Blood-Brain-Barrier Opening Using Focused Ultrasound With IV Contrast Agents in Patients With Early Alzheimer's Disease (BBB-Alzheimers)

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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Device: BBB opening

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Probable AD consistent with NIA/AA criteria (McKhann, Alzheimer & Dementia 2011)
2. Modified Hachinski Ischemia Scale (MHIS) score of <= 4.
3. Mini Mental State Exam (MMSE) scores 18-28
4. Short form Geriatric Depression Scale (GDS) score of <= 6
5. Has a Florbetaben PET scan consistent with the presence of amyloid pathology in the proposed target region (right frontal lobe)
6. Able to communicate sensations during the ExAblate® MRgFUS procedure.

Exclusion Criteria:

1. MRI findings:

   • Active infection/inflammation
   • Acute or chronic hemorrhages, specifically > 4 lobar microbleeds, and no siderosis or macrohemorrhages
   • Tumor/space occupying lesion
   • Meningeal enhancement
2. 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
3. Clips or other metallic implanted objects in the skull or the brain, except shunts; other metallic objects implanted in body
4. Significant cardiac disease or unstable hemodynamic status including:
5. Uncontrolled hypertension on medication or abnormal ECG
6. 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
7. History of a bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or use of anticoagulants
8. Abnormal coagulation profile (PLT < 100,00/μl), PT (>14 sec) or PTT (>36 sec), and INR > 1.3
9. No more than 1 non-strategic lacune <1.5 cm
10. Known cerebral or systemic vasculopathy
11. Significant depression and at potential risk of suicide
12. Known sensitivity/allergy to gadolinium (an alternative product may be used), Definity or any of its components.
13. Any contraindications to MRI scanning such as metallic implants, claustrophibia or too large for MRI scanner
14. Untreated, uncontrolled sleep apnea
15. Impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2
16. 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
17. 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.
18. Currently in a clinical teial involving investigational product.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BBB opening; 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.	Device: BBB opening; Open BBB using ExAblate focused ultrasound and (Definity®) contrast agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Immediately post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in amyloid uptake	Change in amyloid uptake as compared to pre treatment scans in the targeted region	30 days after treatments
Adverse events	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	90 days
MMSE - Mini Mental State Examination	Treatment effect on patients' dementia state	30 days
ADAS-Cog - Alzheimer's Disease Assessment Scale - Cognitive Behavior subscales	Treatment effect on patients' Alzheimer's disease symptoms	30 days
NPI - Neuropsychiatry Inventory	Treatment effect on patients' dementia	30 days
GDS - Geriatric Depression Scale	Treatment effect on patients' depression	30 days
ADCS-ADL - Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory	Treatment effect on patients' activities of daily living	30 days

Collaborators and Investigators

• Sponsor: InSightec
• Investigators: Principal Investigator: Nir Lipsman, MD, PhD, Sunnybrook Health Sciences Centre

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: December 6, 2016
• First Submitted That Met QC Criteria: December 6, 2016
• First Posted (Estimate): December 8, 2016

Study Record Updates

• Last Update Posted (Actual): June 14, 2018
• Last Update Submitted That Met QC Criteria: June 13, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Blood-Brain Barrier
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: AL001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO