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Remyelination in Multiple Sclerosis: a PET-MR Longitudinal Study Investigating Individual Profiles of Myelin Repair and the Contribution of Neuroinflammation (SMARTinMS)

Primary Purpose

Multiple Sclerosis, Inflammatory Disease

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
PET-MRI with [18F]-Florbetaben and PET-MRI with [18F]-DPA-714
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Multiple Sclerosis focused on measuring Multiple sclerosis, Remyelination, Combination of magnetic resonance imaging (MRI) and positron emission tomography (PET)

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

RRMS patients:

  1. Age between 18 and 55 years old
  2. RRMS according to the 2017 Mc Donald criteria
  3. Less than 5 years of disease duration
  4. At least 9 supra-tentorial white matter lesions on T2/FLAIR MRI
  5. Last treatment with methylprednisolone should have been performed at least 1 month before PET examinations
  6. Interferon-beta, glatiramere acetate and oral first line therapy will such as dimethylfumarate or teriflunomide will be admitted
  7. Affiliation to a social security scheme or beneficiary of such a scheme (Except "Aide Médicale d'Etat")

Progressive MS patients:

  1. Age between 18 and 55 years old
  2. Progressive MS (primary or secondary progressive MS) according to the 2017 Mc Donald criteria
  3. Less than 10 years of disease duration in the progressive phase
  4. At least 9 supra-tentorial white matter lesions on T2/FLAIR MRI
  5. Interferon-beta, glatiramere acetate and oral first line therapy will such as dimethylfumarate or teriflunomide will be admitted
  6. Affiliation to a social security scheme or beneficiary of such a scheme (except "Aide Médicale d'Etat")

Healthy volunteers:

  1. Age between 18 and 55 years old
  2. Without any evolutive pathology
  3. Able to understand the study objectives and procedures
  4. Affiliation to a social security scheme or beneficiary of such a scheme (except "Aide Médicale d'Etat")

Exclusion Criteria:

For all participants:

  1. Any reasons, which does not allow to perform MRI, including claustrophobia, the implant of a pace maker or the presence of an intra-ocular foreign body (a contra-indication questionnaire will be filled in beforehand)
  2. PET for clinical research already done within the last 12 months
  3. Low Affinity Binding profile (TSPO polymorphism analyzed at screening visit)
  4. Pregnancy, breast-feeding, lack of efficient contraception
  5. Current symptoms of severe or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary or cardiac disease, or any other chronic neurological diseases
  6. Unwillingness to be informed in case of abnormal MRI (with a significant medical anomaly)
  7. Know hypersensitivity to Myelin PET : [18F]-Florbetaben
  8. Patient under legal protection

Additional exclusion criteria for patients:

  1. Treatment with cyclophosphamide, mitoxantrone, fingolimod, cladribine, alemtuzumab, anti CD20 antibodies or natalizumab will not be admitted. These treatments may be administered after the Baseline visit.
  2. Known allergy to gadoteric acid
  3. Allergies (seafood, pollinosis, urticarial) having required a medical intervention
  4. Severe renal insufficiency (creatinine clearance < 60mL/min).

Sites / Locations

  • CIC Neurosciences - Hôpital Pitié SalpêtrièreRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

PET-MRI with [18F]-Florbetaben and PET-MRI with [18F]-DPA-714

Arm Description

PET-MRI with [18F]-Florbetaben and PET-MRI with [18F]-DPA-714

Outcomes

Primary Outcome Measures

Proportion of lesional demyelinated voxels at baseline that are classified as remyelinating at month 6 of multiple sclerosis patients during the relapsing and the progressive phases of the disease
the percentage of lesional voxels classified as demyelinated on baseline [18F]-Florbetaben PET, that subsequently become normally myelinated on the [18F]-Florbetaben PET performed at 6 months, which attest remyelination

Secondary Outcome Measures

the percentage of voxels classified as significantly activated compared to control white matter, and the number/proportion of MS lesions classified as activated based on [18F]-DPA-714 PET
To define the individual inflammatory profiles from [18F]-DPA-714 PET (regional individual maps of [18F]-DPA-714 binding) of MS patients during the relapsing and the progressive phases of the disease
Proportion of each lymphocyte cluster identified from the single cell sequencing of T lymphocytes over the total T lymphocyte population for each patient
Remyelination level in rodents demyelinated by lysolecithin and grafted with single patient's lymphocytes quantified at week 3 post-graft
Proportion of lesions that persist as chronic active at month 3 post graft over the total number of lesions induced in the rodent demyelinating models by grafting patients' lymphocytes

Full Information

First Posted
October 15, 2021
Last Updated
September 11, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT05147532
Brief Title
Remyelination in Multiple Sclerosis: a PET-MR Longitudinal Study Investigating Individual Profiles of Myelin Repair and the Contribution of Neuroinflammation
Acronym
SMARTinMS
Official Title
Remyelination in Multiple Sclerosis: a PET-MR Longitudinal Study Investigating Individual Profiles of Myelin Repair and the Contribution of Neuroinflammation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 24, 2022 (Actual)
Primary Completion Date
October 2023 (Anticipated)
Study Completion Date
May 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Multiple Sclerosis (MS) is an inflammatory disease where the immune cells invade the central nervous system and destroy an essential element of nerve conduction: the myelin. An interesting feature observed in some patients is a regenerative process, called remyelination, which leads to the production of new myelin. However, the extent of remyelination is very heterogeneous among patients, only a minority of patients show a really efficient repair process along the disease course. In this project, our aim is to explore in vivo the biological mechanisms leading to a successful remyelination in some patients and to a failure in remyelination in others. With this purpose in mind we propose to develop a translational research platform where patients with multiple sclerosis will be investigated in vivo for their potential of remyelination through a follow-up with recently developed imaging technologies using a synergistic combination of magnetic resonance imaging (MRI) and positron emission tomography (PET) to visualize and quantify myelin and neuroinflammation. In parallel blood immune cells from patients will be sampled and profiled to investigate how they could influence remyelination. This part will consist in i) grafting patients' lymphocytes in experimental rodent models of demyelination to characterize how they could promote or inhibit remyelination; ii) performing a functional and multi-omics analysis of peripheral macrophages and analyse relationships with remyelination profiles; iii) profiling T lymphocytes at the single cell level to associate specific subpopulation of the T cells with the remyelination potential assessed in patients with MRI/PET images and in grafted animals.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis, Inflammatory Disease
Keywords
Multiple sclerosis, Remyelination, Combination of magnetic resonance imaging (MRI) and positron emission tomography (PET)

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PET-MRI with [18F]-Florbetaben and PET-MRI with [18F]-DPA-714
Arm Type
Other
Arm Description
PET-MRI with [18F]-Florbetaben and PET-MRI with [18F]-DPA-714
Intervention Type
Procedure
Intervention Name(s)
PET-MRI with [18F]-Florbetaben and PET-MRI with [18F]-DPA-714
Intervention Description
PET-MRI: 2 at baseline visits (V0 and V1) and 1 at M6
Primary Outcome Measure Information:
Title
Proportion of lesional demyelinated voxels at baseline that are classified as remyelinating at month 6 of multiple sclerosis patients during the relapsing and the progressive phases of the disease
Description
the percentage of lesional voxels classified as demyelinated on baseline [18F]-Florbetaben PET, that subsequently become normally myelinated on the [18F]-Florbetaben PET performed at 6 months, which attest remyelination
Time Frame
Month 6
Secondary Outcome Measure Information:
Title
the percentage of voxels classified as significantly activated compared to control white matter, and the number/proportion of MS lesions classified as activated based on [18F]-DPA-714 PET
Description
To define the individual inflammatory profiles from [18F]-DPA-714 PET (regional individual maps of [18F]-DPA-714 binding) of MS patients during the relapsing and the progressive phases of the disease
Time Frame
At baseline
Title
Proportion of each lymphocyte cluster identified from the single cell sequencing of T lymphocytes over the total T lymphocyte population for each patient
Time Frame
Baseline
Title
Remyelination level in rodents demyelinated by lysolecithin and grafted with single patient's lymphocytes quantified at week 3 post-graft
Time Frame
Baseline
Title
Proportion of lesions that persist as chronic active at month 3 post graft over the total number of lesions induced in the rodent demyelinating models by grafting patients' lymphocytes
Time Frame
Baseline, at 3 Months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: RRMS patients: Age between 18 and 55 years old RRMS according to the 2017 Mc Donald criteria Less than 5 years of disease duration At least 9 supra-tentorial white matter lesions on T2/FLAIR MRI Last treatment with methylprednisolone should have been performed at least 1 month before PET examinations Interferon-beta, glatiramere acetate and oral first line therapy will such as dimethylfumarate or teriflunomide will be admitted Affiliation to a social security scheme or beneficiary of such a scheme (Except "Aide Médicale d'Etat") Progressive MS patients: Age between 18 and 55 years old Progressive MS (primary or secondary progressive MS) according to the 2017 Mc Donald criteria Less than 10 years of disease duration in the progressive phase At least 9 supra-tentorial white matter lesions on T2/FLAIR MRI Interferon-beta, glatiramere acetate and oral first line therapy will such as dimethylfumarate or teriflunomide will be admitted Affiliation to a social security scheme or beneficiary of such a scheme (except "Aide Médicale d'Etat") Healthy volunteers: Age between 18 and 55 years old Without any evolutive pathology Able to understand the study objectives and procedures Affiliation to a social security scheme or beneficiary of such a scheme (except "Aide Médicale d'Etat") Exclusion Criteria: For all participants: Any reasons, which does not allow to perform MRI, including claustrophobia, the implant of a pace maker or the presence of an intra-ocular foreign body (a contra-indication questionnaire will be filled in beforehand) PET for clinical research already done within the last 12 months Low Affinity Binding profile (TSPO polymorphism analyzed at screening visit) Pregnancy, breast-feeding, lack of efficient contraception Current symptoms of severe or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary or cardiac disease, or any other chronic neurological diseases Unwillingness to be informed in case of abnormal MRI (with a significant medical anomaly) Know hypersensitivity to Myelin PET : [18F]-Florbetaben Patient under legal protection Additional exclusion criteria for patients: Treatment with cyclophosphamide, mitoxantrone, fingolimod, cladribine, alemtuzumab, anti CD20 antibodies or natalizumab will not be admitted. These treatments may be administered after the Baseline visit. Known allergy to gadoteric acid Allergies (seafood, pollinosis, urticarial) having required a medical intervention Severe renal insufficiency (creatinine clearance < 60mL/min).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bruno STANKOFF, MD
Phone
0171970659
Email
bruno.stankoff@aphp.fr
Facility Information:
Facility Name
CIC Neurosciences - Hôpital Pitié Salpêtrière
City
Paris
ZIP/Postal Code
75013
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Céline LOUAPRE, MD
Email
celine.louapre@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34545219
Citation
Bodini B, Tonietto M, Airas L, Stankoff B. Positron emission tomography in multiple sclerosis - straight to the target. Nat Rev Neurol. 2021 Nov;17(11):663-675. doi: 10.1038/s41582-021-00537-1. Epub 2021 Sep 20.
Results Reference
background
PubMed Identifier
33737372
Citation
Poirion E, Tonietto M, Lejeune FX, Ricigliano VAG, Boudot de la Motte M, Benoit C, Bera G, Kuhnast B, Bottlaender M, Bodini B, Stankoff B. Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis. Neurology. 2021 Apr 6;96(14):e1865-e1875. doi: 10.1212/WNL.0000000000011700. Epub 2021 Mar 18.
Results Reference
background
PubMed Identifier
31686177
Citation
Auvity S, Tonietto M, Caille F, Bodini B, Bottlaender M, Tournier N, Kuhnast B, Stankoff B. Repurposing radiotracers for myelin imaging: a study comparing 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol,11C-MeDAS, and 11C-PiB. Eur J Nucl Med Mol Imaging. 2020 Feb;47(2):490-501. doi: 10.1007/s00259-019-04516-z. Epub 2019 Nov 4.
Results Reference
background
PubMed Identifier
30020560
Citation
Stankoff B, Poirion E, Tonietto M, Bodini B. Exploring the heterogeneity of MS lesions using positron emission tomography: a reappraisal of their contribution to disability. Brain Pathol. 2018 Sep;28(5):723-734. doi: 10.1111/bpa.12641.
Results Reference
background
PubMed Identifier
26891452
Citation
Bodini B, Veronese M, Garcia-Lorenzo D, Battaglini M, Poirion E, Chardain A, Freeman L, Louapre C, Tchikviladze M, Papeix C, Dolle F, Zalc B, Lubetzki C, Bottlaender M, Turkheimer F, Stankoff B. Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis. Ann Neurol. 2016 May;79(5):726-738. doi: 10.1002/ana.24620.
Results Reference
background
PubMed Identifier
21337603
Citation
Stankoff B, Freeman L, Aigrot MS, Chardain A, Dolle F, Williams A, Galanaud D, Armand L, Lehericy S, Lubetzki C, Zalc B, Bottlaender M. Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-(1)(1)C]-2-(4'-methylaminophenyl)- 6-hydroxybenzothiazole. Ann Neurol. 2011 Apr;69(4):673-80. doi: 10.1002/ana.22320. Epub 2011 Feb 18.
Results Reference
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Remyelination in Multiple Sclerosis: a PET-MR Longitudinal Study Investigating Individual Profiles of Myelin Repair and the Contribution of Neuroinflammation

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