Clinical trial NCT06474013: A Clinical Trial to Evaluate the Initial Safety and Efficacy of Repetitive BBB (Blood Brain Barrier) Disruption Using High Intensity Focused Ultrasound 'ExAblate 4000 Type 2.1' in Patients With Alzheimer's Disease
Official title: Initial Safety and Efficacy of Repetitive BBB (Blood Brain Barrier) Disruption Using High Intensity Focused Ultrasound 'ExAblate 4000 Type 2.1' in Patients With Alzheimer's Disease: Single-center, Open, Prospective, Single-arm, Feasibility, Investigator-initiated Trial)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Alzheimer Disease
Keywords: Blood Brain Barrier (BBB) Disruption
ExAblate 4000 Type 2.1
Lead sponsor: Korea University Anam Hospital
Sponsor class: OTHER
First posted: 2024-06-25
Enrollment: 15
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This clinical trial is designed to evaluate the initial safety and efficacy of opening the blood brain barrier (BBB) in patients with Alzheimer's disease using the ExAblate 4000 Type 2.1, a MR guided high-intensity focused ultrasound surgical device that disrupts brain tissue.

Detailed description: This clinical trial aims to evaluate the initial safety and efficacy of opening the blood brain barrier (BBB) in patients with Alzheimer's disease using the ExAblate 4000 Type 2.1, a MR guided high-intensity focused ultrasound surgical device that disrupts brain tissue. It is designed as a single-center, open, prospective, single-arm, feasibility, investigator-initiated trial. Patients with Alzheimer's disease who require opening of the blood-brain barrier will be referred to this clinical trial. Those who voluntarily sign a signed consent form after receiving a full explanation of the clinical trial undergo a screening test. Those who fulfill all inclusion/exclusion criteria will be enrolled in this clinical trial and assigned an enrollment number. Only subjects enrolled in this clinical trial will undergo BBB opening (blood brain barrier disruption) using ExAblate 4000 Type 2.1, a high-intensity focused ultrasound surgical device, to open the BBB by 40-60 cc. After completion of the procedure, the participants will receive follow-up observation for the procedure for at least 2 hours after the procedure. At this time, the investigator checks whether an adverse event that causes dropout, and if the subject is dropped out, follow-up observation of the adverse event continues.

Eligibility criteria: Inclusion Criteria:

1. Age between 50 and 85 years
2. Total score of 23 or less on the K-MMSE (Korean version of the mini mental state exam)
3. Positive 18F-Florbetaben (FBB) PET scan
4. Have mild cognitive impairment or dementia due to Alzheimer's disease, each of which must meet the criteria below.

   * if mild cognitive impairment: amnestic mild cognitive impairment according to Peterson
   * If dementia: probable Alzheimer's disease dementia, according to the national institute of aging and Alzheimer's association (NIA-AA).
5. If a subject is taking medication for Alzheimer's disease such as an acetyl-cholinesterase-inhibitor (AChEI) and/or memantine, etc., the subject should maintained the stable dosage for at least 3 months.
6. A subject who is able to express regarding sensation during the application of an investigational medical device in a clinical trial
7. A subject who has voluntarily decided to participate in this clinical trial and has given written informed consent
8. A subject who is willing to adhere to the protocol

Exclusion Criteria:

1. A severity score of 2 or more for any of the following items on the caregiver-administered neuropsychiatry inventory (CGA-NPI): "delusions," "hallucinations," or "agitation/aggression."
2. Known sensitivity/allergy to or contraindication\* to the MRI contrast agent gadolinium (Gadovist® ) or ultrasound contrast agent Definity®
3. Have a standard contraindication to MR imaging, such as implanted metal devices that are incompatible with MRI.
4. Sensitivity/allergy to or contraindication to local anesthetics and any anesthetic used when conscious sedation is required during application of an investigational medical device in a clinical trial
5. Anyone who has MRI result as any of the following

   * Severe ischemic changes\* have been identified.

     \*Significant ischemic changes: defined as a fazekas score of 3 or greater than 5 lacunes or greater than 3 cerebral microbleeds
   * active or chronic infection/inflammation
   * Acute or chronic bleeding
   * Tumor/space-occupying lesion
   * meningeal enhancement
   * intracranial hypotension
6. ≥30% of the skull area traversed by sonication is covered by scars, scalp disorder, or atrophic scalp.
7. Have a history of seizure disorder or epilepsy that may be worsened by opening the blood-brain barrier
8. Have a history of bleeding disorders or clotting disorders
9. Have a serious heart condition or unstable blood flow (e.g., uncontrolled high blood pressure, arrhythmia, angina, etc.)
10. Decreased renal function (glomerular filtration rate\<30 mL/min/1.73 m )2
11. Unable to target due to severe brain atrophy
12. Patient who positive for human immunodeficiency virus (HIV) and is at increased risk for HIV encephalitis by HIV entry into the brain parenchyma
13. Have a potential blood vessel-derived infection that can enter the brain parenchyma, resulting in meningitis or a brain abscess
14. Carriers of the homozygosity apolipoprotein E allele (ApoE4), which is known to be associated with a thin blood-brain barrier.
15. Pregnant or nursing women
16. For women of childbearing potential\* who agree to use a clinically appropriate method of birth control\*\* for the duration of the clinical trial

    \*Definition of women of childbearing age: means women who have experienced menarche, have not been surgically sterilized (hysterectomy or bilateral oophorectomy), or are not post-menopausal, defined as amenorrhea for 12 months or more for no other reason.

    \*\*Clinically appropriate contraception: defined as "\[intrauterine device (e.g., Loop, Mirena), chemical barrier method (spermicide), or subdermal implantable contraceptive device (e.g., Implanon)\] + physical barrier method (male or female)" for women, tubal surgery, or laparoscopic contraception (a type of tubal ligation).
17. Currently participating in another clinical trial or have participated in another clinical trial within 90 days of the screening date
18. Other, if the investigator determines that participation in the clinical trial is inappropriate ethically or because it could affect the outcome of the clinical trial ☞ Specific reasons must be documented in the case report form.

Primary outcomes:
measure: Change in standardized uptake value ratio (SUVR) on FBB-PET
timeFrame: Baseline and Day 14 following the third treatment
Secondary outcomes:
measure: Percentage change in electroencephalography metrics (%)
timeFrame: Baseline and Day 14 following the first, second, third treatment, and 2 months following third treatment
measure: CGA-NPI score change (points) and percent change (%)
timeFrame: Baseline and Day 14 following the first, second, third treatment, and 2 months following third treatment
measure: K-MMSE test score change (points) and percent change (%)
timeFrame: Baseline and Day 14 following the first, second, third treatment, and 2 months following third treatment
measure: SNSB Test Score Change (points) and Percent Change (%)
timeFrame: Baseline and 2 months following the third treatment
measure: Degree of blood-brain barrier opening (cm3)
timeFrame: first treatment and 2 months, 4 months following the first treatment
Other outcomes:
Locations:
Study officials:
References: