MR-guided Focused Ultrasound Plus GCase

Study Overview
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Brief Summary
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The goal of this study is to establish safety and feasibility of intracerebral delivery of GCase via MRgFUS. This technique may offer potential benefits given the exposure of the putamen to GCase in animal models has been shown to be efficacious in improving Parkinson's disease pathology and phenotype.

Detailed Description
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This is a two-arm, open-label, intervention only phase I/II clinical study. One arm of the study will enroll seven (7) GBA PD patients and the other arm seven (7) idiopathic PD patients. During the intervention phase, the first four subjects of each arm will receive three transcranial bilateral putamenal GCase at 30 IU/kg IV every two weeks, followed by 60 IU/kg in the next three subjects. Following three treatments in this study, the subjects will be followed for twelve months.

Official Title
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A Phase I/II Study for Bilateral Putamenal Delivery of Recombinant Glucocerebrosidase in Patients With Parkinson's Disease Using MR-guided Focused Ultrasound Induced Opening of the Blood-brain Barrier

Conditions
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Parkinsons Disease

Intervention / Treatment
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* Device: Blood Brain Barrier Disruption - Functional


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women between age 35 and 75 years, inclusive. Able and willing to give informed consent. Diagnosis of PD satisfying MDS Clinical Diagnostic Criteria for PD At least 2 years from initial diagnosis Hoehn and Yahr Stage 1-3 on PD medication Dopaminergic deficit by a positive DAT SPECT scan On stable regimen of PD medications for at least 90 days prior to the study American Society of Anesthesiologists (ASA) score 1-3 Harbor at least one GBA mutation if enrolled in the GBA PD arm or two wild-type GBA alleles if enrolled in the idiopathic PD arm Exclusion Criteria: Positive pregnancy test (for pre-menopausal women). Contraindication to DEFINITY ultrasound contrast agent or perflutren (e.g. hypersensitivity, known left or bidirectional cardiac shunt) Contraindication to MRI or gadolinium-DTPA (e.g. incompatible device, hypersensitivity) Insulin-dependent diabetes mellitus that is not well-controlled or that in the Investigator's opinion precludes participation in the study. Severely impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2 and/or on dialysis. Currently participating in another clinical therapeutic trial Patient receiving bevacizumab (Avastin) therapy Subjects with evidence of cranial or systemic infection. Cerebral or systemic vasculopathy. Documented cerebral infarction within the past 12 months or TIA in the past 1 month. Contraindication to GCase enzyme therapy, specifically previous hypersensitivity reaction to GCase enzyme therapy Parkinsonism plus symptoms, secondary parkinsonism Previous neurosurgical procedure for PD

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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A two-arm, open-label, intervention only clinical study. One arm to enroll 7 GBA PD patients, the second arm to enroll 7 idiopathic PD patients. In each arm, the first four subjects will take part in 3 focused ultrasound procedures along with 30 IU/Kg infusion of GCase. The next three subjects will take part in 3 focused ultrasound procedures along with 60 IU/Kg infusion of GCase.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idiopathic PD Patients<br>Idiopathic PD patients receiving 3 cycles of BBBO paired with GCase Treatments | Device: Blood Brain Barrier Disruption - Functional<br>* Delivery of GCase across the BBB to form a disease modifying strategy for patients with Parkinson's Disease<br>|
| Experimental: GBA PD Patients<br>GBA PD patients receiving 3 cycles of BBBO paired with GCase Treatments | Device: Blood Brain Barrier Disruption - Functional<br>* Delivery of GCase across the BBB to form a disease modifying strategy for patients with Parkinson's Disease<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Measure of the adverse events through the intervention phase and follow-up. All adverse events and/or Serious Adverse Events will be documented and reported according to CTCAE criteria. | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of MRgFUS BBB opening for GCase brain delivery | Using MRI images to measure: The qualitative measure of the MRI T1-weighted with gadolinium of contract extravasation in the sonicate putamen. The qualitative measure of the dynamic contrast enhanced (DCE) MRI | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, Glucocerebrosidase, GCase