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The Motor Network in Parkinson's Disease and Dystonia: Mechanisms of Therapy

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ClinicalTrials.gov Identifier: NCT03582891
Recruitment Status : Recruiting
First Posted : July 11, 2018
Last Update Posted : June 18, 2019
Sponsor:
Information provided by (Responsible Party):
Philip Starr, University of California, San Francisco

Brief Summary:

This is an exploratory pilot study to identify neural correlates of specific motor signs in Parkinson's disease (PD) and dystonia, using a novel totally implanted neural interface that senses brain activity as well as delivering therapeutic stimulation. Parkinson's disease and isolated dystonia patients will be implanted unilaterally or bilaterally with a totally internalized bidirectional neural interface, Medtronic Summit RC+S.

This study includes three populations: ten PD patients undergoing deep brain stimulation in the subthalamic nucleus (STN), ten PD patients with a globus pallidus (GPi) target and five dystonia patients. All groups will test a variety of strategies for feedback-controlled deep brain stimulation. Only the STN patients will undergo a blinded, small pilot clinical trial of closed-loop stimulation for thirty days.


Condition or disease Intervention/treatment Phase
Parkinson Disease Dystonia Device: Summit RC+S Diagnostic Test: 1-month pilot trial of Closed-loop vs. Open-loop Stimulation Not Applicable

Detailed Description:

In this project investigators will develop adaptive DBS algorithms based on cortical and subcortical signals using the RC+S. This bidirectional neural interface is rechargeable (for up to 9 years of use), and is capable of delivering therapeutic open-loop stimulation or closed-loop stimulation. Its sensing capability includes four simultaneous time series channels at up to 1000 Hz sampling rate. In addition the device can stream time series data, and calculate and stream spectral power within a preset bandwidth. Twenty patients with idiopathic PD and motor fluctuations, or medically intractable tremor, will be implanted with unilateral or bilateral RC+S devices, each connected to a standard quadripolar DBS lead implanted in STN or globus pallidus, and to a 4-contact paddle type electrode placed subdurally over sensorimotor cortex. The basal ganglia lead will be used for both stimulation and LFP recordings, while the cortical lead will be used only for recording ECoG potentials, not for stimulation.

Patients with motor fluctuations cycle between a hypokinetic state (too little movement) and a hyperkinetic state (excessive movement). During open-loop DBS, brain state continues to fluctuate between these states and stimulation may induce dyskinesia or inadequately relieve akinesia.

With the goal of maintaining motor function within a normal range away from these two extremes, investigators will develop and test stimulation algorithms that utilize putative markers of both kinetic states. The basic strategy is to automatically adjust stimulation parameters until the physiological signature of abnormal function is minimized. First, investigators will prototype adaptive stimulation paradigms and briefly (2 hours) test them in clinic, using a "distributed" configuration (streaming to a computer). Then, investigators will embed these algorithms in RC+S to test chronic and fully closed-loop DBS in a small double-blinded clinical trial. Investigators will pay careful attention to the possibility of progressive reduction in stimulation currents over the course of the study, which could support the hypothesis that "adaptive stimulation" might make the brain progressively less dependent on the device. In quantifying DBS amplitude and comparing open loop with adaptive stimulation, an important parameter is the total electrical energy delivered (TEED). TEED is calculated by the following equation as suggested by Koss and colleagues (TEED1sec = ((voltage2 x frequency x pulsewidth)/impedance) x 1sec). This can be used as measure of the energy saved when stimulation is delivered in closed-loop mode relative to empiric open-loop stimulation.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Investigators will run a pilot clinical trial in which individualized classifier/control strategies for each hemisphere in each subject will be embedded within the RC+S for one month of feedback-controlled stimulation will be compared with one month of empirically optimized open-loop stimulation, administered in randomized order with closed-loop stimulation. During these 1-month trials, patients will be blinded to the state of the stimulator and motor evaluations will be filmed in order for blinded neurologists to rate their motor symptoms. This trial takes place 11 and 12 months post-surgery depending upon which group the subject is randomized to.
Masking: Double (Participant, Outcomes Assessor)
Masking Description:

Subjects with Parkinson's disease who are being implanted in the STN will be blinded to the type of stimulation received (open-loop or closed-loop phases) during month 11 or month 12. Each of these subjects will have blinded open-loop or closed-loop stimulation for one month and the order will be assigned randomly.

The use of objective measures of motor function such as wearable devices, in addition physician administered rating scales, is a strategy to reduce observer bias. For physician administered scales, all exams will be videotaped so that these can be reviewed by a blinded neurologist evaluator.

Primary Purpose: Treatment
Official Title: Closed Loop Deep Brain Stimulation in Parkinson's Disease and Dystonia (Activa RC+S)
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : July 1, 2025
Estimated Study Completion Date : March 2028


Arm Intervention/treatment
Parkinson's Disease STN Target
Parkinson's disease patients implanted in STN
Device: Summit RC+S
Using the RC+S pulse generator, investigators will measure cortical biomarkers of hyper and hypokinesia in Parkinson's and dystonia patients to develop an adaptive algorithm which adjusts the level of deep brain stimulation needed based upon the patient's physiology.

Diagnostic Test: 1-month pilot trial of Closed-loop vs. Open-loop Stimulation
These patients will have a blinded trial of closed-loop stimulation or open-loop stimulation for 1 month at either 11 or 12 months into the study. This trial will take place at either 11 or 12 months into the study, a participants will be randomly assigned to receive closed or open-loop stimulation first.

Parkinson's disease patients GP Target
Parkinson's disease patients implanted in Globus Pallidus
Device: Summit RC+S
Using the RC+S pulse generator, investigators will measure cortical biomarkers of hyper and hypokinesia in Parkinson's and dystonia patients to develop an adaptive algorithm which adjusts the level of deep brain stimulation needed based upon the patient's physiology.

Dystonia patients
Isolated dystonia patients
Device: Summit RC+S
Using the RC+S pulse generator, investigators will measure cortical biomarkers of hyper and hypokinesia in Parkinson's and dystonia patients to develop an adaptive algorithm which adjusts the level of deep brain stimulation needed based upon the patient's physiology.

Diagnostic Test: 1-month pilot trial of Closed-loop vs. Open-loop Stimulation
These patients will have a blinded trial of closed-loop stimulation or open-loop stimulation for 1 month at either 11 or 12 months into the study. This trial will take place at either 11 or 12 months into the study, a participants will be randomly assigned to receive closed or open-loop stimulation first.




Primary Outcome Measures :
  1. Duration of 'on' stimulation time without dyskinesia from motor diaries in adaptive compared to standard open loop stimulation. (Parkinson's disease patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    Duration of 'on' stimulation time without dyskinesia in adaptive compared to standard open loop stimulation determined from the patients' motor diaries. The self-report motor diary is a validated method to capture this information. Every half-hour, patients indicate in this diary which of 4 categories (on, on with troubling dyskinesia, off, or asleep) best reflected their predominant symptoms for the prior 30 minutes. Patients will complete this diary for 3 consecutive days. The total time spent in the 'on' state without troubling dyskinesia will then be summed and averaged over 3 days for all three conditions (baseline, open-loop stimulation and closed-loop stimulation).

  2. The Burke‐Fahn‐Marsden Dystonia Rating Scale-Movement aDBS testing compared to pre-operative baseline(Dystonia Patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    This scales evaluates dystonia in nine body areas, including eyes, mouth, speech and swallowing, neck, trunk, and right and left arm and leg. The maximal total score is 120 - a higher score means worsening symptoms. Investigators will compare the dystonia symptoms and functional disability during adaptive stimulation compared to preoperative baseline.

  3. Toronto Western Spasmodic Torticollis Rating Scale during aDBS testing compared to pre-operative baseline (Dystonia Patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    This is a standardized scale to measure the severity, disability, and pain associated with cervical dystonia. The motor severity subscale consists of 10 items, with variable scaling and weighting. It also includes a disability scale with six items,and a pain scale with three items. The total score is the sum of each of the subscales. A higher score indicates greater disability.


Secondary Outcome Measures :
  1. The Unified Parkinsons Disease Rating Scale (UPDRS) III scores off of medication in adaptive compared to standard open-loop stimulation. (Parkinson's disease patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    The UPDRS III is a motor rating scale. Investigators will compare the severity motor symptoms while the patient is off of Parkinsoniae (UPDRS) III scores off of medication in adaptive compared to standard open-loop stimulation. (Parkinson's disease patients)n medications in conventional (open-loop) versus adaptive (closed-loop) DBS.

  2. Schwab England scale in adaptive compared to standard open loop stimulation. (Parkinson's disease patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    This scale estimates the abilities of individuals living with Parkinson's Disease relative to a completely independent situation. Investigators will use it to compare the abilities of daily living in subjects during the open-loop and adaptive stimulation trial.

  3. Hoehn and Yahr Staging in the medication 'on' state in adaptive compared to standard open loop stimulation. (Parkinson's disease patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    The Hoehn and Yahr scale are used to describe the progression of Parkinson's disease based upon the level of motor impairment. This scale only includes one score ranging from 1 to 5 where a higher score indicates a higher level of motor impairment. Investigators will compare the level of disease progression between the open-loop and adaptive stimulation conditions.

  4. The patient' quality of life report (PDQ-39) in adaptive compared to standard open loop stimulation. The PDQ39 yields a score between 0 to 100, where a higher score indicates more health problems. (Parkinson's disease patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    The PDQ 39 questionnaire has 39 questions to assess the patient's life quality including mobility, emotional state, and bodily comfort. Investigators will make a comparison of patients' life quality of life between open-loop and adaptive stimulation.

  5. Patient's Global Impression of Change (PGIC) in adaptive compared to standard open loop stimulation. (Parkinson's disease patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    Patient Global Impression of Changes measures the self-reported level of overall improvement (motor and non-motor symptoms) in a patient on a 1-7 scale. A one indicates no change and a 7 is the greatest level of improvement.

  6. Total Electric Energy Delivered (TEED) by the pulse generator in adaptive compared to standard open loop stimulation. (all patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    Investigators will compare the total charge delivered by the pulse generator between open-loop and adaptive stimulation to determine if there is a potential energy savings.

  7. Short form 36 Quality of Life measure (Dystonia Patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    The SF-36 is a measure of self-reported health status which is scored on a 0-100 scale. The lower the score the more disability a patient experiences.

  8. Patient Global Impression of Change (Dystonia Patients) [ Time Frame: Comparison will use data from the testing of open and closed-loop stimulation in months 11-12 (post-implantation). Ordering depends upon participant randomization. ]
    Patient Global Impression of Changes measures the self-reported level of overall improvement (motor and non-motor symptoms) in a patient on a 1-7 scale. A one indicates no change and a 7 is the greatest level of improvement.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Parkinson's Disease:

  1. Ability to give informed consent for the study
  2. Movement disorder symptoms that are sufficiently severe, in spite of best medical therapy, to warrant surgical implantation of deep brain stimulators according to standard clinical criteria
  3. Patient has requested surgical intervention with deep brain stimulation for their disorder
  4. No MR abnormalities that suggest an alternative diagnosis or contraindicate surgery
  5. Absence of significant cognitive impairment (score of 20 or greater on the Montreal Cognitive Assessment (MoCA),
  6. Signed informed consent
  7. Ability to comply with study follow-up visits for brain recording, testing of adaptive stimulation, and clinical assessment.
  8. Age 21-75 (for STN patients, minimum age is 25)
  9. Diagnosis of idiopathic PD with duration of motor symptoms for 4 years or greater
  10. Patient has undergone appropriate therapy with oral medications with inadequate relief as determined by a movement disorders neurologist, and has had stable doses of antiparkinsonian medications for 30 days prior to baseline assessment.
  11. UPDRS-III score off medication between 20 and 80 and an improvement of at least 30% in the baseline UPDRS-III on medication score, compared to the baseline off-medication score, and motor fluctuations with at least 2 hours per day of on time without dyskinesia or with non-bothersome dyskinesia.

OR Patients with tremor-dominant PD (a tremor score of at least 2 on a UPDRS-III sub-score for tremor), treatment resistant, with significant functional disability despite maximal medical management

Dystonia:

  1. Ability to give informed consent for the study
  2. Movement disorder symptoms that are sufficiently severe, in spite of best medical therapy, to warrant surgical implantation of deep brain stimulators according to standard clinical criteria
  3. Patient has requested surgical intervention with deep brain stimulation for their disorder
  4. No MR abnormalities that suggest an alternative diagnosis or contraindicate surgery
  5. Absence of significant cognitive impairment (score of 20 or greater on the Montreal Cognitive Assessment (MoCA)
  6. Signed informed consent
  7. Ability to comply with study follow-up visits for brain recording, testing of adaptive stimulation, and clinical assessment.
  8. Age 21-75
  9. Diagnosis of Isolated dystonia, which may be focal cervical, segmental craniocervical, or generalized forms.
  10. Stable doses of anti-dystonia medications (such as trihexyphenydil, Baclofen, or clonazepam) for at least 30 days prior to baseline assessment
  11. For dystonia patients with craniofacial and cervical involvement, prior treatment with botulinum toxin with failure to adequately control dystonia symptoms.

Exclusion Criteria

Parkinson's Disease:

  1. Coagulopathy, anticoagulant medications, uncontrolled hypertension, history of seizures, heart disease, or other medical conditions considered to place the patient at elevated risk for surgical complications
  2. Evidence of a psychogenic movement disorder: Motor symptoms that remit with suggestion or "while unobserved", symptoms that are inconsistent over time or incongruent with clinical condition, plus other manifestation such as "false" signs, multiple somatizations, or obvious psychiatric disturbance.
  3. Pregnancy: all women of child bearing potential will have a negative urine pregnancy test prior to undergoing their surgical procedure.
  4. Significant untreated depression (BDI-II score >20) History of suicidal attempt or active suicidal ideation (Yes to #2-5 on C-SSRS)
  5. Any personality or mood symptoms that study personnel believe will interfere with study requirements.
  6. Subjects who require ECT, rTMS or diathermy
  7. Implanted stimulation systems such as; cochlear implant, pacemaker, defibrillator, neurostimulator or metallic implant
  8. Previous cranial surgery
  9. Drug or alcohol abuse
  10. Meets criteria for Parkinson's disease with mild cognitive impairment (PD-MCI). These criteria are: performance of more than two standard deviations below appropriate norms, for tests from two or more of these five cognitive domains: attention, executive function, language, memory, and visuospatial tests.

Dystonia:

  1. Coagulopathy, anticoagulant medications, uncontrolled hypertension, history of seizures, heart disease, or other medical conditions considered to place the patient at elevated risk for surgical complications
  2. Evidence of a psychogenic movement disorder: Motor symptoms that remit with suggestion or "while unobserved", symptoms that are inconsistent over time or incongruent with clinical condition, plus other manifestation such as "false" signs, multiple somatizations, or obvious psychiatric disturbance.
  3. Pregnancy: all women of child bearing potential will have a negative urine pregnancy test prior to undergoing their surgical procedure.
  4. Significant untreated depression (BDI-II score >20) History of suicidal attempt or active suicidal ideation (Yes to #2-5 on C-SSRS)
  5. Any personality or mood symptoms that study personnel believe will interfere with study requirements.
  6. Subjects who require ECT, rTMS or diathermy
  7. Implanted stimulation systems such as; cochlear implant, pacemaker, defibrillator, neurostimulator or metallic implant
  8. Previous cranial surgery
  9. Drug or alcohol abuse

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03582891


Contacts
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Contact: Joncarmen Mergenthaler, B.S. 415.514.8285 joncarmen.mergenthaler@ucsf.edu
Contact: Sarah Wang, PhD 415.353.2311 Sarah.Wang@ucsf.edu

Locations
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United States, California
University of California at San Francisco Recruiting
San Francisco, California, United States, 94115
Contact: joncarmen v mergenthaler, BS    415-514-8285    joncarmen.mergenthaler@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Philip A Starr, MD/PhD University of California, San Francisco

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Responsible Party: Philip Starr, Endowed Professor of Neurological Surgery, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03582891     History of Changes
Other Study ID Numbers: UCSF Summit RC+S
First Posted: July 11, 2018    Key Record Dates
Last Update Posted: June 18, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Additional relevant MeSH terms:
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Parkinson Disease
Dystonia
Dystonic Disorders
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Dyskinesias
Neurologic Manifestations
Signs and Symptoms