First-in-Human Evaluation of an Astrocytic Glutamate Transporter (EAAT2) PET Tracer in Dementia

Study Overview
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Brief Summary
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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
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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 couldmdetect 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.

Official Title
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First-in-Human Evaluation of an Astrocytic Glutamate Transporter (EAAT2) PET Tracer in the Brains of Healthy Controls and Patients With Dementia.

Conditions
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Alzheimer Disease, Frontotemporal Dementia, Dementia

Intervention / Treatment
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* Drug: [18F]RP-115 PET/MRI or PET/CT and MRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40-75 years old BMI age-suitable Ability to provide written informed consent and willing to comply with protocol requirements, or has a legal authorized representative/guardian who provides surrogate informed consent. No apparent physical disorder. Radial, ulnar or brachial artery suitable for catheterization. Non- smoker, and not taking over the counter nicotine cessation- to limit peripheral metabolism events Devoid of central nervous system prescription drugs for three weeks- to limit peripheral metabolism events. For Cohort 2 part B only: 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 Recent (within 6 mo.) mini mental examination clinical scores. Exclusion Criteria: 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. Inadequate arterial access. 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. The performed [18F]RP-115 scan(s) must not represent > 3 PET studies total within one year. Contra-indication to magnetic resonance, including permanent pacemaker, implantable metallic device, etc.; or severe claustrophobia. Participants who are pregnant (female patients of childbearing age will be tested prior to injection of tracer- positive test excludes from the study) Participants who are breast-feeding. 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - dosimetry of [18F]RP-115 in healthy volunteers<br>Establish [18F]RP-115 safety in the clinic with male and female PET imaging. | Drug: [18F]RP-115 PET/MRI or PET/CT and MRI<br>* An I.V. bolus injection of up to 10 millicurie (mCi) [18F]RP-115 will be administered, followed by a PET/MRI scan or by a combination of PET/CT and MRI<br>|
| Experimental: Cohort 2B - [18F]RP-115 in patients with AD<br>Comparison of [18F]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD | Drug: [18F]RP-115 PET/MRI or PET/CT and MRI<br>* An I.V. bolus injection of up to 10 millicurie (mCi) [18F]RP-115 will be administered, followed by a PET/MRI scan or by a combination of PET/CT and MRI<br>|
| Experimental: Cohort 2C - [18F]RP-115 in patients with FTD<br>Comparison of [18F]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD | Drug: [18F]RP-115 PET/MRI or PET/CT and MRI<br>* An I.V. bolus injection of up to 10 millicurie (mCi) [18F]RP-115 will be administered, followed by a PET/MRI scan or by a combination of PET/CT and MRI<br>|
| Experimental: Cohort 2A - [18F]RP-115 in age-matched controls<br>Comparison of [18F]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD | Drug: [18F]RP-115 PET/MRI or PET/CT and MRI<br>* An I.V. bolus injection of up to 10 millicurie (mCi) [18F]RP-115 will be administered, followed by a PET/MRI scan or by a combination of PET/CT and MRI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Administered dose | Each study participant will undergo a physical examination, vital signs, and ECGs prior to and after the scan and will also be monitored during the scan for adverse events. Additionally, a follow-up with the subject will be conducted 24-48 hours after [18F]RP-115 administration. Outcome Measure: Any adverse events will be recorded and graded according to Common Terminology Criteria for Adverse Events. | A year | 
| Dosimetry of [18F]RP-115 | Whole-body PET/MRI scan will be conducted immediately after an [18F]RP-115 injection and last about 3.5 hours (including breaks) in 8 healthy volunteers (male and female). Equivalent organ radiation doses will be calculated in selected organs using the dynamic PET/MRI data in order to calculate the dosimetry of the tracer. Outcome Measure: Radiation exposure per organ as milliSievert/kg | A year | 
| Biodistribution of [18F]RP-115 | Whole-body PET/MRI scan will be conducted immediately after an [18F]RP-115 injection and last about 3.5 hours (including breaks) in 8 healthy volunteers (male and female). Percent injected activity (%IA) will be calculated in selected organs using the dynamic PET/MRI data in order to calculate the biodistribution of the tracer. Outcome Measure: Percent injected activity (%Injected radioactivity) in selected organs. | A year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| [18F]RP-115 diagnostic performance | Sixty (90) subjects (subjects with AD, FTD, and healthy age-matched controls) will undergo a brain PET/MRI scan that will be start 30-90 minutes after an [18F]RP-115 injection and will last about 60-90 minutes. In selected subjects, blood sample collection via arterial catheter will be performed. Significant changes in the [18F]RP-115 cerebral tracer binding parameters will be used in order to identify the primary affected regions in patients with Alzheimer disease compared to healthy age-matched controls. Outcome Measure: Radioactivity distribution volume in select organs, mCi/L | Three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer Disease, Nuclear medicine, Positron emission tomography, Magnetic resonance imaging, Frontotemporal Dementia