SV2A & TSPO PET Imaging Measures to Reveal Mechanisms of HIV Neuropathogenesis During Antiretroviral Therapy

NCT05586581 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 20000335825R01MH125396
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to longitudinally characterize and evaluate changes in synaptic density in the brain using novel positron-emission tomography (PET) scans; magnetic resonance imaging (MRI), and clinical laboratory markers associated with HIV-related injury in the central nervous system. This study will test hypotheses relating to the presence and mechanisms of aberrant brain structure at the synaptic level in living humans with virologically controlled HIV on antiretroviral therapy. To evaluate associations between PET imaging radiotracers \[11C\]UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein expressed in synapses, and PET \[11C\]PBR28 a measure of microglia function in the brain, the Yale PET center has developed an advanced approach of combining multiple distinct ligands in coordinated same-day PET imaging. Additionally, the study will evaluate the associations of this novel synaptic density marker with well-established clinical measures of neurocognitive performance and laboratory measures of blood and cerebrospinal fluid (CSF).

Conditions

HIV Associated Neurocognitive Disorder; HIV Dementia; HIV Encephalitis; Healthy

Keywords

Human immunodeficiency virus; Positron-Emission Tomography Imaging; Magnetic Resonance Imaging; Cerebrospinal Fluid; SV2A PET; TSPO PET; Neuro-immune dysfunction; Neuro-Inflammation; Biomarkers of inflammation; Neuronal Injury; Neurocognitive functioning; Hippocampus; Microglia; Neuropathogenesis; antiretroviral therapy

Outcome Measures

Primary Outcomes (2)

• The primary outcome measure for 11C-UCB-J will be the binding potential of 11C-UCB-J, specifically non-displaceable binding potential (BPND), the ratio of the specifically bound radioligand to that of nondisplaceable radioligand in tissue.

  Preliminary data from the investigators' pilot study revealed SV2A PET imaging with radiotracer 11C-UCB-J identified regions of reduced synaptic density in suppressed PLWH compared to matched HIV-negative controls. PET and MRI imaging data will be processed for quantification of 11C-UCB-J imaging data in a larger group of suppressed PLWH compared to matched HIV-negative controls to test-retest reproducibility of 11C-UCB-J.

  Through study completion date, an average of 5 years.

• Change in cross-sectional differences and 24-month longitudinal changes in synaptic density in PLWH on suppressive ART relative to matched HIV-negative controls

  Baseline and 24 Month PET and MRI imaging data will be processed for a linear mixed-effects model (LMM) to compare changes in hippocampal-frontostriatal 11C-UCB-J BPND between PLWH and healthy controls.

  Baseline and 24 months

Study Arms (2)

People living with treated suppressed HIV infection (PLWH)

EXPERIMENTAL

40 PLWH participants will be scanned using anatomical magnetic resonance imaging (MRI) and undergo two SV2A (11C-UCB-J) PET scans with arterial sampling and full radio metabolite analysis to obtain measures of synaptic density at baseline and 24 months (2 years). For each SV2A PET, up to 20 millicurie (mCi) of \[11C\], UCB-J will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes. A subset of PLWH (n=20) will participate in TSPO (11C-PBR28) PET scans on the same day as the baseline SV2A PET scan. For a TSPO PET, up to 20 mCi of \[11C\], PBR28 will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes.

Drug: SV2A PET; Drug: TSPO PET

HIV-Negative Control (HIV-)

EXPERIMENTAL

30 HIV-Negative Control (HIV-) participants will be scanned using anatomical magnetic resonance imaging (MRI) and undergo two SV2A (11C-UCB-J) PET scans with arterial sampling and full radio metabolite analysis to obtain measures of synaptic density at baseline and 24 months (2 years). For each SV2A PET, up to 20 mCi of \[11C\], UCB-J will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes.

Drug: SV2A PET

Interventions

SV2A PET DRUG

SV2A PET scan with radiotracer \[11C\]UCB-J for imaging synaptic density in the brain

Also known as: [11C]UCB-J, [11C]APP311

HIV-Negative Control (HIV-); People living with treated suppressed HIV infection (PLWH)

TSPO PET DRUG

TSPO PET scan with radiotracer \[11C\]PBR28 for imaging of neuroimmune status

Also known as: [11C]PBR28

People living with treated suppressed HIV infection (PLWH)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Voluntary, written, informed consent (signed and dated)
• For females, a negative urine or serum pregnancy (HCG) test at screening and on each scan day before initiation of any scan procedures.
• HIV infection on cART with documented viral suppression for at least one year. Plasma viral suppression will be defined as no more than one viral load
• Test above 20 HIV RNA cps/mL in the year prior to screening and no HIV RNA tests above 200 cps/mL in the same span.
• Willingness to participate in MRI, PET, phlebotomy, and Neuropsychological Testing (NPT) Assessments \& Surveys.

You may not qualify if:

• Active substance dependence (e.g., heroin, alcohol, cocaine, sedative hypnotics, methamphetamine) as determined by the standardized Behavioral Assessments.
• A history of significant non-HIV related neurological illness (e.g., cerebrovascular, seizures, traumatic brain injury).
• Medical contraindications to the administration of radioactivity (e.g., prior radiation exposure within the past year from research, or from workplace exposure, that in combination with the planned scans would exceed the FDA limit for annual radiation exposure).
• Medical contraindications to participation in a magnetic resonance imaging procedure (e.g., ferromagnetic implants/foreign bodies, claustrophobia, cardiac pacemaker, prosthetic valve, otologic implant, etc.).
• History of a bleeding disorder, low platelet count, or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto).
• Voluntary, written, informed consent (signed and dated)
• For females, a negative urine or serum pregnancy (HCG) test at screening and on each scan day before initiation of any scan procedures.
• Willingness to participate in phlebotomy, NPT Assessments \& Surveys, MRI, and PET.
• Physically healthy by medical history, physical, neurological, and laboratory examinations, as judged by the principal investigator.
• Have a negative test for HIV on file within the last three months or willing to have an HIV test in the current study.
• Active substance dependence (e.g., heroin, alcohol, cocaine, sedative hypnotics, methamphetamine) as determined by the standardized Behavioral Assessments.
• A history of significant neurological illness (e.g., cerebrovascular, seizures, traumatic brain injury).
• Medical contraindications to the administration of radioactivity (e.g., prior radiation exposure within the past year, from research, or from workplace exposure, that in combination with the planned scans would exceed the FDA limit for annual radiation exposure)
• Medical contraindications to participation in a magnetic resonance imaging procedure (e.g., ferromagnetic implants/foreign bodies, claustrophobia, cardiac pacemaker, prosthetic valve, otologic implant, etc.
• History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto

Sponsors & Collaborators

• Yale University: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Yale School of Medicne, Neuro ID Research Program

New Haven, Connecticut, 06510, United States

RECRUITING

MeSH Terms

Conditions

AIDS Dementia Complex; Acquired Immunodeficiency Syndrome

Interventions

1-((3-(methylpyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (methyl-(11)C)N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Neurocognitive Disorders; Mental Disorders; Slow Virus Diseases

Study Officials

• Serena Spudich, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Allison Nelson, RN

CONTACT

(475) 434-4324; allison.nelson@yale.edu

Paige Ryall

CONTACT

(475) 375-7424; paige.ryall@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Gilbert H. Glaser Professor of Neurology

Model Details: In this study, people living with treated suppressed HIV infection (PLWH) and matched HIV-negative controls will be scanned using anatomical magnetic resonance imaging (MRI) and PET. All participants will receive two SV2A PET scans (baseline and 2 years). A subset of PLWH participants will be asked to complete a TSPO PET scan on the same day as the baseline SV2A PET scan. Participants will undergo phlebotomy and medical/mental health and substance use histories for eligibility, and may also complete an ECG, blood tests, an optional lumbar puncture, neurocognitive testing \& behavioral/mood questionnaires.

Study Record Dates

• First Submitted: October 16, 2022
• First Posted: October 19, 2022
• Study Start: May 17, 2023
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2030
• Last Updated: September 9, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)