Clinical trial NCT06600880: Neuronavigation-guided FUS-induced BBB Opening in Alzheimer's Disease Patients and Its Effects on Brain Amyloid and Tau
Official title: Neuronavigation-guided Focused Ultrasound-induced Blood-brain Barrier Opening in Alzheimer's Disease Patients and Its Effects on Brain Amyloid and Tau
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Alzheimer Disease, Early Onset
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2024-09-19
Enrollment: 6
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DEVICE_FEASIBILITY

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.

Detailed description: Regarding the primary purpose of this study, the human module for the neuronavigator was implemented in our phase 1a trial, and initial feasibility and safety in a small cohort of AD patients had been tested, with a fast procedural time that required no anesthesia.

Regarding the secondary objective, both amyloid beta and tau protein load in the brain will be assessed at baseline (before FUS-BBBO treatment), and 3-weeks and 3-months after FUS-BBBO treatment, to assess any short-term or long-term changes, respectively.

Eligibility criteria: Inclusion Criteria. AD patients will be recruited in person and have to be over 50 years of age and able to give consent. Patients diagnosed with MCI or AD will be included in our study. Other more severe symptomatic patients will be eligible to enroll, as long as they have the ability to consent for their participation. Screening is essential and will be performed by our collaborator and neurologist of the study, Dr. Lawrence Honig, MD at the Taub Institute of Alzheimer's Disease and Aging at Columbia. After the initial screening we will acquire MRI scans as part of the study and finalize enrollment or exclusion of the patient. Inclusion criteria thus include:

* 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.

Exclusion Criteria. Exclusion criteria include surgeries and other pathologies not associated with AD, as outlined in the following list:

* 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.
* Any uncontrolled medical disorder that might interfere with the ability to safely perform the study.

Primary outcomes:
measure: Total Number of Individuals With Successful Opening of the BBB
timeFrame: 4 days, including the day of treatment
Secondary outcomes:
measure: Total Number of Safety Events Related to Opening of BBB
timeFrame: 4 days, including the day of treatment
measure: Percent Change in Amyloid PET Signal Intensity
timeFrame: 3 months (±2 weeks)
measure: Percent Change in MK-6240 PET Signal Intensity
timeFrame: 3 months (±2 weeks)
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Grace McIlvain, PhD
role: PRINCIPAL_INVESTIGATOR
References: