Blood-Brain-Barrier Opening Using Focused Ultrasound With IV Contrast Agents in Patients With Early Alzheimer's Disease (BBB-Alzheimers)
Primary Purpose
Alzheimer Disease
Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
BBB opening
Sponsored by
About this trial
This is an interventional treatment trial for Alzheimer Disease focused on measuring Blood-Brain Barrier
Eligibility Criteria
Inclusion Criteria:
- Probable AD consistent with NIA/AA criteria (McKhann, Alzheimer & Dementia 2011)
- Modified Hachinski Ischemia Scale (MHIS) score of <= 4.
- Mini Mental State Exam (MMSE) scores 18-28
- Short form Geriatric Depression Scale (GDS) score of <= 6
- Has a Florbetaben PET scan consistent with the presence of amyloid pathology in the proposed target region (right frontal lobe)
- Able to communicate sensations during the ExAblate® MRgFUS procedure.
Exclusion Criteria:
MRI findings:
- Active infection/inflammation
- Acute or chronic hemorrhages, specifically > 4 lobar microbleeds, and no siderosis or macrohemorrhages
- Tumor/space occupying lesion
- Meningeal enhancement
- More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp
- Clips or other metallic implanted objects in the skull or the brain, except shunts; other metallic objects implanted in body
- Significant cardiac disease or unstable hemodynamic status including:
- Uncontrolled hypertension on medication or abnormal ECG
- Medications known to increase risk of hemorrhage, (e.g.: patients should be off of aspirin or another anticoagulants for at least 7 days prior to treatment) or anticoagulants (class I and III) or off Avastin for 30 days
- History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or use of anticoagulants
- Abnormal coagulation profile (PLT < 100,00/μl), PT (>14 sec) or PTT (>36 sec), and INR > 1.3
- No more than 1 non-strategic lacune <1.5 cm
- Known cerebral or systemic vasculopathy
- Significant depression and at potential risk of suicide
- Known sensitivity/allergy to gadolinium (an alternative product may be used), Definity or any of its components.
- Any contraindications to MRI scanning such as metallic implants, claustrophibia or too large for MRI scanner
- Untreated, uncontrolled sleep apnea
- Impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2
- Does not have a reliable caregiver in frequent contact with the patient and can accompany the patient to the clinic and treatment or be available by telephone at designated times. Participants living in retirement homes may be included. Caregiver not willing to sign the Informed Consent Form
- Respiratory: chronic pulmonary disorders e.g. severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, patients with a history of drug allergies, asthma or hay fever, and multiple allergies where the benefit/risk of administering Definity® is considered unfavorable by the study physicians in relation to the product monograph for Definity.
- Currently in a clinical teial involving investigational product.
Sites / Locations
- Sunnybrook Health Sciences Centre
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
BBB opening
Arm Description
ExAblate focused ultrasound under MRI-guidance delivered through the intact human skull in conjunction with timed intravenous ultrasound contrast agents (Definity®) to temporarily and focally open the BBB.
Outcomes
Primary Outcome Measures
Change in contrast enhancement (intensity) following BBB disruption
Change in contrast enhancement (intensity) following BBB disruption to pre-sonication images as a comparative ratio measured in percent as read from MR images and normalized to the contralateral hemisphere
Secondary Outcome Measures
Change in amyloid uptake
Change in amyloid uptake as compared to pre treatment scans in the targeted region
Adverse events
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
MMSE - Mini Mental State Examination
Treatment effect on patients' dementia state
ADAS-Cog - Alzheimer's Disease Assessment Scale - Cognitive Behavior subscales
Treatment effect on patients' Alzheimer's disease symptoms
NPI - Neuropsychiatry Inventory
Treatment effect on patients' dementia
GDS - Geriatric Depression Scale
Treatment effect on patients' depression
ADCS-ADL - Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory
Treatment effect on patients' activities of daily living
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02986932
Brief Title
Blood-Brain-Barrier Opening Using Focused Ultrasound With IV Contrast Agents in Patients With Early Alzheimer's Disease
Acronym
BBB-Alzheimers
Official Title
A Study to Evaluate the Safety and Feasibility of Blood-Brain Barrier (BBB) Opening Using Transcranial MR-Guided Focused Ultrasound With Intravenous Ultrasound Contrast Agents in Patients With Early Alzheimer's Disease
Study Type
Interventional
2. Study Status
Record Verification Date
June 2018
Overall Recruitment Status
Completed
Study Start Date
December 2016 (undefined)
Primary Completion Date
December 2017 (Actual)
Study Completion Date
December 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
InSightec
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a prospective, non-randomized, single-arm, feasibility study to evaluate the safety and initial effectiveness of opening of the Blood-Brain Barrier with intravenous contrast agents using the ExAblate Neuro System in patients with early stage Alzheimer's Disease.
Detailed Description
This study is a prospective, single-arm, non-randomized, feasibility, phase I trial to evaluate the safety of focal BBB opening using the ExAblate® Transcranial (220 kHz) system and Definity® ultrasound contrast in 6 patients with mild Alzheimer's Disease. This phase I trial will be divided into two stages. In the first stage, patients will undergo small volume BBB opening, establishing the minimum required sonication parameters to open the BBB, as evidenced by gadolinium enhancement on T1-weighted MRI. Stage I is defined as a discrete region of approximately 9 mm x 9 mm area in the right frontal lobe. Multiple sonications will be performed starting at low energy and ramping up until the BBB is observed to open. The subjects will then be removed from the ExAblate® Neuro device and followed for safety for 30 days. If the subject experienced BBB opening without any serious adverse effects (such as brain edema), then the subject may proceed to Stage two where a larger volume (2.5-3.0 cm) will be targeted. Subjects will be followed for an additional 60 days for safety and preliminary effectiveness.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Disease
Keywords
Blood-Brain Barrier
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
Transcranial ExAblate
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
BBB opening
Arm Type
Experimental
Arm Description
ExAblate focused ultrasound under MRI-guidance delivered through the intact human skull in conjunction with timed intravenous ultrasound contrast agents (Definity®) to temporarily and focally open the BBB.
Intervention Type
Device
Intervention Name(s)
BBB opening
Intervention Description
Open BBB using ExAblate focused ultrasound and (Definity®) contrast agent
Primary Outcome Measure Information:
Title
Change in contrast enhancement (intensity) following BBB disruption
Description
Change in contrast enhancement (intensity) following BBB disruption to pre-sonication images as a comparative ratio measured in percent as read from MR images and normalized to the contralateral hemisphere
Time Frame
Immediately post treatment
Secondary Outcome Measure Information:
Title
Change in amyloid uptake
Description
Change in amyloid uptake as compared to pre treatment scans in the targeted region
Time Frame
30 days after treatments
Title
Adverse events
Description
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame
90 days
Title
MMSE - Mini Mental State Examination
Description
Treatment effect on patients' dementia state
Time Frame
30 days
Title
ADAS-Cog - Alzheimer's Disease Assessment Scale - Cognitive Behavior subscales
Description
Treatment effect on patients' Alzheimer's disease symptoms
Time Frame
30 days
Title
NPI - Neuropsychiatry Inventory
Description
Treatment effect on patients' dementia
Time Frame
30 days
Title
GDS - Geriatric Depression Scale
Description
Treatment effect on patients' depression
Time Frame
30 days
Title
ADCS-ADL - Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory
Description
Treatment effect on patients' activities of daily living
Time Frame
30 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
55 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Probable AD consistent with NIA/AA criteria (McKhann, Alzheimer & Dementia 2011)
Modified Hachinski Ischemia Scale (MHIS) score of <= 4.
Mini Mental State Exam (MMSE) scores 18-28
Short form Geriatric Depression Scale (GDS) score of <= 6
Has a Florbetaben PET scan consistent with the presence of amyloid pathology in the proposed target region (right frontal lobe)
Able to communicate sensations during the ExAblate® MRgFUS procedure.
Exclusion Criteria:
MRI findings:
Active infection/inflammation
Acute or chronic hemorrhages, specifically > 4 lobar microbleeds, and no siderosis or macrohemorrhages
Tumor/space occupying lesion
Meningeal enhancement
More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp
Clips or other metallic implanted objects in the skull or the brain, except shunts; other metallic objects implanted in body
Significant cardiac disease or unstable hemodynamic status including:
Uncontrolled hypertension on medication or abnormal ECG
Medications known to increase risk of hemorrhage, (e.g.: patients should be off of aspirin or another anticoagulants for at least 7 days prior to treatment) or anticoagulants (class I and III) or off Avastin for 30 days
History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or use of anticoagulants
Abnormal coagulation profile (PLT < 100,00/μl), PT (>14 sec) or PTT (>36 sec), and INR > 1.3
No more than 1 non-strategic lacune <1.5 cm
Known cerebral or systemic vasculopathy
Significant depression and at potential risk of suicide
Known sensitivity/allergy to gadolinium (an alternative product may be used), Definity or any of its components.
Any contraindications to MRI scanning such as metallic implants, claustrophibia or too large for MRI scanner
Untreated, uncontrolled sleep apnea
Impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2
Does not have a reliable caregiver in frequent contact with the patient and can accompany the patient to the clinic and treatment or be available by telephone at designated times. Participants living in retirement homes may be included. Caregiver not willing to sign the Informed Consent Form
Respiratory: chronic pulmonary disorders e.g. severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, patients with a history of drug allergies, asthma or hay fever, and multiple allergies where the benefit/risk of administering Definity® is considered unfavorable by the study physicians in relation to the product monograph for Definity.
Currently in a clinical teial involving investigational product.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nir Lipsman, MD, PhD
Organizational Affiliation
Sunnybrook Health Sciences Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sunnybrook Health Sciences Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
34815790
Citation
Mathew AS, Gorick CM, Price RJ. Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption. Theranostics. 2021 Oct 11;11(20):9847-9858. doi: 10.7150/thno.65064. eCollection 2021.
Results Reference
derived
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Blood-Brain-Barrier Opening Using Focused Ultrasound With IV Contrast Agents in Patients With Early Alzheimer's Disease
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