Study Results
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Basic Information
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RECRUITING
25 participants
OBSERVATIONAL
2024-06-19
2027-06-30
Brief Summary
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* How does abnormal neural inflammation compare to cellular and molecular inflammation in MS?
* Once treated, why does abnormal inflammation persist?
Detailed Description
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Current MS disease modifying therapies (DMT) focus on reducing the inflammatory or auto-immune component of the disease. Highly effective DMTs are incredibly effective at reducing this inflammation such that new lesions and clinical relapses are increasingly rare. However, despite these advances, most patients will experience clinical worsening independent of relapse activity. This eventually manifests as progressive MS and stubbornly resists therapy. One hypothesized driver of this clinical progression is smoldering inflammation. Smoldering inflammation is defined as ongoing inflammation sufficient to cause accumulating tissue injury but insufficient to cause clinical relapse. The nature of this smoldering inflammation is poorly understood. Emerging imaging biomarkers have identified smoldering inflammation, but those markers are not well-linked to cellular mechanisms. A key innovation of this approach is that, by comparing pre- vs. post-treatment single-cell RNA sequencing data, the researchers will identify cell populations that are most sensitive and resistant to treatment and relate these findings to imaging changes. Identifying components of persistent inflammation may identify future treatment targets.
25 adult patients with relapsing remitting multiple sclerosis will be enrolled in this study. Patients will be recruited from the John L. Trotter MS Center at Washington University in St. Louis. Participants will be referred to the study by their treating neurologist.
\[11C\]-CS1P1 and \[11C\]-DPA-713 are the investigational radiotracers used in this study. Participation in this study consists of several visits. Visits include 1) (pre-)screening and clinical, 2) baseline lumbar puncture, 3) baseline \[11C\]-DPA-713 PET/CT, 4) baseline \[11C\]-CS1P1 PET/CT, 5) baseline \[18F\]-FDG PET/MRI, 6) follow-up lumbar puncture, 7) follow-up \[11C\]-DPA-713 PET/CT, 8) follow-up \[11C\]-CS1P1 PET/CT, and 9) follow-up \[18F\]-FDG PET/MRI. Baseline and follow-up visits of the same type (e.g., steps 3 and 7) are identical with baseline occurring at enrollment and follow-up occurring at least nine months but no more than 12 months after DMT initiation. Screening session must precede the clinical sessions. At each the baseline and follow-up time point, the lumbar puncture and each imaging session may occur in any order. At baseline and follow up, all sessions will take place within approximately 1 month. Multiple sessions can occur on the same day. Consecutive imaging sessions will be separated by 6 half-lives of the initially injected radiotracer.
This pilot study will link the molecular specificity and high spatial resolution of combined positron emission tomography and magnetic resonance imaging with the molecular explanatory power of single-cell RNA sequencing to investigate the effects of B cell depletion, or other similarly efficacious treatments, on smoldering inflammation and characterize the nature of persistent inflammation which contributes to disability in patients with MS. A key innovation of this approach is that, by comparing pre- vs. post-treatment single-cell RNA sequencing data, researchers will identify cell populations that are most sensitive and resistant to treatment and relate these findings to imaging changes. Identifying components of persistent inflammation may identify future treatment targets.
Conditions
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Keywords
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Study Design
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COHORT
OTHER
Study Groups
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Participants
Adults with MS taking part in this study.
Radiotracer [11C]-CS1P1
Radiotracer used in PET/CT scans of the head and neck Dose range: 12-17 mCi
Radiotracer [11C]-DPA-713
Radiotracer used in PET/CT scans of the head and neck Dose range:15-20 mCi
anti-CD20 MS treatment
MS treatment taken indepenently after initial testing
Radiotracer [12F]-FDG
used in PET/CT scans of the head and neck Dose: 5-7 mCi
Interventions
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Radiotracer [11C]-CS1P1
Radiotracer used in PET/CT scans of the head and neck Dose range: 12-17 mCi
Radiotracer [11C]-DPA-713
Radiotracer used in PET/CT scans of the head and neck Dose range:15-20 mCi
anti-CD20 MS treatment
MS treatment taken indepenently after initial testing
Radiotracer [12F]-FDG
used in PET/CT scans of the head and neck Dose: 5-7 mCi
Eligibility Criteria
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Inclusion Criteria
* Age ≥ 18 years
* Capable of providing written informed consent for volunteering to undergo research procedures
* Diagnosis of MS as established by the referring physician and confirmed by the Sponsor-Investigator. Only patients with active disease, defined as at least 1 enhancing lesion present in the preceding 6 months, will be enrolled
* Treatment naïve except for relapse-related treatments such as corticosteroids or plasmapheresis,
* Planned initiation, at the discretion of the referring physician, of a high efficacy DMT. High efficacy DMT will be defined to include ocrelizumab, natalizumab, or any MS treatment in the opinion of the Sponsor-Investigator to have similar efficacy as the named treatments
* Clinical labs, including at least a CBC and BMP, without significant abnormality as determined by the Sponsor-Investigator or designee, within the 3 months prior to enrollment
Exclusion Criteria
* Hypersensitivity to \[11C\]-CS1P1, \[11C\]-DPA-713, \[18F\]-FDG, or any of their excipients
* Contraindications to PET, CT or MRI (e.g. certain incompatible electronic medical devices, inability to lie still for extended periods) that make it potentially unsafe for the individual to participate
* eGFR less than 60 (for gadolinium)
* Severe claustrophobia
* Women who are currently pregnant or breast-feeding
* Currently undergoing radiation therapy
* Insulin dependent diabetes
* Contraindication to lumbar puncture (LP), including use of antiplatelet therapy (other than aspirin 81mg), therapeutic anticoagulation, or space occupying intracranial mass. History of a coagulopathy is also exclusionary
* Any condition that, in the opinion of the Sponsor-Investigator or designee could increase risk to the participant, limit the participant's ability to tolerate the research procedures or interfere with collection of the data (e.g., renal or liver failure, advanced cancer)
* Current or recent (within 12 months prior to screening) participation in research studies involving radioactive agents such that the total research-related radiation dose to the participant in any given year would exceed 5 rem
18 Years
ALL
No
Sponsors
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Washington University School of Medicine
OTHER
Responsible Party
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Matthew Brier
Assistant Professor of Neurology Adult, Neuroimmunology
Locations
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Barnes Jewish Center for Clinical Imaging Research
St Louis, Missouri, United States
Countries
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Central Contacts
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Facility Contacts
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Matthew R Brier, MD, PhD
Role: primary
Nicole E Shelley, MA
Role: backup
References
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Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21.
Maggi P, Sati P, Nair G, Cortese ICM, Jacobson S, Smith BR, Nath A, Ohayon J, van Pesch V, Perrotta G, Pot C, Theaudin M, Martinelli V, Scotti R, Wu T, Du Pasquier R, Calabresi PA, Filippi M, Reich DS, Absinta M. Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study. Ann Neurol. 2020 Nov;88(5):1034-1042. doi: 10.1002/ana.25877. Epub 2020 Sep 9.
Endres CJ, Pomper MG, James M, Uzuner O, Hammoud DA, Watkins CC, Reynolds A, Hilton J, Dannals RF, Kassiou M. Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans. J Nucl Med. 2009 Aug;50(8):1276-82. doi: 10.2967/jnumed.109.062265. Epub 2009 Jul 17.
Brier MR, Hamdi M, Rajamanikam J, Zhao H, Mansor S, Jones LA, Rahmani F, Jindal S, Koudelis D, Perlmutter JS, Wong DF, Nickels M, Ippolito JE, Gropler RJ, Schindler TH, Laforest R, Tu Z, Benzinger TLS. Phase 1 Evaluation of 11C-CS1P1 to Assess Safety and Dosimetry in Human Participants. J Nucl Med. 2022 Nov;63(11):1775-1782. doi: 10.2967/jnumed.121.263189. Epub 2022 Mar 24.
Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012 Nov 5;8(11):647-56. doi: 10.1038/nrneurol.2012.168. Epub 2012 Sep 25.
Hemond CC, Baek J, Ionete C, Reich DS. Paramagnetic rim lesions are associated with pathogenic CSF profiles and worse clinical status in multiple sclerosis: A retrospective cross-sectional study. Mult Scler. 2022 Nov;28(13):2046-2056. doi: 10.1177/13524585221102921. Epub 2022 Jun 24.
Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015 Feb;14(2):183-93. doi: 10.1016/S1474-4422(14)70256-X.
Other Identifiers
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202403168
Identifier Type: -
Identifier Source: org_study_id