Assessment of Initial Efficacy and Safety of High Intensity Focused Ultrasound 'ExAblate 4000 Type 2' for Blood Brain Barrier Disruption in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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The proposed study is to evaluate initial efficacy and safety of the BBB disruption with transcranial MRI-guided focused ultrasound (ExAblate 4000 type 2.0) in patients with Alzheimer's disease. This study iw designed as a prospective, single-site, single-aarm, nonrandomized study. Assessments will be made before and three months after 2 sessions of BBB disruption with radiologic, nuclear medicine imaging and neurophysiological examinations. Relative safety will be evaluated using a common description of Significant Clinical Complications for patients treated in this study.

Official Title
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Single-center, Open, Prospective, Single-arm, Feasibility, Investigator-initiated Trail for Assessment of Initial Efficacy and Safety of High Intensity Focused Ultrasound 'ExAblate 4000 Type 2' for Blood Brain Barrier Disruption in Patients With Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Device: transcranial magnetic resonance guided focused ultrasound BBB disruption


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 50 and 85 years, inclusive. Total score of 23 or less on the Korean version of Mini Mental state Exam (K-MMSE) FBB (18F-Florbetaben)-PET test result positive FDB (18F-Fluorodeoxyglucose)-PET test results suspected of Alzheimer disease-induced neurodegeneration Mild cognitive impairment or dementia caused by Alzheimer's disease A participant who has been given a drug at a stable dose for at least three months to improve symptoms of Alzheimer's disease Able to communicate during the ExAblate BBB disruption procedure Able and willing to give informed consent Able to attend all study visits Exclusion Criteria: CGA-NPI (Caregiver-Administrated Neuropsychiatry Inventory) severity score of more than 2 points for any of Delusion, Hallucination or Agitation/Aggression Known sensitivity/allergy or contraindications to MRI contrast agent(Gadovist®) or the ultrasound contrast agent (Definity®) Contraindications to MRI such as non-MRI compatible implanted devices. Any of the following items in MRI severe ischemic changes active or chronic infection/inflammation acute or chronic hemorrhage tumor/space occupying lesion meningeal enhancement intracranial hypotension 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 Active seizure disorder or epilepsy (seizures despite medical treatment) History of a bleeding disorder, coagulopathy Cardiac disease or unstable hemodynamics Severely impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2 Severe brain atrophy HIV (Human immunodeficiency virus) positive, who have a high probability of developing HIV encephalitis due to the influx of HIV in to the brain parenchyma Subjects with evidence of cranial or systemic infection A homozygosity of Apolipoprotein E allele (ApoE4) known to have a thin blood-brain barrier Positive pregnancy test (women of childbearing potential) A participant in other clinical trials or have experience in other clinical trials within 90 days from the screening date

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BBB disruption<br>All participant in this arm will undergo 2 sessions of transcranial magnetic resonance guided focused ultrasound blood brain barrier disruption every 3 months. | Device: transcranial magnetic resonance guided focused ultrasound BBB disruption<br>* The ExAblate BBB disruption procedure will be performed with ExAblate 4000 type 2.0 system, and this will be performed twice every 3 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events safety profile | The type and severity of post-procedure adverse events will be assessed for overall safety. Safety of the BBBD procedure will be evaluated through patient examination and MRI assessements during the treatment and by their standard care of follow-up MRI scans and clinical visits. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of BBB disruption : evaluated by radiologic imaging | The efficacy of BBB disruption in Alzheimer's disease will be evaluated by radiologic, nuclear medicine imaging and neurophysiological examination. | 6 months | 
| Efficacy of BBB disruption : evaluated by nuclear medicine imaging | The efficacy of BBB disruption in Alzheimer's disease will be evaluated by radiologic, nuclear medicine imaging and neurophysiological examination. | 6 months | 
| Efficacy of BBB disruption : evaluated by neurophysiological examination | The efficacy of BBB disruption in Alzheimer's disease will be evaluated by radiologic, nuclear medicine imaging and neurophysiological examination. | 6 months |