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Non-invasive Blood-brain Barrier Opening in Alzheimer's Disease Patients Using Focused Ultrasound

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04118764
Recruitment Status : Recruiting
First Posted : October 8, 2019
Last Update Posted : November 5, 2020
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Elisa Konofagou, Columbia University

Brief Summary:
The purpose of this study is to test a new technique that may, in the future, help deliver medications to the brain of people with Alzheimer's disease. Participants in this study will undergo a focused ultrasound treatment to the brain, along with Magnetic Resonance Imagine (MRI) and Positron Emission Tomography (PET) scans.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Device: Neuronavigation-guided single-element focused ultrasound transducer Drug: Definity Other: Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents Other: Positron Emission Tomography (PET) Other: Amyvid Not Applicable

Detailed Description:

Central nervous system disorders are currently being symptomatically treated since the molecular events provoking their onset have not been yet identified. Drug delivery techniques have to overcome the almost impermeable blood-brain barrier (BBB) and can be grouped into two main categories: (i) invasive and targeted, and (ii) non-invasive and non-targeted methods. However, the technological advances of the past decades revealed the immense potential of focused ultrasound (FUS) in transcranial applications. In contrast to other techniques, FUS-mediated BBB opening is both non-invasive and targeted. The localized energy delivery coupled with the circulation of intravenously administered microbubbles initiates biological effects confined only to the vessel walls and contained only in the targeted region within the brain.

The purpose of the study is to assess the safety and feasibility of focused ultrasound-induced blood-brain barrier opening in Alzheimer's disease patients, using a single-element transducer with neuronavigation guidance. The investigators will also test whether treatment with focused ultrasound alone alters the amyloid protein levels in the treated brain areas and its potential effects on the cognitive function of Alzheimer's patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Device Feasibility
Official Title: Neuronavigation-guided Focused Ultrasound-induced Blood-brain Barrier Opening in Alzheimer's Disease Patients
Actual Study Start Date : October 1, 2020
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2021


Arm Intervention/treatment
Experimental: Focused ultrasound treatment
Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg).
Device: Neuronavigation-guided single-element focused ultrasound transducer
Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.

Drug: Definity
Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier.
Other Name: Perflutren Lipid Microsphere

Other: Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents
MRI scans will be completed at baseline and immediately after the focused ultrasound treatment to confirm BBB opening and safety. A follow-up MRI will be performed three days after treatment to confirm BBB closure, only in the case of successful BBB opening.

Other: Positron Emission Tomography (PET)
A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load.

Other: Amyvid
To be used during the PET scan to determine uptake of Amyvid within the treated area.
Other Name: 18F-Florbetapir




Primary Outcome Measures :
  1. Total Number of Individuals with Successful Opening of the BBB [ Time Frame: Baseline through 3 days post-treatment ]
    The total number of individuals with successful opening of the BBB will be assessed. Blood-brain barrier opening volume will be measured in mm^3 through contrast-enhanced T1-weighted MRI on the day of the focused ultrasound treatment and 3 days after treatment, to confirm blood-brain barrier restoration.

  2. Total number of Safety Events Related to Opening of BBB [ Time Frame: Baseline through 3 days post-treatment ]
    The total number of safety events related to opening of the BBB as assessed by T2 and susceptibility-weighted (SWI) MRI. Safety will be established by the presence and the total area of hyper-intense or hypo-intense areas in the T2 and SWI scans.


Secondary Outcome Measures :
  1. Percent Change in Amyloid PET Signal Intensity [ Time Frame: Screening through 3 days post-treatment ]
    Amyloid plaques will be assessed through PET imaging before and after the focused ultrasound treatment. The standardized uptake value ratio images (SUVr) will be compared before and after the FUS treatment, to investigate if there is a change in the uptake of 18F-Florbetapir within the treated area.

  2. Change in Mini-Mental State Examination (MMSE) Score [ Time Frame: Screening through 3 months post-treatment ]
    The MMSE is a 30-point questionnaire that is used to measure cognitive impairment. MMSE scores range from 0 (worst outcome)-30 (better outcome). Cognitive function will be assessed before and after the focused ultrasound treatment to determine a the change in MMSE.



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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 50 years of age or older.
  • Diagnosis of early Alzheimer's disease (AD) or mild cognitive impairment (MCI) at minimum. All following criteria must be met:

    • Probable MCI or AD consistent with criteria outlined in (McKhann et al 2011, Petersen et al 2018).
    • Mini Mental State Examination (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).
  • Ability to provide informed consent.

Exclusion Criteria:

  • Contraindication for Magnetic Resonance Imaging (MRI).
  • Contra-indication history or hypersensitivity to MRI contrast agents (e.g., Dotarem) or microbubbles (e.g., Definity).
  • Prior brain surgery, including deep brain stimulation.
  • Metallic implants.
  • Moderate or severe uncontrolled hypertension (systolic blood pressure > 140 mmHg).
  • Abnormal coagulation profile, e.g. hemophilia A or B.
  • Coagulopathy or under anticoagulant therapy.
  • History of stroke or cardiovascular disease.
  • Active/detectable gingivitis, herpes simplex, hepatitis, tuberculosis, and minor skin or respiratory infections.
  • History of seizure disorder.
  • History of asthma or allergies to food or medication with significant symptoms in past 3 years.
  • Severe brain atrophy.
  • Inability to comply with the procedures of the protocol, including follow-up MRI scans.
  • Pregnancy or lactation.
  • Impaired renal function with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 provided by a standard blood test at maximum 2 weeks prior to the ultrasound treatment.
  • Active infection/inflammation.
  • Acute or chronic hemorrhages, i.e. > 4 lobar microbleeds, and no siderosis or macrohemorrhages.
  • Tumors or space occupying lesions.
  • Meningeal enhancements.
  • Intracranial hypotension.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04118764


Contacts
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Contact: Elisa Konofagou, PhD (212) 342-1612 ek2191@columbia.edu
Contact: Antonios Pouliopoulos, PhD (212) 342-1612 ap3623@columbia.edu

Locations
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United States, New York
Columbia University Irving Medical Center/NYPH Recruiting
New York, New York, United States, 11021
Contact: Elisa Konofagou, PhD    212-342-1612    ek2191@columbia.edu   
Contact: Antonios Pouliopoulos, PhD    (212) 342-1612    ap3623@columbia.edu   
Principal Investigator: Elisa Konofagou, PhD         
Sub-Investigator: Lawrence S. Honig, MD, PhD         
Sponsors and Collaborators
Elisa Konofagou
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Elisa Konofagou, PhD Columbia University
Additional Information:
Publications:
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Responsible Party: Elisa Konofagou, Robert and Margaret Hariri Professor in Biomedical Engineering and Radiology, Columbia University
ClinicalTrials.gov Identifier: NCT04118764    
Other Study ID Numbers: AAAS5163
R01AG038961 ( U.S. NIH Grant/Contract )
First Posted: October 8, 2019    Key Record Dates
Last Update Posted: November 5, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No individual participant data (IPD) will be shared with other researchers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by Elisa Konofagou, Columbia University:
focused ultrasound
blood-brain barrier opening
non-invasive therapy
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders