ExAblate BBB Disruption for Alzheimer's Disease

Recruiting at 14 trial locations

Overseen By Brian Dalm, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: InSightec

Must be taking: Alzheimer's medications

Disqualifiers: Cardiac disease, Depression, Seizure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Varies

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether the ExAblate Model 4000 Type 2.0 can safely and effectively open the blood-brain barrier (a protective shield around the brain) in individuals with probable Alzheimer's Disease. The researchers aim to determine if disrupting this barrier might aid in treating Alzheimer's by allowing medications or therapies to reach the brain more effectively. This study suits individuals who can walk, have been living with probable Alzheimer's, and have been on stable Alzheimer's medication for at least three months. As an unphased trial, it offers a unique opportunity to contribute to groundbreaking research that could pave the way for future Alzheimer's treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on Alzheimer's medication, you must have been taking it for at least 2 months and at a stable dose for at least 3 months.

What prior data suggests that the ExAblate Model 4000 Type 2.0 System is safe for disrupting the blood-brain barrier in Alzheimer's patients?

Research shows that the ExAblate Model 4000 Type 2.0 System has been tested for its ability to safely open the blood-brain barrier (BBB). This system uses focused ultrasound, employing sound waves to create tiny openings in the BBB. In earlier studies, most patients handled the treatment well.

Some people reported mild side effects, such as headaches or temporary confusion, but these typically resolved on their own without lasting issues. Researchers are further studying the treatment to ensure its safety for people with Alzheimer's Disease, and initial safety results appear promising.

Since the trial is still in its early stages, researchers continue to gather more information about its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the ExAblate Model 4000 Type 2.0 System because it offers a groundbreaking approach for treating Alzheimer's disease by temporarily disrupting the blood-brain barrier (BBB). Unlike traditional treatments, which often rely on medications to manage symptoms, this technique uses focused ultrasound to open the BBB, potentially allowing for direct delivery of therapeutic agents to the brain. This method could enhance the effectiveness of treatments by ensuring that medications reach their target more efficiently, offering hope for slowing or even reversing the progression of Alzheimer's.

What evidence suggests that the ExAblate Model 4000 Type 2.0 System is effective for disrupting the blood-brain barrier in Alzheimer's Disease?

Research has shown that the ExAblate Model 4000 Type 2.0 System, which participants in this trial will receive, is being tested for its ability to temporarily open the blood-brain barrier (BBB) in people with Alzheimer's. In earlier studies, this system safely and effectively opened the BBB. This opening could help deliver treatments directly to the brain, which the BBB usually protects. Some studies found that the procedure was well-tolerated and showed promise in improving drug delivery to the brain. While more research is needed, early results suggest it could be a promising method for treating Alzheimer's. ^{1 3 4 5 6}

Are You a Good Fit for This Trial?

This trial is for people aged 50-85 with probable Alzheimer's Disease who can walk and report sensations during the procedure. They must have been on stable Alzheimer's medication for at least 3 months if applicable. Exclusions include significant heart disease, MRI contraindications, bleeding disorders, severe liver or kidney issues, untreated sleep apnea, seizure history, current participation in other trials, chronic lung problems, HIV positive status or certain genetic risk factors.

Inclusion Criteria

I am between 50 and 85 years old.

I have been diagnosed with probable Alzheimer's Disease.

You can tell the doctor how you are feeling during the procedure.

Exclusion Criteria

Any contraindications to MRI scanning

I cannot have a lumbar puncture due to health reasons.

My kidney function is severely impaired.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo three serial ExAblate BBB disruption procedures

Varies

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• ExAblate Model 4000 Type 2.0 System

Trial Overview The study tests the safety and effectiveness of the ExAblate Model 4000 Type 2.0 System to temporarily disrupt the blood-brain barrier in patients with Alzheimer's Disease. This disruption could potentially allow better delivery of treatments to the brain.

How Is the Trial Designed?

Group I: Blood Brain Barrier (BBB) Disruption Experimental Treatment 1 Intervention

ExAblate Model 4000 Type 2.0 System

ExAblate Model 4000 Type 2.0 System is already approved in United States, Canada for the following indications:

Approved in United States as ExAblate Model 4000 Type 2.0 System for:

• Essential Tremor
• Parkinson's Disease
• Neuropathic Pain
• Bone Metastases
• Uterine Fibroids
• Adenomyosis

Approved in Canada as ExAblate Model 4000 Type 2.0 System for:

• Essential Tremor
• Parkinson's Disease
• Alzheimer's Disease (clinical trials)

Who Is Running the Clinical Trial?

InSightec

Lead Sponsor

Trials

92

Recruited

3,800+

Dr. Maurice R. Ferré

InSightec

Chief Executive Officer

MD

Dr. Arjun Desai

InSightec

Chief Medical Officer

MD

Published Research Related to This Trial

The study utilized a computational platform called The Virtual Brain (TVB) to create personalized virtual brain models for patients with mild cognitive impairment and Alzheimer's disease, linking amyloid beta levels to neural hyperexcitability and altered brain dynamics.

Simulations successfully replicated known EEG alterations in Alzheimer's patients, showing that higher amyloid beta loads lead to slower brain wave frequencies, and suggested that NMDA receptor antagonism from memantine could potentially reverse these changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease. Stefanovski, L., Triebkorn, P., Spiegler, A., et al.[2023]

Alzheimer's disease leads to significant disruption of cortical circuitry, particularly affecting memory-related systems, which results in severe cognitive dysfunction and behavioral disturbances.

The early and selective degeneration of specific cortical circuits, such as those connecting the hippocampus and the cholinergic system, is likely responsible for the pronounced memory loss in Alzheimer's patients, highlighting the need for early diagnosis and targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormalities of neural circuitry in Alzheimer's disease: hippocampus and cortical cholinergic innervation. Geula, C.[2019]

In a study of 16 aged subjects with varying levels of Alzheimer's disease pathology, changes in the GABA(B) receptor R1 protein (GBR1) were observed, indicating its potential role in the vulnerability of hippocampal neurons as the disease progresses.

In early stages of Alzheimer's, increased GBR1 expression may help protect neurons, but in advanced stages, particularly in the CA1 region, reduced GBR1 levels are linked to neuronal loss, suggesting that these changes could disrupt the balance of neurotransmitters and contribute to cognitive dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in hippocampal GABABR1 subunit expression in Alzheimer's patients: association with Braak staging. Iwakiri, M., Mizukami, K., Ikonomovic, MD., et al.[2023]

In a study using the J20 transgenic mouse model of familial Alzheimer's disease, researchers found that early amyloid beta (Aβ) buildup leads to significant impairments in the medial entorhinal cortex (MEC) grid cell network, affecting spatial coding.

These impairments in grid cells occurred early in the disease process, coinciding with reduced spatial memory performance, highlighting the critical role of Aβ in disrupting neural circuits essential for navigation and memory.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disruption of the grid cell network in a mouse model of early Alzheimer's disease. Ying, J., Keinath, AT., Lavoie, R., et al.[2022]

MRI-guided low-intensity focused ultrasound (FUS) safely opened the blood-brain barrier in 10 participants with mild Alzheimer's disease, with no serious adverse events reported during the 6-12 month follow-up period.

The treatment resulted in a 14% reduction in β-amyloid plaque in targeted brain regions, and cognitive assessments showed no significant worsening, indicating that FUS may not negatively impact disease progression while potentially allowing for therapeutic delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes. Rezai, AR., Ranjan, M., Haut, MW., et al.[2023]

The ExAblate Neuro 4000 system uses Magnetic Resonance guided Focused UltraSound (MRgFUS) to precisely target and thermally ablate specific brain tissues, showing promise particularly in treating conditions like Essential Tremor.

Current clinical applications demonstrate that MRgFUS is both safe and effective, but ongoing advancements in technology are needed to enhance its efficacy and expand its use for various neurological diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Device profile of exAblate Neuro 4000, the leading system for brain magnetic resonance guided focused ultrasound technology: an overview of its safety and efficacy in the treatment of medically refractory essential tremor. Jameel, A., Bain, P., Nandi, D., et al.[2021]

The ExAblate device, approved for treating movement disorders like tremor-dominant Parkinson's disease, shows minimal cognitive decline in patients post-treatment, particularly in areas like verbal fluency and inhibition.

Current research on the neurocognitive effects of MRgFUS in Parkinson's disease is limited, with only two studies using comprehensive evaluations, highlighting the need for more rigorous assessments to understand cognitive risks associated with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetic resonance-guided focused ultrasound for Parkinson's disease since ExAblate, 2016-2019: a systematic review. Lennon, JC., Hassan, I.[2022]

In the ongoing phase 1b PRIME study involving patients with prodromal or mild Alzheimer's disease, aducanumab treatment led to significant reductions in amyloid PET SUVR, indicating a decrease in amyloid plaque burden over time and with higher doses.

The choice of reference regions for calculating SUVR significantly influenced effect sizes, with subcortical white matter and the pons yielding the largest effect sizes, while using the anterior cingulate cortex as a target ROI provided better results than a composite cortex approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab. Chiao, P., Bedell, BJ., Avants, B., et al.[2019]

The study suggests that highly connected 'hub' regions in the brain are particularly vulnerable to Alzheimer's disease due to their excessive neuronal activity, which leads to increased amyloid-β deposition.

Using a computational model, the research found that this excessive activity can cause structural and functional changes in the brain, indicating that targeting neuronal activity may be a potential strategy for early detection and intervention in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity dependent degeneration explains hub vulnerability in Alzheimer's disease. de Haan, W., Mott, K., van Straaten, EC., et al.[2022]

Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) was safely used to temporarily increase blood-brain barrier (BBB) permeability in nine older participants with Alzheimer's disease, without causing serious adverse events or worsening cognitive decline over six months.

While MRgFUS showed some reduction in amyloid levels in specific brain regions, it did not lead to significant changes in Alzheimer's disease biomarkers in the cerebrospinal fluid or blood, indicating that while the technique is safe, its efficacy in altering disease pathology needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound. Meng, Y., Goubran, M., Rabin, JS., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03739905

NCT03739905 | ExAblate Blood-Brain Barrier Opening for ... The purpose of this study is to evaluate the safety and efficacy of the ExAblate® Model 4000 Type 2.0 system as a tool to open the blood-brain barrier (BBB) in ...

2. adventhealth.com adventhealth.com/medical/adventhealthmd/news/adventhealth-study-exploring-use-mr-guided-focused-ultrasound-mrgfus-disrupt-blood-brain-barrier

AdventHealth Study Exploring the Use of MR-Guided ... This prospective, multi-center, single-arm study is evaluating the safety and efficacy of the Exablate Model 4000 Type 2.0 System (Exablate) as a tool to ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03671889?c=dmcso

ExAblate Blood-Brain Barrier (BBB) Disruption for the ... The purpose of this study is to evaluate the safety and efficacy of the ExAblate Model 4000 Type 2.0 System as a tool to disrupt the blood-brain barrier (BBB) ...

4. ufhealth.org ufhealth.org/clinical-trials/al002-feasibility-study-for-treatment-of-alzheimer-s-disease

AL002 Feasibility Study for Treatment of Alzheimer s Disease The purpose of this study is to evaluate the safety and efficacy of the ExAblate Model 4000 Type 2.0 System as a tool to disrupt the blood-brain barrier ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12275862/

Safety, Efficacy and Clinical Applications of Focused ... We review the safety, efficacy, and potential biological effects of FUS-mediated BBB opening in AD patients. Key words: Alzheimer's disease, ...

6. accessdata.fda.gov accessdata.fda.gov/cdrh_docs/pdf15/P150038S037B.pdf

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) Once targeting is complete, the treatment outcome is confirmed with adequate post-treatment MRI sequences. The Exablate Model 4000 Type 1.0 & ...