Pilot Clinical Trial to Assess the Safety of NMS-01 in Patients With Mild to Moderate Alzheimer's Disease

Prior treatment

• Subjects with standard contraindications for MR imaging, such as the presence of MRI-incompatible metallic implants.
• Subjects with a history of receiving anticoagulant or antiplatelet agents within 2 weeks before or after the application of the investigational medical device, or who are scheduled to receive them.
• Subjects currently participating in another clinical trial or who have participated in another clinical trial within 90 days prior to the screening date.

Other illness

• An uncontrolled psychiatric disorder/condition that could affect cognitive function or its assessment (e.g., schizophrenia, bipolar disorder, major depression). (However, subjects are permitted if they have been on a stable drug regimen without changes in dosage for at least the past 4 weeks).
• Subjects with pulmonary disease (e.g., pneumonia, pulmonary edema) confirmed by chest X-ray.
• Subjects with a known sensitivity, allergy, or contraindication to MRI contrast agents (Gadovist® injection) or ultrasound contrast agents (SonoVue®).
• Subjects with a known sensitivity, allergy, or contraindication to local anesthetics or anesthetic agents used for conscious sedation during the procedure, if required.
• More than 30% of the skull area in the intended ultrasound sonication path is covered by scar tissue, scalp disorders (e.g., eczema), or atrophied scalp.
• A history of bleeding disorders.
• Significant cardiac disease or unstable hemodynamic status (e.g., uncontrolled hypertension, arrhythmia, angina pectoris, etc.).
• Subjects who are HIV (Human Immunodeficiency Virus) positive and are at high risk of HIV encephalitis due to the influx of HIV into the brain parenchyma.
• Subjects with a potential blood-borne infection that could enter the brain parenchyma and lead to meningitis or a brain abscess.
• Subjects with uncontrolled hypertension or diabetes.
• Any other condition for which the investigator deems participation in the clinical trial to be inappropriate for ethical reasons or because it could influence the trial results.

Other

• A severity score greater than 2 on any one of the following items on the Caregiver Administered Neuropsychiatry Inventory (CGA-NPI): "Delusions," "Hallucinations," or "Agitation/Aggression."
• Subjects meeting any of the following criteria based on MRI findings:
• Subjects with impaired renal function (Glomerular filtration rate \<30 mL/min/1.73 m²).
• Severe brain atrophy that would preclude targeting.
• Subjects with clinically significant abnormal findings on an electrocardiogram (ECG).
• Pregnant or lactating women.
• Women of childbearing potential who do not agree to use a clinically appropriate method of contraception for the duration of the clinical trial.

• Adults aged 50 to 85 years, inclusive.
• Individuals previously diagnosed with probable Alzheimer's Disease (AD) by a specialist according to the National Institute on Aging and Alzheimer's Association (NIA-AA) 2011 criteria.
• Individuals with a previously confirmed positive 18F-Florbetaben (FBB) position emission tmography (PET) scan.
• Individuals with a Clinical Dementia Rating (CDR) global score between 1 and 2, inclusive.
• Individuals with a total score on the Korean version of the Mini-Mental State Examination (K-MMSE) between 12 and 26, inclusive.
• Individuals who have been on a stable dose and regimen of approved medications for the treatment of Alzheimer's disease for at least 3 months prior to screening.
• Individuals capable of expressing sensations or discomfort to the investigator during the procedure.
• Availability of a caregiver or informant who either lives with the participant or has sufficient contact (averaging at least 10 hours per week) to provide reliable information about the participant's overall functioning. This person must be able to accompany the participant to clinic visits, actively participate in clinical trial procedures, including interviews and questionnaire completion, and must voluntarily provide written informed consent for their own participation.
• Participants (or their legally authorized representatives) must provide voluntary written informed consent for participation in the clinical trial. If a participant is illiterate and unable to provide written consent, verbal consent is permissible but must be formally documented. Furthermore, as all participants are considered vulnerable subjects, consent must also be provided and signed by a legal representative.