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

Primary Purpose

Parkinson Disease

Status

Active

Phase

Not Applicable

Locations

Canada

Study Type

Interventional

Intervention

Exablate BBBD with Cerezyme

About this trial

This is an interventional device feasibility trial for Parkinson Disease focused on measuring Exablate, Focused Ultrasound

Eligibility Criteria

35 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

Previous neurosurgical procedure for PD
Cerezyme hypersensitivity
Patients who had recent intracranial hemorrhage or stroke
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.
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).
Patients with a history of a bleeding disorder, blood clotting, coagulopathy or with a history of spontaneous tumor hemorrhage.
Patients receiving bevacizumab (Avastin) therapy.
Currently participating in another clinical therapeutic trial
Documented myocardial infarction within six months of enrollment.
Unstable angina on medication.
Congestive heart failure.
Unstable cardiac arrhythmia.
Cardiac pacemaker.
Severe hypertension (diastolic BP > 100 on medication).
Documented cerebral infarction within the past 12 months or TIA in the past 1 month.
Insulin-dependent diabetes mellitus that is not well-controlled or that in the Investigator's opinion precludes participation in the study.
Known sensitivity to gadolinium
Known sensitivity to DEFINITY ultrasound contrast agent or perflutren.
Contraindications to MRI such as non-MRI-compatible implanted devices.
Large subjects not fitting comfortably into the MRI scanner.
Difficulty lying supine and still for up to 4 hours in the MRI unit or claustrophobia.
Untreated, uncontrolled sleep apnea.
Positive pregnancy test (for pre-menopausal women).
Known life-threatening systemic disease.
Severely impaired renal function and/or on dialysis.
Right to left or bi-directional cardiac shunt.
Subjects with evidence of cranial or systemic infection.
Subjects with uncontrolled chronic pulmonary disorders.
Subjects with a history of severe asthma, hay fever, or multiple allergies that is not well-controlled (e.g. with anaphylaxis).
Subjects with a family or personal history of cardiac arrhythmia.
Severe liver injury.

Sites / Locations

Sunnybrook Health Sciences Centre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open label single arm

Arm Description

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

Outcomes

Primary Outcome Measures

Contrast enhancement on MR imaging

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.

Secondary Outcome Measures

Safety --Adverse events

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.

Full Information

NCT ID

NCT04370665

First Posted

April 15, 2020

Last Updated

August 1, 2022

Sponsor

InSightec

1. Study Identification

Unique Protocol Identification Number

NCT04370665

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

July 16, 2020 (Actual)

Primary Completion Date

December 31, 2021 (Actual)

Study Completion Date

December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

InSightec

4. Oversight

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.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Parkinson Disease

Keywords

Exablate, Focused Ultrasound

7. Study Design

Primary Purpose

Device Feasibility

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

4 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Open label single arm

Arm Type

Experimental

Arm Description

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

Intervention Type

Device

Intervention Name(s)

Exablate BBBD with Cerezyme

Intervention Description

Blood Brain Barrier Disruption via Exablate to deliver Cerezyme. Other Names: Exablate Neuro

Primary Outcome Measure Information:

Title

Contrast enhancement on MR imaging

Description

Time Frame

Immediately after MRgFUS BBBD procedure

Secondary Outcome Measure Information:

Title

Safety --Adverse events

Description

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.

Time Frame

Through study completion, an average of 3 months

Other Pre-specified Outcome Measures:

Title

Exploratory effectiveness of Cerezyme delivery via MRgFUS BBB Opening

Description

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.

Time Frame

1 day after the final BBBD procedure

Title

Exploratory effectiveness of Cerezyme treatment via MRgFUS BBB Opening

Description

Exploratory effectiveness of Cerezyme treatment via MRgFUS BBB Opening will be measured by changes in cognitive impairment via Mini-Mental Status Exam (MMSE).

Time Frame

3 months after the final BBBD procedure.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

35 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Men or women between age 35 and 75 years, inclusive. Able and willing to give informed consent. Diagnosis of Parkinson's Disease. At least 2 years from initial diagnosis On stable regiment of PD medications for at least 90 days prior to the study Able to communicate during the Exablate MRgFUS procedure. Able to attend all study visits. Exclusion Criteria: Previous neurosurgical procedure for PD Cerezyme hypersensitivity Patients who had recent intracranial hemorrhage or stroke 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. 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). Patients with a history of a bleeding disorder, blood clotting, coagulopathy or with a history of spontaneous tumor hemorrhage. Patients receiving bevacizumab (Avastin) therapy. Currently participating in another clinical therapeutic trial Documented myocardial infarction within six months of enrollment. Unstable angina on medication. Congestive heart failure. Unstable cardiac arrhythmia. Cardiac pacemaker. Severe hypertension (diastolic BP > 100 on medication). Documented cerebral infarction within the past 12 months or TIA in the past 1 month. Insulin-dependent diabetes mellitus that is not well-controlled or that in the Investigator's opinion precludes participation in the study. Known sensitivity to gadolinium Known sensitivity to DEFINITY ultrasound contrast agent or perflutren. Contraindications to MRI such as non-MRI-compatible implanted devices. Large subjects not fitting comfortably into the MRI scanner. Difficulty lying supine and still for up to 4 hours in the MRI unit or claustrophobia. Untreated, uncontrolled sleep apnea. Positive pregnancy test (for pre-menopausal women). Known life-threatening systemic disease. Severely impaired renal function and/or on dialysis. Right to left or bi-directional cardiac shunt. Subjects with evidence of cranial or systemic infection. Subjects with uncontrolled chronic pulmonary disorders. Subjects with a history of severe asthma, hay fever, or multiple allergies that is not well-controlled (e.g. with anaphylaxis). Subjects with a family or personal history of cardiac arrhythmia. Severe liver injury.

Facility Information:

Facility Name

Sunnybrook Health Sciences Centre

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M4N 3M5

Country

Canada

12. IPD Sharing Statement

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

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