Unilateral and Staged Bilateral Pallidothalamic Tractotomy Using Exablate MRgFUS in Advanced Parkinson's Disease. (FREEDOM)
An MR Guided Focused Ultrasound (MRgFUS) Randomized Trial Using the Exablate Neuro System to Assess the Effectiveness and Safety Outcomes of Unilateral and Staged Bilateral Ablation in the Subthalamic Region Involving the Pallidothalamic Tract (PTT) in Advanced Parkinson's Disease (PD) With Motor Complications.
This study is a randomized clinical trial evaluating a focused ultrasound treatment for people with advanced Parkinson's disease (PD) who have disabling motor complications and symptoms.
The study uses the Exablate Neuro System, which delivers MR-guided Focused Ultrasound (MRgFUS). This technology focuses ultrasound energy on a specific brain target and generates heat to create a small lesion (ablation) without making a surgical incision.
The target in this study is the Pallidothalamic Tract (PTT), a pathway involved in the abnormal brain circuits that contribute to Parkinson's symptoms and complications.
This study is evaluating whether treating one side of the brain or treating both sides (in separate procedures) provides better outcomes for people with advanced Parkinson's disease who have motor complications and symptoms.
The main outcome measure is the change in the MDS-UPDRS Part III Upper/Lower Extremity (ULE) score at 3 months after first and second side treatment, compared with the respective control groups.
MDS-UPDRS Part III is a standard clinical scale used to assess Parkinson's motor symptoms. ULE score focuses on motor function in the arms and legs. Assessments are performed in the OFF-medication state, meaning Parkinson's medications are temporarily withheld so that the treatment effect can be measured more accurately.
In addition improvement in motor complications will be assessed with MDS-UPDRS Part IV and Patient diaries.
Study Overview
Status
Conditions
Detailed Description
A Post Approval Study (US) / Pre Market Extension Study (Outside US), international prospective, multi-center, assessor-blinded, two-stage (2:1) randomized controlled trial evaluating successive Exablate treatment (first and second side) versus BMT (Best Medical Treatment).
In individuals eligible for the staged, bilateral Exablate PTT procedure, building on evidence from the predicate pivotal staged bilateral study that led to PMA approval in the United States, this trial aims to evaluate the successive treatment of 1st and 2nd side Exablate PTT ablation using a two-stage randomized controlled design. In Stage 1, patients will be randomized to receive either 1st side PTT procedure or best medical treatment (BMT). Patients who initially randomized to receive BMT will cross over to receive 1st side PTT procedure after 3 months (if they still qualify for the treatment). All patients will continue to be followed through a 6-month period post 1st side treatment. All eligible patients who reach Stage 2 will be re-randomized to undergo 2nd side PTT procedure or continue with BMT. Patients randomized to receive BMT in stage 2 will cross over to receive 2nd side PTT procedure after 3 months (if they still qualify for the treatment). All patients will continue to be followed through a 12-month period post 2nd side treatment. This design enables evaluation between staged-bilateral treatment, unilateral treatment alone, and standard of care (SOC)/BMT medical therapy. This study will generate real-world comparative data to better inform decision-makers about the generalizability in subthalamic region ablations involving the PTT. Outcomes will be assessed using relevant lateralized Parkinson-specific clinical scales, measures of functional impairment, disease-specific quality of life, adverse events, and patient-reported perceptions of overall treatment effectiveness.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Elisa Cerutti, PhD
- Phone Number: +39 3459182413
- Email: elisac@insightec.com
Study Contact Backup
- Name: Jai Shetake, PhD
- Phone Number: +1 469 426 1022
- Email: jais@insightec.com
Study Locations
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Seoul, South Korea
- Korea University Anam Hospital
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Contact:
- Kyoungwon Baik
- Phone Number: +82-10-6620-8492
- Email: baikkw88@gmail.com
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Principal Investigator:
- Kyoungwon Baik
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Men or women, age 30 years and older
- Subject is able and willing to give informed consent and able to attend all study visits
- Subject with a diagnosis of idiopathic PD by UK Brain Bank Criteria as confirmed by a movement disorder neurologist at the site.
- Subject is interested in receiving bilateral treatment if they qualify.
- Subject is Levodopa responsive as defined by at least a 30% reduction in MDS-UPDRS motor subscale in the ON vs OFF medication state.
- Subject has MDS-UPDRS Part III OFF ULE score of ≥ 15 on each side in the meds OFF condition.
- Subject experiencing motor complications of PD on optimum medical treatment characterized by dyskinesia (MDS-UPDRS item 4.2 score of ≥ 2) OR Motor fluctuations (MDS-UPDRS item 4.4 score of ≥ 2)
- Subject is on a stable dose of all PD medications for 30 days prior to screening visit PD assessments as determined by medical records
- Subject is able to communicate sensations during the Exablate procedure.
- Subject's pallidothalamic region can be targeted by the Exablate device.
Exclusion Criteria:
Subject with severe premorbid risks as specified in the MDS-UPDRS Part II subsection motor aspects of experiences of daily living scores:
- 3 or 4 on question 2.1 (speech) OR
- 3 or 4 on question 2.3 (chewing and swallowing) OR
- 4 on question 2.2 (saliva and drooling).
- Subject where there is suspicion that Parkinsonian symptoms are a side effect from neuroleptic medications.
- Subject has an MMSE score < 24.
- Subject has other central neurodegenerative disease suspected on neurological examination. These include: multisystem atrophy, progressive supranuclear palsy, corticobasal syndrome, dementia with Lewy bodies, and Alzheimer's disease.
- Subject with unstable psychiatric disease, uncontrolled depressive symptoms, psychosis, delusions, hallucinations, or suicidal ideation.
- Female subject who is pregnant.
- Female subject of childbearing potential not willing to use contraceptives throughout the duration of the study (~ 24 months)
- Subject exhibiting any behavior(s) consistent with ethanol or substance abuse.
- Subject with unstable cardiac status or severe hypertension.
- Subject with history of abnormal bleeding, hemorrhage, or coagulopathy.
- Subject with cerebrovascular disease.
- Subject is receiving anticoagulant (e.g., warfarin) or antiplatelet (e.g., aspirin) therapy within one week of focused ultrasound procedure or drugs known to increase risk or hemorrhage (e.g., Avastin) within one month of focused ultrasound procedure.
- Subject with advanced kidney disease or on dialysis.
- Subject with a history of seizures within the past year.
- Subject with a brain tumor.
- Subject with life-threatening systemic disease (e.g. HIV, liver failure, blood dyscrasias, etc.).
- Subject with any illness that in the investigator's opinion precludes participation in this study.
- Subject with standard contraindications for MR imaging such as implanted metallic devices.
- Subject who had prior deep brain stimulation of the basal ganglia or thalamus.
- Subject who is unable to tolerate the required prolonged stationary supine position during treatment.
- Subject who has an Overall Skull Density Ratio of less than 0.40 as calculated from the screening CT (if this is the only exclusion, subject can participate in the study as part of the reference group).
- Subject who is participating in another clinical investigation with an active treatment arm
- Subject who is unable to communicate with the investigator and staff.
Subject who is in a nursing home in the last 30 days.
Additional Exclusion Criteria for Staged Bilateral PTT procedure
- Clinically significant neurological event of dysphagia, abnormal speech function, or gait abnormalities that are moderate to severe following first procedure.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Sequential Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Experimental: Active Group 1_Unilateral Exablate Pallidothalamic Tractotomy
Subjects will undergo the 1st side Exablate procedure (< 30 days after randomization) and will be followed for 6 months.
At their Month 6 visit, subjects will have their re-baseline assessment and undergo staged randomization for the 2nd side treatment.
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1st side Exablate MRgFUS Pallidothalamic Tractotomy for Parkinson's Disease
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Active Comparator: Control Group 1_Best Medical Treatment (BMT)
Subjects will have their standard of care (SOC) treatment adjusted to best effect (BMT), and will be followed for 3 months.
After their Month 3 visit, subjects will cross over to receive the 1st side treatment and be followed for 6 months.
At their Month 6 visit, subjects will have their Treatment 2 re-baseline assessment and undergo staged randomization for the 2nd side treatment.
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Subjects will be managed according to conventional therapeutic guidelines (i.e., best medical treatment) for Parkinson's Disease
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Experimental: Active Group 2_Staged Bilateral Exablate Pallidothalamic Tractotomy
Subjects will undergo the 2nd side Exablate procedure (< 30 days after re-baseline assessment, and will be followed for 12 months.
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1st side Exablate MRgFUS Pallidothalamic Tractotomy for Parkinson's Disease
2nd side staged Exablate MRgFUS Pallidothalamic Tractotomy for Parkinson's Disease
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Active Comparator: Control Group 2_BMT after Unilateral Exablate Pallidothalamic Tractotomy
Subjects will continue with their SOC BMT and will be followed for 3 months.
After their Month 3 visit, subjects will cross over to receive the 2nd side treatment and be followed for 12 months.
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1st side Exablate MRgFUS Pallidothalamic Tractotomy for Parkinson's Disease
Subjects will be managed according to conventional therapeutic guidelines (i.e., best medical treatment) for Parkinson's Disease
|
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Active Comparator: Reference Group_BMT with low SDR
Subjects will be offered the option to receive best medical treatment and will be followed to capture natural disease progression at approximately the same time schedule as patients in the randomized groups (~ every 3 - 6 months for up to 24 months).
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Subjects will be managed according to conventional therapeutic guidelines (i.e., best medical treatment) for Parkinson's Disease
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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MDS-UPRDS Part III ULE score in the OFF-medication (unilateral treatment)
Time Frame: 3 Months
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Between-group difference (Active Group 1 vs. Control Group 1) in the treatment effect (point change) in the MDS-UPRDS Part III ULE score in the OFF-medication state from Baseline to 3 month. This assessment will be performed by a Movement Disorders neurologist blinded to patient study group allocation. |
3 Months
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MDS-UPRDS Part III ULE score in the OFF-medication (bilateral treatment)
Time Frame: 3 Months
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Between-group difference (Active Group 2 vs. Control Group 2) in the treatment effect (point change) in the MDS-UPRDS Part III ULE score in the OFF-medication state from Baseline to 3 month. This assessment will be performed by a Movement Disorders neurologist blinded to patient study group allocation. |
3 Months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
MDS-UPDRS III Total score in the OFF-medication state
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
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Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
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MDS-UPDRS Part III OFF ULE score
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
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Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
|
|
MDS-UPDRS Part III ON Total score
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
|
Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
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MDS-UPDRS Part IV Total score
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
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Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
|
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Number of hours per day in ON time without troublesome dyskinesia- as measured by patient diaries (unilateral)
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
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Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
|
|
Number of hours per day in the OFF time as measured by patient diaries (unilateral)
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
|
Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
|
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Number of hours per day with troublesome dyskinesia (unilateral)
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
|
Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
|
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Quality of Life as measured by PDQ-39 (unilateral)
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
|
Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
|
|
Levodopa equivalent dose change usage (milligrams) (unilateral)
Time Frame: 1 Month, 3 Months, 6 Months, 12 Months
|
Between-group comparison (Active Group 1 vs Control Group 1) of the treatment effect at Month 3 following Treatment 1 (unilateral) and within-group comparison (Active Group 1) of the treatment effect at all study visits (Month 1, 3 and 6) following Treatment 1 compared to baseline. Between-group comparison (Active Group 2 vs Control Group 2) of the treatment effect at Month 3 following Treatment 2 (staged bilateral) and within-group comparison (Active Group 2) of the treatment effect at all study visits (Month 1, 3, 6 and 12) following Treatment 2 compared to baseline. |
1 Month, 3 Months, 6 Months, 12 Months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Joohi Jimenez-shahed, MD, Mount Sinai, Clinical Neurosciences Center
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- PD018
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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