow for the direct comparison of each condition in a homogeneous patient population and will furthermore allow an intra-individual comparison of the different stimulation conditions (Ventral intermediate nucleus (Vim/DRT) - Subthalamic nucleus (STN) - Vim/DRT+STN) with the outcome parameter quality of life. Patients will be registered to the trial and will undergo screening procedures (for eligibility criteria please see Inclusion and Exclusion criteria). If the patient is eligible the Investigational Medical Device (IMD) will be implanted (which is the Vercise™ Deep Brain Stimulation System manufactured by Boston Scientific). After implantation the IMD will remain OFF for a period of 1 month. 1 month after implantation treatment will be started. Patients will be randomized to one of the following 3 treatment groups: Subthalamic nucleus (STN) or Ventral intermediate nucleus (Vim/DRT) or combined stimulation (Vim/DRT+STN). Patients will undergo all three treatment groups each lasting 3 months. The patient is blinded meaning that study patients will not know what kind of treatment (e.g. mode/region of stimulation) they receive. 10 months after implantation the final visit of the randomized study will be performed. After that, patients will be asked to take part in an open label extension phase of the study where they will be treated unblinded according to established guidelines and according to their own preferred stimulation mode, just as they would be in a clinical routine setting. The extension phase is concluded by an end of study visit at 36 months after implantation. After the end of the trial, further treatment will be performed at the Department of Stereotactic and Functional Neurosurgery in Freiburg (Germany) according to established guidelines. Devices will be monitored 3-6 monthly Patient's medications will be adjusted as to the level of best treatment adjunct to stimulation. Study endpoints (e.g. quality of life) will be evaluated by a blinded rater. In addition, an external video rating will be performed.

Official Title
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One Pass thalamIc aNd subthalamIc stimulatiON

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Device: Vercise™ Deep Brain Stimulation System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged ≥ 35 and ≤ 75 years with a life expectancy of at least 5 years Patients with Parkinson's disease according to the criteria of the British Brain Bank as diagnosed by an in movement disorder specialized neurologist Parkinson patients are included with a medical treatment resistant and disabling resting and/or postural tremor as their major complaint and with a less prominent or absent hypokinetic-rigid component of their disease. Absence of postural instability (which would be aggravated under STN DBS) Hoehn & Yahr stage 1-3. After stadium 3 patients will show increased incidence of falling that can be aggravated by (typical) STN DBS Disease duration for at least 2 years and routine DAT-scan shows clear indication for Parkinsonism and atypical Parkinson syndromes are ruled out by routine glucose (FDG) PET PDQ-39 to be completed within 42 days prior surgery Written informed consent Exclusion Criteria: Major Depression with suicidal thoughts Dementia (Mattis Dementia Rating Score ≤ 130) Patients with lifetime primary psychotic disorder, schizophrenia, or schizoaffective disorder Patients with acute psychosis as diagnosed by a psychiatrist Nursing care at home Unable to give written informed consent Surgical contraindications like deformed or displaced or not discernable target region, scarring after brain disease (infarction), need for continuous anticoagulation that cannot be bridged in order to obtain normal coagulation Patients with advanced stage cardiovascular disease Patients under immunosuppressive or chemotherapy because of malignant disease Patients who had previous intracranial surgery Patients who are already under DBS therapy Patients with aneurysm clips Patients with cochlear implants Simultaneous participation or previous participation within 30 days prior to start of screening in a clinical trial involving investigational medicinal product(s) or investigational medical device(s) Medications that are likely to cause interactions in the opinion of the investigator Known or persistent abuse of medication, drugs or alcohol Persons who are in a relationship of dependence/employment with the sponsor or the investigator Fertile women not using adequate contraceptive methods: female condoms, diaphragm or coil, each used in combination with spermicides; intra-uterine device; hormonal contraception in combination with a mechanical method of contraception; Current or planned pregnancy, nursing period Contraindications according to device instructions or Investigator's Brochure: Diathermy: Shortwave, microwave, and/or therapeutic ultrasound diathermy. The energy generated by diathermy can be transferred to the Vercise™ DBS System, causing tissue damage at the contact site resulting in severe patient injury or death. Magnetic Resonance Imaging (MRI): Patients implanted with the Vercise™ DBS System should not be subjected to MRI. Patient incapability: Patients who are unable to properly operate the Remote Control and Charging System should not be implanted with the Vercise™ DBS System. Poor surgical risks: The Vercise™ DBS System is not recommended for patients who - because of their primary disease or additional co-morbidities - are not likely to benefit from the DBS system implantation.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STN<br>Deep Brain Stimulation of Nucleus subthalamicus with Vercise™ Deep Brain Stimulation System. The STN will be typically reached with the most distal contacts of the DBS electrode (8 contact). Imaging studies (postop helical CT and re-fusion to planning MRI data) will allow for the identification of contacts located in the STN. We expect the STN to be typically covered by contacts 1-4 of the Vercise™ DBS lead. Typically, only the most superficial contacts (3,4) will be activated after a monopolar review of each contact. In this monopolar review the therapeutic widths of each contact will be tested for its effectiveness in tremor reduction, reduction of rigidity and bradykinesia. Typical settings will be: Frequency 130-180 Hz, pulse width 60-90 us, Amplitude 1-7 mA. | Device: Vercise™ Deep Brain Stimulation System<br>* The Vercise™ DBS System includes a Stimulator with DBS Leads for unilateral or bilateral stimulation. There are also DBS Extensions that allow the DBS Leads mounted in the skull to be extended to reach the Stimulator implanted near the clavicle. The rechargeable Vercise DBS System utilizes current steering across eight contacts per DBS Lead to provide precise positioning of stimulation. The Stimulator is controlled by a handheld Remote Control, and can be interfaced with a Clinician's Programmer using the Bionic Navigator™ Software. Periodically, the Stimulator battery must be replenished with an RF (radiofrequency) charging device provided in the Patient DBS Charging Kit.<br>* Other names: Vercise DBS;|
| Experimental: Vim/DRT<br>Deep Brain Stimulation of Ventral intermediate nucleus with Vercise™ Deep Brain Stimulation System. The thalamic target (Vim/DRT) will be typically reached with the proximal contacts. Imaging studies (postop helical CT and re-fusion to planning MRI data) will allow for the identification of contacts located the thalamic target. We expect the thalamic target to be typically covered by contacts 5-8 of the Vercise™ DBS lead. We will perform a monopolar review of each contact. In this monopolar review the therapeutic widths of each contact will be tested for its effectiveness in tremor reduction and the occurrence of side effects (typically capsular e.g. facial contraction). Typical settings will be: Frequency 130-180 Hz, pulse width 60-90 us, Amplitude 1-7 mA. | Device: Vercise™ Deep Brain Stimulation System<br>* The Vercise™ DBS System includes a Stimulator with DBS Leads for unilateral or bilateral stimulation. There are also DBS Extensions that allow the DBS Leads mounted in the skull to be extended to reach the Stimulator implanted near the clavicle. The rechargeable Vercise DBS System utilizes current steering across eight contacts per DBS Lead to provide precise positioning of stimulation. The Stimulator is controlled by a handheld Remote Control, and can be interfaced with a Clinician's Programmer using the Bionic Navigator™ Software. Periodically, the Stimulator battery must be replenished with an RF (radiofrequency) charging device provided in the Patient DBS Charging Kit.<br>* Other names: Vercise DBS;|
| Experimental: STN+Vim/DRT<br>Combined Deep Brain Stimulation of Nucleus subthalamicus and Ventral intermediate nucleus with Vercise™ Deep Brain Stimulation System. STN+Vim/DRT stimulation is essentially a combination of the previously described procedure. | Device: Vercise™ Deep Brain Stimulation System<br>* The Vercise™ DBS System includes a Stimulator with DBS Leads for unilateral or bilateral stimulation. There are also DBS Extensions that allow the DBS Leads mounted in the skull to be extended to reach the Stimulator implanted near the clavicle. The rechargeable Vercise DBS System utilizes current steering across eight contacts per DBS Lead to provide precise positioning of stimulation. The Stimulator is controlled by a handheld Remote Control, and can be interfaced with a Clinician's Programmer using the Bionic Navigator™ Software. Periodically, the Stimulator battery must be replenished with an RF (radiofrequency) charging device provided in the Patient DBS Charging Kit.<br>* Other names: Vercise DBS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PDQ-39 total score | Change in PDQ-39 total score from base value (i.e. mean value of screening and baseline visit) until end of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) 3 months after start of each treatment up to 9 months | From baseline every 3 months up to 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FTMTRS | Change in Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS), and at 36 months, compared to base value (i.e. mean value of screening and baseline visit)recording at the tremor peak in tremor analysis | From baseline every 3 months up to 9 months, and at 36 months | 
| Change in UPDRS motor score (part III, except items 20 & 21) | Change in Unified Parkinson's Disease Rating Scale (UPDRS) motor score (part III, except items 20 & 21) every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS), and at 36 months, compared to base value (i.e. mean value of screening and baseline visit) | From baseline every 3 months up to 9 months, and at 36 months | 
| Change in UPDRS (part III, tremor subscore (items 20 & 21)) or total power of accelerometry recording at the tremor peak in tremor analysis | Change in UPDRS (part III, tremor subscore (items 20 & 21)) or total power of accelerometry recording at the tremor peak in tremor analysis every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS), and at 36 months, compared to base value (i.e. mean value of screening and baseline visit) | From baseline every 3 months up to 9 months, and at 36 months | 
| Clinical Global Impression Scale (CGI-I) | Assessment of Clinical Global Impression Scale (CGI-I) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months | Screening, baseline, then every 3 months until month 10, and at 36 months | 
| Change in PDQ-39 total score at 36 months | Change in PDQ-39 total score from base value (i.e. mean value of screening and baseline visit) until 36 months after implantation | Baseline, month 36 | 
| Psychiatric assessment: C-SSRS | Psychiatric assessment: Columbia Suicide Severity Rating Scale (C-SSRS) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months | Screening, baseline, then every 3 months until month 10, and at 36 months | 
| Psychiatric assessment: YMRS | Psychiatric assessment: Young Mania Rating Scale (YMRS) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months | Screening, baseline, then every 3 months until month 10, and at 36 months | 
| Psychiatric assessment: MADRS | Psychiatric assessment: Montgomery-Asberg Depression Scale (MADRS) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months | Screening, baseline, then every 3 months until month 10, and at 36 months | 
| Psychiatric assessment: BIS-11 | Psychiatric assessment: Barratt Impulsiveness Scale (BIS-11) at screening, at baseline (month 1) and then every three months after start of each treatment (Vim/DRT-DBS, STN-DBS, combined STN+Vim/DRT-DBS) until month 10, and at 36 months | Screening, baseline, then every 3 months until month 10, and at 36 months | 
| Assessment of (Serious) Adverse Events related to Investigational Medical Device, surgical procedures, stimulation settings and/or changes to medication | Assessment of Adverse Events (AEs) and Serious Adverse Events (SAEs) related to Investigational Medical Device (IMD), surgical procedures, stimulation settings and/or surgical procedures | Starting from implantation of device until last visit at month 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease