Central Nervous System Uptake of Anti-CD8+ T Cell Minibodies in Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy
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| ClinicalTrials.gov Identifier: NCT05849467 |
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Recruitment Status :
Recruiting
First Posted : May 9, 2023
Last Update Posted : April 5, 2024
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Background:
Multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML) are disorders that affect the central nervous system (CNS). The CNS includes the brain, spinal cord, and optic nerves. Both diseases can cause muscle weakness and impair vision, speech, and coordination. Researchers are working to better understand how MS and PML affect the CNS.
Objective: To test whether an experimental radioactive tracer (minibody) can help positron emission tomography (PET) scans detect certain immune cells in the CNS of people with MS and PML.
Eligibility:
People aged 18 years and older with MS or PML.
Design:
Participants will come to the clinic for at least 3 visits over 4 to 6 weeks.
Participants will undergo testing. They will have a physical and neurological exam. They will have blood tests and tests of their heart function. They will have a magnetic resonance imaging (MRI) scan of the brain. They may have a spinal tap: Their lower back will be numbed, and a needle will be inserted between the bones of the spine to withdraw fluid from around the spinal cord.
Minibody is given through a tube with a needle placed in a vein in the arm. This takes 5 to 10 minutes. Participants will have heart function tests before and after receiving the minibody.
Participants will return the next day for the PET scan. They will lie on a table that moves through a doughnut-shaped machine. This scan will take about 1 hour.
Participants with PML may opt to repeat the minibody infusion and the PET scan within 6 months.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Multiple Sclerosis Progressive Multifocal Leukoencephalopathy | Drug: 89 Zr-Df-crefmirlimab | Phase 1 |
Study Description:
This study will obtain pilot data for noninvasive positron emission tomography (PET) imaging of CD8+ T lymphocytes in two inflammatory central nervous system (CNS) demyelinating diseases, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML), by characterizing CNS uptake of anti-CD8+ T cell antibody fragment (aka minibody ) (89Zr-Dfcrefmirlimab), an investigational, intravenous PET tracer.
Objectives:
Primary Objective: To detect and localize infiltration of CD8+ T cells in the CNS of adults with MS and PML via PET-CT (computed tomography) scans using a minibody with high affinity for CD8+ T cells.
Secondary Objectives: (1) To characterize safety and tolerability of 89Zr-Df-crefmirlimab in the participant population. (2) For the PML cohort with longitudinal evaluation, to determine the effects of immune reconstitution, either spontaneous or facilitated, on 89Zr-Dfcrefmirlimab uptake.
Endpoints:
Primary Endpoints: Standardized uptake values (SUV) in different tissue types (lesions, white matter, gray matter, meninges, choroid plexus, as determined from coregistered MRI) in each cohort (MS or PML) by region-of-interest (ROI) analysis.
Secondary Endpoints: (1) Frequency and nature of adverse events; (2) For the PML cohort with longitudinal evaluation, changes in SUV over time.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 10 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Central Nervous System Uptake of Anti-CD8+ T Cell Minibodies in Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy: A Pilot Study |
| Actual Study Start Date : | October 19, 2023 |
| Estimated Primary Completion Date : | June 30, 2024 |
| Estimated Study Completion Date : | June 30, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Multiple Sclerosis
MS cohort- Three study visits. (1) Baseline; (2) Day 0: MRI brain/spinal cord (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka"PET/CT tracer"); (3) Day 1: PET/CT scan
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Drug: 89 Zr-Df-crefmirlimab
an 80 kDa minibody (Mb) with high affinity to CD8 glycoprotein (binding EC50 = 0.4 nM) that is conjugated with deferoxamine (Df) and radiolabeled with the positron emitting radionuclide, Zr-89 (T1/2 78.4 hours). |
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Experimental: Progressive Multifocal Leukoencephalopathy
PML cohort- Up to five study visits. (1) Baseline; (2) Day 0: MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer"); (3) Day 1: PET/CT scan; (4) Study visit 4 (optional; time-period between study visit 3 and 4 is variable): MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer") following clinical, radiological and/or laboratory-defined immune reconstitution (spontaneous or facilitated); (5) Study visit 5: PET/ CT scan
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Drug: 89 Zr-Df-crefmirlimab
an 80 kDa minibody (Mb) with high affinity to CD8 glycoprotein (binding EC50 = 0.4 nM) that is conjugated with deferoxamine (Df) and radiolabeled with the positron emitting radionuclide, Zr-89 (T1/2 78.4 hours). |
- Infiltration of CD8+ T cells in the CNS of adults with MS and PML via PET-CT scans using a minibody with high affinity for CD8+ T cells. [ Time Frame: Day 1 Study Visit ]To detect and localize infiltration of CD8+ T cells in the CNS of adults with MS and PML via PET-CT scans using a minibody with high affinity for CD8+ T cells.
- Safety of 89Zr-Dfcrefmirlimab in the participants with CNS disease. [ Time Frame: At each study visit ]To assess the safety of 89Zr-Dfcrefmirlimab in participants with CNS disease.
- For the PML cohort with longitudinal evaluation, effects of immune reconstitution, either spontaneous or facilitated, on 89Zr-Dfcrefmirlimab uptake. [ Time Frame: up to 6 months after first PET/CT scan ]Comparison of SUV before and after immune reconstitution, either spontaneous or facilitated (for participants with optional follow-up imaging).
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| Ages Eligible for Study: | 18 Years to 120 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
- INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
Multiple Sclerosis Inclusion Criteria
- Enrolled in the NINDS Natural History Study for MS (protocol 89-N-0045)
- Able to understand, and willing to sign, a written, informed consent document.
- Willing to comply with all study procedures and available for the duration of the study.
- Male or female, aged >=18.
- Diagnosis of MS according to the 2017 revision of the McDonald diagnostic criteria48 (in the presence or absence of a clinical relapse).
- For females of reproductive potential: agrees to use highly effective contraception for at least one month prior to screening and during study participation.
- Creatinine clearance >= 60 mL/min as estimated by the Cockcroft-Gault equation.
- Has aspartate transaminase (AST) or alanine transaminase (ALT) levels less than 1.5x ULN.
PML Inclusion Criteria
- Enrolled in the NINDS Natural History Study for PML (protocol 13-N-0017)
- Able to understand and willing to sign a written, informed consent document
- Willing to comply with all study procedures and available for the duration of the study.
- Male or female, aged >=18.
- Diagnosis of definite PML according to 2013 AAN Consensus Criteria49 or PML-IRIS based on clinical, radiological and laboratory evidence.
- For females of reproductive potential: agrees to use highly effective contraception for at least one month prior to screening and during study participation.
- Creatinine clearance >= 60 mL/min as estimated by the Cockcroft-Gault equation.
- Has aspartate transaminase (AST) or alanine transaminase (ALT) levels less than 1.5x ULN.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
- Pregnant or lactating.
- Contraindications for MRI gadolinium contrast administration or 3T MRI.
- History of, or current diagnosis with, concomitant medical or clinical conditions that would adversely affect participation in this study.
- Weighs > 350 lb (158 kg; weight limit for the scanner table) or is unable to fit within the MRI or PET imaging gantry.
- Severe claustrophobia unresponsive to oral anxiolytics.
- Has an alkaline phosphatase level greater than 2x ULN unless known to have non-liver related disorder, and AST and ALT remain stable.
- Has a total bilirubin >1.5X ULN, unless known to have elevated bilirubin due to nonliver related disorder or Gilbert s.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05849467
| Contact: Maria I Gaitan, M.D. | (301) 496-1801 | maria.gaitan@nih.gov | |
| Contact: Daniel S Reich, M.D. | (301) 496-1801 | reichds@ninds.nih.gov |
| United States, Maryland | |
| National Institutes of Health Clinical Center | Recruiting |
| Bethesda, Maryland, United States, 20892 | |
| Contact: NIH Clinical Center Office of Patient Recruitment (OPR) 800-411-1222 ext TTY dial 711 ccopr@nih.gov | |
| Principal Investigator: | Daniel S Reich, M.D. | National Institute of Neurological Disorders and Stroke (NINDS) |
| Responsible Party: | National Institute of Neurological Disorders and Stroke (NINDS) |
| ClinicalTrials.gov Identifier: | NCT05849467 |
| Other Study ID Numbers: |
10001519 001519-N |
| First Posted: | May 9, 2023 Key Record Dates |
| Last Update Posted: | April 5, 2024 |
| Last Verified: | March 25, 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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89 Zr-Df-crefmirlimab PET Imaging |
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Leukoencephalopathy, Progressive Multifocal Multiple Sclerosis Leukoencephalopathies Sclerosis Pathologic Processes Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases Brain Diseases |
Central Nervous System Diseases Encephalitis, Viral Central Nervous System Viral Diseases Central Nervous System Infections Infections Infectious Encephalitis Virus Diseases Polyomavirus Infections DNA Virus Infections Slow Virus Diseases Encephalitis Neuroinflammatory Diseases |