Alzheimer DiseaseNCT04118764
Non-invasive Blood-brain Barrier Opening in Alzheimer's Disease Patients Using Focused Ultrasound
A study testing Neuronavigation-guided single-element focused ultrasound transducer, Definity and Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents in people with Alzheimer Disease, run by Columbia University at 1 site in United States.
Trial 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)… Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- Neuronavigation-guided single-element focused ultrasound transducer, Definity and Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 6 Aug 2020to 28 Sep 2022
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 20Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Columbia University Irving Medical Center/NYPH
New York, New York, 11021
About this study
Official title: Neuronavigation-guided Focused Ultrasound-induced Blood-brain Barrier Opening in Alzheimer's Disease Patients
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.
Read the 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.
- Conditions
- Alzheimer Disease
- Being tested
- Neuronavigation-guided single-element focused ultrasound transducer, Definity, Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents, Positron Emission Tomography (PET), Amyvid
- Keywords
- focused ultrasound, blood-brain barrier opening, non-invasive therapy
- Medical subject headings
- Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Neuronavigation-guided single-element focused ultrasound transducerDevice
Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.
DefinityDrug
Also called Perflutren Lipid Microsphere
Definity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier.
Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agentsOther
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.
Positron Emission Tomography (PET)Other
A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load.
AmyvidOther
Also called 18F-Florbetapir
To be used during the PET scan to determine uptake of Amyvid within the treated area.
| Study group | Role | What they receive |
|---|---|---|
| Focused ultrasound treatment | Experimental | Neuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg). Receives: 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Total Number of Individuals With Successful Opening of the BBB
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.
Measured: Baseline through 3 days post-treatment
Total Number of Safety Events Related to Opening of BBB
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.
Measured: Baseline through 3 days post-treatment
Secondary outcomes (2)
Percent Change in Amyloid PET Signal Intensity
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.
Measured: Screening through 3 weeks post-treatment
Change in Mini-Mental State Examination (MMSE) Score
The MMSE is a questionnaire that is used to measure cognitive impairment. The total score range is 0 to 30, with a higher score indicating a better outcome. Cognitive function will be assessed before and after the focused ultrasound treatment to determine the change in MMSE.
Measured: Screening through 3 months post-treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Oct 2019
- Study start6 Aug 2020
- Primary completion11 Jul 2022
- Study completion28 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Device feasibility
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Sponsor
- Investigators
- Elisa Konofagou, PhD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04118764
- Sponsor's protocol ID
- AAAS5163
- Other IDs
- R01AG038961
- Status last verified
- Jul 2024
- First submitted
- 1 Oct 2019
- Last updated
- 26 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No: No individual participant data (IPD) will be shared with other researchers.
Publications
Wu SY, Aurup C, Sanchez CS, Grondin J, Zheng W, Kamimura H, Ferrera VP, Konofagou EE. Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping. Sci Rep. 2018 May 22;8(1):7978. doi: 10.1038/s41598-018-25904-9.
PubMed 29789530Pouliopoulos AN, Wu SY, Burgess MT, Karakatsani ME, Kamimura HAS, Konofagou EE. A Clinical System for Non-invasive Blood-Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer. Ultrasound Med Biol. 2020 Jan;46(1):73-89. doi: 10.1016/j.ultrasmedbio.2019.09.010. Epub 2019 Oct 25.
PubMed 31668690Karakatsani ME, Ji R, Murillo MF, Kugelman T, Kwon N, Lao YH, Liu K, Pouliopoulos AN, Honig LS, Duff KE, Konofagou EE. Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients. Theranostics. 2023 Jul 14;13(12):4102-4120. doi: 10.7150/thno.79898. eCollection 2023.
PubMed 37554284Mathew AS, Gorick CM, Price RJ. Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption. Theranostics. 2021 Oct 11;11(20):9847-9858. doi: 10.7150/thno.65064. eCollection 2021.
PubMed 34815790
Study at a glance
From the registry record, last updated by the sponsor on 26 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neuronavigation-guided Focused Ultrasound-induced Blood-brain Barrier Opening in Alzheimer's Disease Patients
- ClinicalTrials.gov ID
- NCT04118764
- Acronym / sponsor ID
- AAAS5163
- Conditions
- Alzheimer Disease
- Keywords
- focused ultrasound, blood-brain barrier opening, non-invasive therapy
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Columbia UniversityUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- 6 Aug 2020 (actual)
- Primary completion
- 11 Jul 2022 (actual)
- Study completion
- 28 Sep 2022 (actual)
- First posted
- 8 Oct 2019 (actual)
- Results
- Posted 26 Aug 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Device feasibility
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Focused ultrasound treatment | Experimental | 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: AmyvidNeuronavigation-guided focused ultrasound treatment in Alzheimer's disease patients using a single-element transducer in conjunction with Definity Microbubbles (10 μl/kg). |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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:
- Ability to provide informed consent.
Key exclusion criteria (20 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Neuronavigation-guided single-element focused ultrasound transducerNon-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system. | Device | Focused ultrasound treatment |
| DefinityAlso: Perflutren Lipid MicrosphereDefinity microbubbles (10 μl/kg) will be used in conjunction with the ultrasound transducer to temporarily open the blood brain barrier. | Drug | Focused ultrasound treatment |
| Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agentsMRI 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 | Focused ultrasound treatment |
| Positron Emission Tomography (PET)A follow-up PET scan will be performed three days after treatment to determine amyloid plaque load. | Other | Focused ultrasound treatment |
| AmyvidAlso: 18F-FlorbetapirTo be used during the PET scan to determine uptake of Amyvid within the treated area. | Other | Focused ultrasound treatment |
Primary outcome
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.
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.
2 secondary outcomes
Percent Change in Amyloid PET Signal Intensity
Time frame: Screening through 3 weeks post-treatment
Change in Mini-Mental State Examination (MMSE) Score
Time frame: Screening through 3 months post-treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 29789530Wu SY, Aurup C, Sanchez CS, Grondin J, Zheng W, Kamimura H, Ferrera VP, Konofagou EE. Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping. Sci Rep. 2018 May 22;8(1):7978. doi: 10.1038/s41598-018-25904-9.
- Background: PubMed 31668690Pouliopoulos AN, Wu SY, Burgess MT, Karakatsani ME, Kamimura HAS, Konofagou EE. A Clinical System for Non-invasive Blood-Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer. Ultrasound Med Biol. 2020 Jan;46(1):73-89. doi: 10.1016/j.ultrasmedbio.2019.09.010. Epub 2019 Oct 25.
- Derived from this study: PubMed 37554284Karakatsani ME, Ji R, Murillo MF, Kugelman T, Kwon N, Lao YH, Liu K, Pouliopoulos AN, Honig LS, Duff KE, Konofagou EE. Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients. Theranostics. 2023 Jul 14;13(12):4102-4120. doi: 10.7150/thno.79898. eCollection 2023.
- Derived from this study: PubMed 34815790Mathew AS, Gorick CM, Price RJ. Multiple regression analysis of a comprehensive transcriptomic data assembly elucidates mechanically- and biochemically-driven responses to focused ultrasound blood-brain barrier disruption. Theranostics. 2021 Oct 11;11(20):9847-9858. doi: 10.7150/thno.65064. eCollection 2021.
- Individual participant dataSharing planned: No. No individual participant data (IPD) will be shared with other researchers.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Elisa Konofagou, PhD principal investigator
Columbia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Neuronavigation-guided single-element focused ultrasound transducer, Definity and Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents in people with Alzheimer Disease, run by Columbia University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Aug 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Total Number of Individuals With Successful Opening of the BBB (time frame: Baseline through 3 days post-treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04118764, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Aug 2024.