Blood-Brain-Barrier Disruption With Cerezyme in Patient's With Parkinson's Disease

• ClinicalTrials.gov Identifier: NCT04370665
• Recruitment Status: Active, not recruiting
• First Posted: May 1, 2020
• Last Update Posted: August 2, 2022
• Sponsor: InSightec
• Information provided by (Responsible Party): InSightec

Tracking Information

• First Submitted Date: April 15, 2020
• First Posted Date: May 1, 2020
• Last Update Posted Date: August 2, 2022
• Actual Study Start Date: July 16, 2020
• Actual Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 28, 2020)

Contrast enhancement on MR imaging [ Time Frame: Immediately after MRgFUS BBBD procedure ]

MRgFUS BBB Opening will be determined qualitatively by contrast enhancement in the sonicated putamen on T1-weighted with gadolinium MRI, and quantitatively by the change in intensity relative to contralateral unsonicated putamen immediately after MRgFUS BBBD procedure.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 28, 2020)

Safety --Adverse events [ Time Frame: Through study completion, an average of 3 months ]

Safety will be assessed by recording all adverse events and/or Serious Adverse Events that are BBBD related. Each Adverse Event will be documented for patterns of occurrence.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: April 28, 2020)

• Exploratory effectiveness of Cerezyme delivery via MRgFUS BBB Opening [ Time Frame: 1 day after the final BBBD procedure ]
  Exploratory effectiveness of Cerezyme delivery via MRgFUS BBB Opening will be measured by changes in levels of Cerezyme (GCase) and GCase substrates levels (e.g. GL1 and glucosylsphingosine or lyso-GL1) in cerebralspinal fluid (CSF) samples.
• Exploratory effectiveness of Cerezyme treatment via MRgFUS BBB Opening [ Time Frame: 3 months after the final BBBD procedure. ]
  Exploratory effectiveness of Cerezyme treatment via MRgFUS BBB Opening will be measured by changes in cognitive impairment via Mini-Mental Status Exam (MMSE).

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Blood-Brain-Barrier Disruption With Cerezyme in Patient's With Parkinson's Disease
• Official Title: A Pilot Study for Brain Delivery of Cerezyme® in Patients With Parkinson's Disease Using MR-guided Focused Ultrasound Induced Opening of the Blood-brain Barrier
• Brief Summary: This clinical trial focus on the delivery of Cerezyme® in Parkinson's Disease (PD) patients using MR-guided focused ultrasound (MRgFUS) induced opening of the blood-brain barrier (BBB).
• Detailed Description: Leveraging the preclinical evidence and clinical experience with MRgFUS BBB opening in human subjects, the investigators propose a phase I open-label study to determine the safety and feasibility of three biweekly delivery of Cerezyme® (an analogue of the human enzyme beta-glucocerebrosidase) via MRgFUS induced BBB opening to unilateral putamen in PD. The putamen contains terminals of dopaminergic neurons from the substantia nigra, and is a critically affected brain region in PD. The primary objective is to determine the feasibility of repeated MRgFUS BBB opening for Cerezyme delivery in unilateral putamen. The secondary objective is to describe the safety and tolerability of the procedure. Another objective is to measure changes in PD relevant clinical scores and Cerezyme relevant biomarkers in the study.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

This is a prospective, single-center, single-arm, open-labelled study to enroll six (6) patients with Parkinson's disease for three biweekly deliveries of Cerezyme® to the unilateral putamen corresponding to the most affected side using Exablate and Definity®-induced BBB opening. This is a dose escalation study. Each subject will be followed for three months after the final procedure.

Masking: None (Open Label)
Primary Purpose: Device Feasibility

• Condition: Parkinson Disease

Intervention

Device: Exablate BBBD with Cerezyme

Blood Brain Barrier Disruption via Exablate to deliver Cerezyme.

Other Names:

Exablate Neuro

Study Arms

Experimental: Open label single arm

Using Exablate Model 4000 Type-2 to temporarily disrupt the blood brain barrier to deliver Cerezyme in patients with Parkinson's Disease.

Intervention: Device: Exablate BBBD with Cerezyme

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 11, 2021): 4
• Original Estimated Enrollment (submitted: April 28, 2020): 6
• Estimated Study Completion Date: December 2022
• Actual Primary Completion Date: December 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Men or women between age 35 and 75 years, inclusive.
2. Able and willing to give informed consent.
3. Diagnosis of Parkinson's Disease.
4. At least 2 years from initial diagnosis
5. On stable regiment of PD medications for at least 90 days prior to the study
6. Able to communicate during the Exablate MRgFUS procedure.
7. Able to attend all study visits.

Exclusion Criteria:

1. Previous neurosurgical procedure for PD
2. Cerezyme hypersensitivity
3. Patients who had recent intracranial hemorrhage or stroke
4. Skull covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp. Patients who have clips or other metallic implanted objects in the skull or the brain.
5. Patients who are on blood thinners within washout period prior to treatment (i.e., antiplatelet or vitamin K inhibitor anticoagulants within 7 days, non-vitamin K inhibitor anticoagulants within 72 hours, or heparin-derived compounds within 48 hours of treatment).
6. Patients with a history of a bleeding disorder, blood clotting, coagulopathy or with a history of spontaneous tumor hemorrhage.
7. Patients receiving bevacizumab (Avastin) therapy.
8. Currently participating in another clinical therapeutic trial
9. Documented myocardial infarction within six months of enrollment.
10. Unstable angina on medication.
11. Congestive heart failure.
12. Unstable cardiac arrhythmia.
13. Cardiac pacemaker.
14. Severe hypertension (diastolic BP > 100 on medication).
15. Documented cerebral infarction within the past 12 months or TIA in the past 1 month.
16. Insulin-dependent diabetes mellitus that is not well-controlled or that in the Investigator's opinion precludes participation in the study.
17. Known sensitivity to gadolinium
18. Known sensitivity to DEFINITY ultrasound contrast agent or perflutren.
19. Contraindications to MRI such as non-MRI-compatible implanted devices.
20. Large subjects not fitting comfortably into the MRI scanner.
21. Difficulty lying supine and still for up to 4 hours in the MRI unit or claustrophobia.
22. Untreated, uncontrolled sleep apnea.
23. Positive pregnancy test (for pre-menopausal women).
24. Known life-threatening systemic disease.
25. Severely impaired renal function and/or on dialysis.
26. Right to left or bi-directional cardiac shunt.
27. Subjects with evidence of cranial or systemic infection.
28. Subjects with uncontrolled chronic pulmonary disorders.
29. Subjects with a history of severe asthma, hay fever, or multiple allergies that is not well-controlled (e.g. with anaphylaxis).
30. Subjects with a family or personal history of cardiac arrhythmia.
31. Severe liver injury.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 35 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT04370665
• Other Study ID Numbers: PD013
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: InSightec
• Original Responsible Party: Same as current
• Current Study Sponsor: InSightec
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: InSightec
• Verification Date: August 2022