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

Primary Purpose

Alzheimer Disease, Frontotemporal Dementia, Dementia

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

[18F]RP-115 PET/MRI or PET/CT and MRI

About this trial

This is an interventional diagnostic trial for Alzheimer Disease focused on measuring Alzheimer Disease, Nuclear medicine, Positron emission tomography, Magnetic resonance imaging, Frontotemporal Dementia

Eligibility Criteria

40 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

China Basin, UCSFRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Cohort 1 - dosimetry of [18F]RP-115 in healthy volunteers

Cohort 2B - [18F]RP-115 in patients with AD

Cohort 2C - [18F]RP-115 in patients with FTD

Cohort 2A - [18F]RP-115 in age-matched controls

Arm Description

Establish [18F]RP-115 safety in the clinic with male and female PET imaging.

Comparison of [18F]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD

Outcomes

Primary Outcome Measures

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.

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

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.

Secondary Outcome Measures

[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

Full Information

NCT ID

NCT05374278

First Posted

December 24, 2021

Last Updated

September 14, 2023

Sponsor

David Wilson

Collaborators

Rio pharmaceuticals Inc.

1. Study Identification

Unique Protocol Identification Number

NCT05374278

Brief Title

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

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 2, 2021 (Actual)

Primary Completion Date

November 2, 2024 (Anticipated)

Study Completion Date

July 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

David Wilson

Collaborators

Rio pharmaceuticals Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer Disease, Frontotemporal Dementia, Dementia

Keywords

Alzheimer Disease, Nuclear medicine, Positron emission tomography, Magnetic resonance imaging, Frontotemporal Dementia

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

102 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1 - dosimetry of [18F]RP-115 in healthy volunteers

Arm Type

Experimental

Arm Description

Establish [18F]RP-115 safety in the clinic with male and female PET imaging.

Arm Title

Cohort 2B - [18F]RP-115 in patients with AD

Arm Type

Experimental

Arm Description

Comparison of [18F]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD

Arm Title

Cohort 2C - [18F]RP-115 in patients with FTD

Arm Type

Experimental

Arm Description

Comparison of [18F]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD

Arm Title

Cohort 2A - [18F]RP-115 in age-matched controls

Arm Type

Experimental

Arm Description

Comparison of [18F]RP-115 PET binding between AD patients and age-matched cognitively normal controls and between AD and FTD

Intervention Type

Drug

Intervention Name(s)

[18F]RP-115 PET/MRI or PET/CT and MRI

Intervention Description

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

Primary Outcome Measure Information:

Title

Safety of Administered dose

Description

Time Frame

A year

Title

Dosimetry of [18F]RP-115

Description

Time Frame

A year

Title

Biodistribution of [18F]RP-115

Description

Time Frame

A year

Secondary Outcome Measure Information:

Title

[18F]RP-115 diagnostic performance

Description

Time Frame

Three years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

David Wilson, MD, PhD

Phone

415-514-6229

david.m.wilson@ucsf.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Henry Vanbrocklin, PhD

Phone

415-353-4569

henry.vanbrocklin@ucsf.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David Wilson, MD, PhD

Organizational Affiliation

University of California, San Francisco

Official's Role

Principal Investigator

Facility Information:

Facility Name

China Basin, UCSF

City

San Francisco

State/Province

California

ZIP/Postal Code

94107

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Wilson, MD, PhD

david.m.wilson@ucsf.edu

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

All of the individuals participants data collected during the trial, after de-identification.

IPD Sharing Time Frame

Immediately following publication. No end date.

IPD Sharing Access Criteria

Anyone who wishes to access the data

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

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