Safety and Feasibility of Exablate Blood-Brain Barrier Disruption for Mild Cognitive Impairment or Mild Alzheimer's Disease Undergoing Standard of Care Monoclonal Antibody (mAb) Therapy

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and feasibility of administering standard of care monoclonal antibody (mAb) infusion therapy in combination with opening the blood-brain barrier with the Exablate Model 4000 Type 2 device in patients with mild Alzheimer's disease (AD) or mild cognitive impairment (MCI).

Detailed Description
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The primary objectives of this study is to evaluate the safety and feasibility of BBBO (blood-brain barrier opening) using the Exablate Model 4000 Type 2 in the setting of standard aducanumab or lecanemab therapy among patients with mild cognitive impairment (MCI) or mild Alzheimer's disease (AD) with confirmed β-amyloid, who are eligible for aducanumab or lecanemab infusion therapy, and to also evaluate the safety of the BBO procedure through patient examination (neurological and cognitive/behavioral) and MRI assessments during the treatment and follow-up. The secondary objectives of this study is to determine the effect of BBBO in patients with MCI or mild AD treated with aducanumab or lecanemab on brain β-amyloid plaque measured by amyloid positron emission tomography (PET), as well as to assess the clinical impact of BBBO with standard aducanumab or lecanemab therapy, if any, as assessed with ADAS Cog 11 and MMSE over time following BBBO.

Official Title
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Assessment of Safety and Feasibility of Exablate Blood-Brain Barrier Disruption for the Treatment of Patients With With Mild Cognitive Impairment (MCI) or Mild Alzheimer's Disease (AD) Undergoing Standard of Care Monoclonal Antibody (mAb) Therapy

Conditions
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Mild Cognitive Impairment, Alzheimer Disease 1

Intervention / Treatment
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* Drug: Aducanumab
* Device: Exablate Model 4000 Type 2
* Drug: Lecanemab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to give informed consent Probable mild cognitive impairment due to AD Modified Hachinski Ischemia Scale (MHIS) score of <= 4 Mini Mental State Exam (MMSE) scores > 21+. Short form Geriatric Depression Scale (GDS) score of <= 7 Amyloid PET scan consistent with the presence of β-amyloid (A+) Able to communicate sensations during the Exablate MRgFUS procedure Able to attend all study visits (i.e., life expectancy of 1 year or more) Exclusion Criteria: MRI findings: Significant cardiac disease or unstable hemodynamic status History of a liver disease, bleeding disorder, coagulopathy or a history of spontaneous hemorrhage Known cerebral or systemic vasculopathy Significant depression (GDS > 7) and/or at potential risk of suicide (C-SSRS > 2) A severity score of 2 or more on any of the 'Delusions', 'Hallucinations' or 'Agitation/Aggression' subscales of the Neuropsychiatry Inventory (NPI-Q) Known sensitivity/allergy to gadolinium(gadobutrol), DEFINITY or its components, or 18F-florbetaben. Known hypersensitivity to DEFINITY or its components. Any contraindications to MRI scanning Untreated, uncontrolled sleep apnea History of untreated or uncontrolled seizure disorder or epilepsy. Impaired renal function Does not have a reliable caregiver Currently in a clinical trial involving an investigational product or non-approved use of a drug or device or in any other type of medical research. Respiratory: chronic pulmonary disorders History of clinically significant recent drug or alcohol use disorder who may be at higher risk for seizure or infection. Positive human immunodeficiency virus (HIV) which can lead to increased entry of HIV into the brain parenchyma leading to HIV encephalitis. Potential blood-borne infections, which can lead to increased entry to brain parenchyma leading to meningitis or brain abscess.

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: Device Feasibility
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infusion plus Exablate BBBO Treatment<br>Intravenous infusion of Aducanumab or Lecanemab every 2-4 weeks (per standard of care) followed by blood brain barrier opening by FUS. | Drug: Aducanumab<br>* Standard aducanumab therapy will be given by intravenous infusion every 4 weeks for 6 cycles with blood brain barrier opening<br>* Other names: Aduhelm;Device: Exablate Model 4000 Type 2<br>* The Exablate Model 4000 will be utilized for the BBBO (blood-brain barrier opening) after each cycle of Aducanumab or Lecanemab administered per label.<br>* Other names: Focused Ultrasound;Drug: Lecanemab<br>* Standard lecanemab therapy will be given by intravenous infusion every 2 weeks for up to 6 cycles with blood brain barrier opening<br>* Other names: Leqembi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment intervention related adverse events | The total number of adverse events following each treatment through end of the study | From baseline, up to 5 year post last treatment | 
| Treatment intervention related serious adverse events | The total number of serious adverse events following each treatment through end of the study | From baseline, up to 5 year post last treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beta-Amyloid plaques within the brain | Beta-Amyloid uptake value measured by Amyloid PET scan | From baseline, up to 5 year post last treatment | 
| Cognitive performance (ADAS COG 11) | Change in cognitive performance using the Alzheimer's Disease Assessment Cognitive Subscale, rating scores from 0-70. The greater the dysfunction, the greater the score. A score of 70 represents the most severe impairment and 0 represents the least impairment. | From baseline, up to 5 year post last treatment | 
| Cognitive performance (MMSE) | Change in cognitive performance using the Mini Mental Status Exam, rating scores from 0-30. 25 or higher being classed as normal. A score below 24 is considered abnormal, indicating possible cognitive impairment. | From baseline, up to 5 year post last treatment |