Neuronavigation-guided FUS-induced BBB Opening in Alzheimer's Disease Patients and Its Effects on Brain Amyloid and Tau

NCT06600880 | Not Yet Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: AAAV4854
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

The primary purpose of this phase 1b study is to further assess the safety and reversibility of focused ultrasound induced blood-brain barrier opening (FUS-BBBO) in participants with Alzheimer´s Disease (AD) using a single-element transducer with neuronavigation guidance. Preliminary results from our phase 1a study demonstrate that our neuronavigation-guided FUS system was capable of safely and transiently open the BBB in participants with AD. The information collected in this new study may be used to design future clinical trials to ultimately provide a viable alternative for treatment of AD in a safe and noninvasive manner. Our secondary objective includes the assessment of the therapeutic efficacy of FUS-BBBO in reducing amyloid beta and neurofibrillary tangles, the main hallmark pathologies of AD, using PET tracers. Based on our preclinical studies in AD transgenic mouse models, FUS-BBBO alone was able to reduce both the amyloid beta and tau protein load, resulting in improvements in behavioral tasks assessing memory. Therefore, in this new study, the effect of FUS-BBBO on the amyloid beta and tau protein load in patients with AD will be assessed through the use of PET tracers.

Conditions

Alzheimer Disease, Early Onset

Outcome Measures

Primary Outcomes (1)

• Total Number of Individuals With Successful Opening of the BBB

  Opening the BBB successfully in all the patients, while obtaining a volume of BBB opened being similar and consistent for all patients

  4 days, including the day of treatment

Secondary Outcomes (3)

• Total Number of Safety Events Related to Opening of BBB

  4 days, including the day of treatment

• Percent Change in Amyloid PET Signal Intensity

  3 months (±2 weeks)

• Percent Change in MK-6240 PET Signal Intensity

  3 months (±2 weeks)

Study Arms (1)

Focused ultrasound treatment

EXPERIMENTAL

Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with microbubbles.

Device: Neuronavigation-guided single-element focused ultrasound transducer; Drug: Lumason; Other: Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents; Radiation: Positron Emission Tomography (PET); Drug: Amyvid; Drug: MK-6240; Drug: Dotarem; Diagnostic Test: Blood draw; Device: UR5e; Diagnostic Test: Urine test

Interventions

Neuronavigation-guided single-element focused ultrasound transducer DEVICE

Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.

Focused ultrasound treatment

Lumason DRUG

New packages of Lumason microbubbles will be shipped from Bracco Diagnostics Inc. and will be used in conjunction with the ultrasound transducer to temporarily open the BBB. Lumason microbubbles will be freshly activated before treatment sonication and will be drawn using a 10-ml syringe to reach the desired dosage of 0.1mL/kg right before the intravenous injection.

Focused ultrasound treatment

Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents OTHER

A high-resolution MRI (with and without gadolinium (Dotarem) contrast agent) will be acquired prior to BBB opening on the GE SIGNATM Premier (3T) (same scanner as in the NHP study) for pre-treatment planning and screening purposes. Then, a second MRI (with and without gadolinium) will be acquired and read by a Board-Certified Radiologist immediately after the treatment sonication in order to assess the BBB opening and safety. Finally, a final follow-up MRI (with and without gadolinium) will be conducted 3 days (±1 day) after the treatment to confirm BBB closing and/or safety. This will be read by a Board-Certified Radiologist as well. All MRI procedures will be performed at the CUIMC/Neurological Institute of New York.

Focused ultrasound treatment

Positron Emission Tomography (PET) RADIATION

A first PET/CT scan with Amyvid (18F-Florbetapir) and MK-6240 (F18-Florquinitau) tracers will be performed on the SIEMENS Biograph 64 to assess the baseline amyloid plaque load and tau load before the treatment, respectively. Finally, two follow-up PET/CT scans will be conducted 3 weeks (±1 week) and 3 months (±2 weeks) post-treatment to assess amyloid plaque load (using Amyvid) and tau load (using MK-6240).

Focused ultrasound treatment

Amyvid DRUG

Amyloid PET tracer Amyvid (18F- Florbetapir) will be stored in their original container with proper radiation shielding at 25 °C and only handled by properly trained personnel in the handling and administration of radioactive materials, which requires employing proper radiation protection procedures.

Also known as: 18F-Florbetapir

Focused ultrasound treatment

MK-6240 DRUG

\[18F\]MK-6240 will be synthesized, purified, and formulated at the local radiochemistry synthesis laboratory and will be administered as a sterile, pyrogen-free solution by IV injection. The radiotracer \[18F\]MK-6240 is supplied in a sterile, ready-to-use solution, direct from the Columbia University PET Center. It is supplied for a targeted calibration time, the precise volume to be administered at a given time can be calculated based on the decay of F-18. Only personnel properly trained in the handling and administration of radioactive materials should handle \[18F\]MK-6240. Usual radiation protection procedures should be used for handling radiotracers, including shielding (lead or tungsten containers/shields), and personal protective equipment including gloves. There are no specific procedures required for the handling of \[18F\]MK-6240. The expiry of \[18F\]MK-6240 is eight hours from the time at End of Synthesis (EOS).

Focused ultrasound treatment

Dotarem DRUG

FDA-approved medication. Dotarem will be handled in accordance with the CUMC Research Pharmacy procedures and NYP policy P168, Version 4. Dotarem will be used according to its labeling. 0.2 ml/kg.

Focused ultrasound treatment

Blood draw DIAGNOSTIC_TEST

Blood samples will be collected through an intravenous catheter or a finger prick during screening, on the day of the FUS treatment and the follow up examinations (week 3 and month 3). These samples will be processed to assess any blood content changes induced by the focused ultrasound treatment.

Focused ultrasound treatment

UR5e DEVICE

Universal Robots robotic arm used for the accurate positioning of the neuronavigation-guided single-element focused ultrasound transducer with respect to the patient's head.

Focused ultrasound treatment

Urine test DIAGNOSTIC_TEST

Urine test required following the MRI and PET Centers policy used clinically for pregnancy screening

Focused ultrasound treatment

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than 50 years old.
• Diagnosis of MCI or AD. All following criteria must be met:
• MMSE score between 12 and 26.
• Modified Hachinski Ischemia Scale (MHIS) score of \<= 4
• Short form Geriatric Depression Scale (GDS) score of \<= 6.
• PET scan confirming amyloid plaque load using Amyvid (18F-Florbetapir).
• PET scan confirming tau positivity in the frontal lobe using MK-6240 (F18-Florquinitau).
• Ability to provide informed consent.

You may not qualify if:

• Prior administration of any amyloid-reducing agent such as aducanumab or lecanemab.
• Contraindication for MRI.
• Contra-indication history or hypersensitivity to MRI contrast agents (e.g., Dotarem) or microbubbles (e.g., Definity, Lumason), including polyethylene glycol (PEG) allergy.
• Prior brain surgery, including deep brain stimulation.
• Metallic implants.
• Abnormal coagulation profile (significant abnormality in PT, PTT, or platelets).
• Anticoagulant therapy.
• History of seizure disorder.
• Brain atrophy to a degree that would interfere with ultrasound delivery.
• Inability to comply with the procedures of the protocol, including follow-up scans.
• Women with capacity to bear children or lactating.
• Impaired renal function with estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m2 provided by a standard blood test 2-4 weeks prior to the ultrasound treatment.
• Active infection/inflammation.
• Acute or chronic hemorrhages, i.e. \> 4 lobar microbleeds, or an area of siderosis or macrohemorrhages.
• Tumors or space-occupying lesions of significance.

Sponsors & Collaborators

• Columbia University: lead

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Magnetic Resonance Spectroscopy; florbetapir; MK-6240; gadoterate meglumine; Blood Specimen Collection; Urinalysis

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Clinical Chemistry Tests; Diagnostic Techniques, Urological

Study Officials

• Grace McIlvain, PhD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sergio Jimenez Gambin, PhD

CONTACT

9295455655; sj3044@columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DEVICE FEASIBILITY
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 11, 2024
• First Posted: September 19, 2024
• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: May 11, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)