Clinical trial NCT05374278: First-in-Human Evaluation of an Astrocytic Glutamate Transporter (EAAT2) PET Tracer in Dementia
Official title: First-in-Human Evaluation of an Astrocytic Glutamate Transporter (EAAT2) PET Tracer in the Brains of Healthy Controls and Patients With Dementia.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Alzheimer Disease
Frontotemporal Dementia
Dementia
Keywords: Alzheimer Disease
Nuclear medicine
Positron emission tomography
Magnetic resonance imaging
Frontotemporal Dementia
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Rio pharmaceuticals Inc.
First posted: 2022-05-16
Enrollment: 102
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: This is a first in human study that will assess the safety and diagnostic performance of \[18F\]RP-115 (fluorine-18 labeled RP115), a positron emission tomography (PET) agent. This agent has the potential to identify the early changes that occur in the brains of patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD).

Detailed description: AD and FTD are the two leading causes of dementia with tremendous impact on patients and their families. Early diagnosis of both AD and FTD is essential to increase patients' quality of life, identify and treat reversible causes, and enhance the development and effectiveness of treatments. However, no single diagnostic agent is currently available for either AD or FTD; instead, clinicians must rely on the patient's history and cognitive testing which often leads to delayed or incorrect diagnosis. Importantly AD and FTD have distinct regional patterns of neuronal loss and dysfunction in the brain; an agent that could detect these regionally specific changes early in the course of the disease process could revolutionize diagnosis and treatment development for these conditions.

This study aims to develop a novel radiotracer to fill this unmet need. The excitatory amino acid transporter 2 (EAAT2) is the main transporter for glutamate in the brain and has been shown to be downregulated in the context of AD and other neurodegenerative conditions. EAAT2 is responsible for over 90% of glutamate uptake in the brain where it is primarily located on astrocytes and plays a key role in maintaining the homeostasis of the tripartite synapse. The goal of this study is to test the EAAT2 targeted positron emitting agent, \[18F\]RP-115, to evaluate early changes in astrocytes in healthy controls versus patients with AD and FTD by quantitative PET imaging of EAAT2. We have preclinical data that demonstrates that this agent is a good predictor of EAAT2 levels in animal models, hence, can potentially detect early signs of neurodegeneration. We now wish to test this agent in humans.

In summary, the primary objective of this study is to demonstrate human safety and measure the biodistribution of \[18F\]RP-115 in healthy controls as well as in age-matched patients with AD and FTD.

Eligibility criteria: Inclusion Criteria:

1. Age 40-75
2. Age-suitable BMI
3. Ability to provide written informed consent and willingly comply with protocol requirements or has a legal authorized representative/guardian who provides surrogate informed consent.
4. No apparent physical disorder.
5. Radial, ulnar, or brachial artery suitable for catheterization.
6. Non-smoker, and not taking OTC nicotine cessation - to limit peripheral metabolism events.
7. Devoid of CNS prescription drugs for three weeks - to limit peripheral metabolism events.

   For Cohort 2B and 2C:
8. Must have a study partner (informant) who spends a minimum average of 5 hours per week with the participant (e.g. family member, significant other, friend, caregiver), is generally aware of the participant's daily activities, can provide information about the participant's cognitive and functional performance, and will accompany the participant in all study procedure.
9. Recent (within 6 mo.) MME clinical scores.

Exclusion Criteria:

1. Unable to provide written informed consent and unwilling to comply with protocol requirements, or does not have a legal authorized representative/guardian who can provide surrogate informed consent.
2. Inadequate arterial access.
3. Receipt of radioisotope \< 5 half-lives within \[18F\]RP-115 imaging- as to not confound any scans with radiation background for previous scanning, and unsuitable organ dosimetry thresholds from previous (\> two weeks) PET scans.
4. The performed \[18F\]RP-115 scan(s) must not represent \> 3 PET studies total within one year.
5. Contra-indication to magnetic resonance, including permanent pacemaker, implantable metallic device, etc.; or severe claustrophobia.
6. Participants who are pregnant (female patients of childbearing age will be tested prior to injection of tracer- positive test excludes from the study)
7. Participants who are breast-feeding.
8. Have a medical condition or other circumstances that in the opinion of the project physicians would significantly decrease chances of obtaining reliable data, achieving the study objective or completing the study.

Primary outcomes:
measure: Safety of Administered dose
timeFrame: A year
measure: Dosimetry of [18F]RP-115
timeFrame: A year
measure: Biodistribution of [18F]RP-115
timeFrame: A year
Secondary outcomes:
measure: [18F]RP-115 diagnostic performance
timeFrame: Three years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: China Basin, UCSF
state: California
Study officials:
affiliation: University of California, San Francisco
name: David Wilson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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