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

Primary Purpose

HIV Associated Neurocognitive Disorder, HIV Dementia, HIV Encephalitis

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

SV2A PET

TSPO PET

About this trial

This is an interventional basic science trial for HIV Associated Neurocognitive Disorder focused on measuring 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

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

PLWH Inclusion Criteria:

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.

PLWH Exclusion Criteria:

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).

HIV - Inclusion Criteria:

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.

HIV- Exclusion Criteria:

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

Sites / Locations

Yale School of Medicne, Neuro ID Research ProgramRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

People living with treated suppressed HIV infection (PLWH)

HIV-Negative Control (HIV-)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

Full Information

NCT ID

NCT05586581

First Posted

October 16, 2022

Last Updated

June 26, 2023

Sponsor

Yale University

Collaborators

National Institutes of Health (NIH), National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT05586581

Brief Title

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

Acronym

ART

Official Title

PET Imaging of Synaptic Density Combined With Neuroimmunologic Measures to Reveal Mechanisms of HIV Neuropathogenesis During ART

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Recruiting

Study Start Date

May 17, 2023 (Actual)

Primary Completion Date

December 2027 (Anticipated)

Study Completion Date

December 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Yale University

Collaborators

National Institutes of Health (NIH), National Institute of Mental Health (NIMH)

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

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).

Detailed Description

The HIV PET plus study builds upon the compelling preliminary findings of the investigators HIV PET pilot study (Yale Internal Review Board (IRB) #2000024620) that brain SV2A PET successfully identifies regions of reduced synaptic density, including a hippocampal-frontostriatal neural circuit that is relevant to central nervous system (CNS) dysfunction in PLWH on ART The primary aims of this study are as follows: Aim 1. To evaluate cross-sectional differences and 24-month longitudinal changes in synaptic density in PLWH on suppressive ART relative to matched HIV-negative (HIV-) controls. Synaptic density will be measured with SV2A PET scans acquired at baseline and two years in 40 PLWH on ART and in 30 HIV-, matched for age, gender, ethnicity, and history of substance use. Hypotheses: (1a) Synaptic density in a hippocampal-frontostriatal neural circuit will be reduced in PLWH relative to matched HIV-; (1b) Synaptic density in this circuit will decline at a greater rate in PLWH relative to HIV-. Aim 2. To determine, in PLWH on ART, the extent to which microglia levels impact synaptic density. Microglia levels will be measured with TSPO PET scans concurrently acquired with SV2A PET scans in a subset of 20 PLWH from Aim 1 at baseline, followed by repeat SV2A PET scans at 24 months. Hypotheses: (2a) Greater microglia levels in a hippocampal-frontostriatal circuit will be associated with decreased synaptic density in this circuit; and (2b) Greater microglial levels at baseline will be a longitudinal predictor of a greater decline in synaptic density in this neural circuit over 24 months. Aim 3. To determine the role of synaptic density in mediating the relation between microglia level, laboratory biomarkers of inflammation and neuronal injury, and neurocognitive functioning in PLWH. Blood, cerebrospinal fluid, and neurocognitive measures will be acquired in 40 PLWH on ART at baseline and 2 years with SV2A PET. The investigators will use parallel processing statistical approaches to examine multimodal longitudinal associations between baseline microglial activation, and changes in synaptic density, laboratory biomarkers and neurocognitive functioning to understand the molecular neuropathogenesis of CNS impairment in PLWH on ART. Hypothesis: (3) In PWLH on ART, greater hippocampal-frontostriatal microglial activation at baseline will be associated with greater 24-month reductions in synaptic density, which will in turn be associated with greater reductions in neurocognitive functioning, particularly on measures of learning and memory.

6. Conditions and Keywords

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

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

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

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.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

People living with treated suppressed HIV infection (PLWH)

Arm Type

Experimental

Arm Description

Arm Title

HIV-Negative Control (HIV-)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

SV2A PET

Other Intervention Name(s)

[11C]UCB-J, [11C]APP311

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

TSPO PET

Other Intervention Name(s)

[11C]PBR28

Intervention Description

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

Primary Outcome Measure Information:

Title

Description

Time Frame

Through study completion date, an average of 5 years.

Title

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

Description

Time Frame

Baseline and 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

PLWH Inclusion Criteria: 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. PLWH Exclusion Criteria: 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). HIV - Inclusion Criteria: 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. HIV- Exclusion Criteria: 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

Central Contact Person:

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

Alliosn Nelson, RN

Phone

203-308-9361

allison.nelson@yale.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Serena Spudich, MD

Organizational Affiliation

Yale School of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Yale School of Medicne, Neuro ID Research Program

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06510

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Allison Nelson, RN

Phone

203-308-9361

allison.nelson@yale.edu

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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