Repetitive Blood Brain Barrier Opening for Alzheimer's Disease.

Alzheimer Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT06158789
• Other study ID #: YUSHAD-02
• Status: Active, not recruiting
• Phase: N/A
• Start date: June 2, 2022
• Est. completion date: January 19, 2024

Study information

• Verified date: November 2023
• Source: Severance Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study was focused on comparing the efficacy of repetitive Focused ultrasound mediated BBB opening in alzhemer's disease in increased number of treatment session and shorter intervals.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 6
• Est. completion date: January 19, 2024
• Est. primary completion date: July 19, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

Inclusion Criteria:

• Age over 50 to 85

• MMSE below 23

• FBB-PET positive

• FDG-PET shows alzheimer -induced neurodegeneration

• Dementia or cognitive impairment due to alzhemer's disease

• participants who have taken over 3 months of medication related with cognitive improvement

• Someone who can express their sensations during the procedure.

• Individuals who have voluntarily decided to participate in this clinical trial and have provided written consent on the informed consent form.

• Individuals with a commitment to adhere to the clinical trial protocol.

Exclusion Criteria:

• If any of the following exclusion criteria apply, participation in this clinical trial is not allowed.

If the severity score for the items "Delusions," "Hallucinations," or "Agitation/Aggression" in the CGA-NPI (Caregiver-Administrated Neuropsychiatry Inventory) test is greater than 2.

Note: Since the CGA-NPI requires the patient's caregiver to complete the survey, the caregiver must be present during the questionnaire.

Individuals with sensitivity/allergy or contraindications to the MRI contrast agents Gadolinium (Gadovist®) or ultrasound contrast agent Definity.

Contraindications:

Gadolinium (Gadovist®): Patients with untreated hypokalemia. Definity: Patients who have undergone right-left shunt, bidirectional shunt, or temporary right-left shunt, patients scheduled to undergo extracorporeal shock wave lithotripsy within 24 hours, clinically unstable or worsening congestive heart failure patients, acute myocardial infarction or acute coronary syndrome patients, patients at high risk of arrhythmias due to severe ventricular arrhythmias or prolongation of the QT interval, patients showing signs and symptoms of carbon dioxide retention or hypoxemia, patients with conditions that may induce pulmonary artery hypertension due to severe pulmonary insufficiency, severe pulmonary fibrosis, or damage to the pulmonary artery structure.

Individuals with standard contraindications to MR imaging, including the presence of metal devices incompatible with MRI.

Individuals with sensitivity/allergy or contraindications to anesthetic agents used for conscious sedation during procedures where conscious sedation is required.

Individuals with any of the following findings in the MRI examination:

Severe ischemic changes (Fazeka criteria score > 2, Lacunes count > 5, or Cerebral microbleeds count > 3).

Active or chronic infection/inflammation. Acute or chronic bleeding. Tumor/space-occupying lesion. Meningeal enhancement. Intracranial hypotension.

Individuals with more than 30% of the skull area through which the sonication (Sonication) path passes covered with scars, scalp disorders (e.g., eczema), or atrophied scalp.

Individuals with a history of seizure disorder or epilepsy that could be exacerbated due to blood-brain barrier opening.

Individuals with a history of bleeding disorders.

Individuals with severe cardiac conditions or unstable hemodynamic status (e.g., uncontrollable hypertension, arrhythmias, angina, etc.).

Individuals with impaired kidney function (Glomerular filtration rate < 30 mL/min/1.73 m²).

Individuals with severe brain atrophy to an extent that cannot be targeted.

Individuals who are HIV (Human Immunodeficiency Virus) positive and have a high likelihood of developing HIV encephalitis as HIV enters the brain parenchyma.

Individuals with potential vascular-origin infections that can enter the brain parenchyma, leading to meningitis or brain abscess.

Individuals with a thin blood-brain barrier, known to have homozygosity of the Apolipoprotein E allele (ApoE4).

Pregnant or lactating women.

For fertile women*, those who have agreed to use clinically appropriate contraceptive methods** during the trial period.

Definition of fertile women: Women who have experienced menarche and are not defined as postmenopausal after 12 months of amenorrhea without any surgical infertility procedures (e.g., hysterectomy or bilateral oophorectomy).

** Clinically appropriate contraceptive methods: For women, it is defined as "[Intrauterine device (e.g., loop, Mirena), chemical contraception (birth control pills), or subcutaneous contraceptive devices (e.g., Implanon)] + Physical contraceptive methods (male or female)," and for tubal ligation or laparoscopic contraception (a type of tubal ligation).

Individuals currently participating in another clinical trial or who have participated in another clinical trial within 90 days of the screening date.

Other cases where the investigator deems participation in the clinical trial inappropriate due to ethical or potential impact on clinical trial results.

Specific reasons should be documented in the case record.

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Procedure:
• MR guided low intensity focused ultrasound
Low intensity focused ultrasound opens the blood brain barrier

Locations

Country	Name	City	State
Korea, Republic of	Yonsei University Severance Hospital	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Kyung Won Chang	Yonsei University

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (1)

Park SH, Baik K, Jeon S, Chang WS, Ye BS, Chang JW. Extensive frontal focused ultrasound mediated blood-brain barrier opening for the treatment of Alzheimer's disease: a proof-of-concept study. Transl Neurodegener. 2021 Nov 5;10(1):44. doi: 10.1186/s40035-021-00269-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Standard Uptake Value Ratios (SUVR) on FBB-PET	Conducting FBB (18F-Florbetaben)-PET scans to confirm the presence of Amyloid beta protein (Aß) plaques in the brain, the study compares and analyzes the global and regional standard uptake value ratios (SUVR) before the first procedure (Visit 1) and after the third procedure (Visit 12). The cerebellar gray matter is used as a reference region, and the analysis includes whole-brain as well as regional (Frontal/Temporal) SUVR.	Screening, 2weeks after final procedure
Primary	Changes in CGA-NPI (Caregiver-administered neuropsychiatric inventory) Scores and Percentage Change	To assess the cognitive function of participants, the CGA-NPI (Caregiver-Administered Neuropsychiatric Inventory) test is administered before the first procedure (Visit 1) and compared to scores after the first, second, and third procedures (Visits 4, 8, 12, 13). Changes in CGA-NPI scores and percentage changes (%) are investigated at each assessment point, with responses provided by the same participant's caregiver. Higher scores indicate severity of neuropsychiatric symptoms and 0 indicates no symptom.	Screening, 2weeks after every session, 2months after final session
Primary	Changes in K-MMSE(Korean version of Mini Mental State Exam) Test Scores and Percentage Change	For evaluating cognitive function, the K-MMSE (Korean version of Mini Mental State Exam) test is conducted before the first procedure (Visit 1) and compared to scores after the third procedure (Visits 12, 13). Changes in K-MMSE scores and percentage changes (%) are examined. Higher scores indicate better cognition.	Screening, 2months after final session
Primary	Changes in SNSB(Seoul Neuropsychological Screening Battery)Test Scores and Percentage Change	Assessing cognitive function, the SNSB (Seoul Neuropsychological Screening Battery) test is performed before the first procedure (Visit 1) and compared to scores after the third procedure (Visit 13). Changes in SNSB scores and percentage changes (%) are investigated. Higher scores indicate better cognition.	Screening, 2months after final session