Unilateral and Staged Bilateral Pallidothalamic Tractotomy Using Exablate MRgFUS in Advanced Parkinson's Disease.

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.

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.