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PET With [18F]Flumazenil as an Index of Neurodegeneration in MS (FLUMA-SEP-T)

Primary Purpose

Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis

Status
Unknown status
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
PET with [11C]Flumazenil
Sponsored by
Institut National de la Santé Et de la Recherche Médicale, France
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Multiple Sclerosis focused on measuring Patients,, Multiple Sclerosis,, Relapsing-Remitting

Eligibility Criteria

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

Inclusion Criteria:

  • Patient group:

    • Aged 18-55 years old
    • Diagnosis of RRMS or PPMS according to the 2010 Mc Donald criteria
    • Disease duration < 10 years
    • Able to understand the study objective and procedure
    • Efficient contraception for women of potential child-bearing
    • Inscription to the national health care system
    • Having signed the written consent form
    • No current benzodiazepine or other GABAA-interacting drug (that have to be stopped 15 days before inclusion)
    • Accept to be informed of any incidental finding on imaging acquisitions

  • Healthy subjects

    • Aged 18-55 years old
    • No evolutive pathology
    • Able to understand the study objective and procedure
    • Efficient contraception for women of potential child-bearing
    • Inscription to the national health care system
    • Having signed the written consent form
    • No concurrent benzodiazepine or other GABAA-interacting drug treatment (that have to be stopped 15 days before inclusion)
    • Accept to be informed of any incidental finding on imaging acquisitions

Exclusion Criteria:

  • Any reason, which does not allow to perform MRI, including claustrophobia, the implant of a pace-maker or the presence of an intra-ocular foreign body.
  • For women: pregnancy, lactation, lack of efficient contraception. A positive pregnancy test conducted at visit 2 will lead to the immediate exclusion of the subject.
  • Current symptoms of severe or uncontrolled renal, hepatic, hematological, gastrointestinal pulmonary or cardiac disease.
  • Radiation exposure during the last year before inclusion due to prior participations to other research protocols
  • Other chronic neurological diseases.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Other

    Other

    Arm Label

    Patients with multiple sclerosis

    healthy subjects

    Arm Description

    The multiple sclerosis group (n=30) will be subdivided in two subgroups: 15 patients with a relapsing remmitting MS (RRMS), and 15 patients with a primary progressive MS (PPMS).

    15 healthy subjects will be included. Among them 7 to 8 subjects will be matched for age and gender with the RRMS subgroup, and 7 to 8 will be matched for age and gender with the PPMS subgroup.

    Outcomes

    Primary Outcome Measures

    Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding in different groups
    11C -Flumazenil binding in the grey matter : Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding kinetic analysis, and expressed as a Bmax estimation, in the cortex and deep grey matter of subjects.

    Secondary Outcome Measures

    individual maps of neurodegeneration: changes in individual mapping of Flumazenil binding in different groups
    Individual mapping of Flumazenil binding changes in the grey matter of patients with MS compared to healthy controls at the voxel level
    volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume
    volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume
    volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load
    volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load
    Volume of gadolinium-enhanced white matter lesions on T1 sequence
    Volume of gadolinium-enhanced white matter lesions assessed on T1 sequence
    Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups
    Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups
    functional connectivity changes in patients
    functional connectivity assessed on resting state fMRI

    Full Information

    First Posted
    January 21, 2019
    Last Updated
    January 30, 2019
    Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03825601
    Brief Title
    PET With [18F]Flumazenil as an Index of Neurodegeneration in MS
    Acronym
    FLUMA-SEP-T
    Official Title
    PET With [18F]Flumazenil as an Index of Neurodegeneration in MS: Sensitivity at an Early Disease Stage and Pathophysiological Meaning
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    January 2019
    Overall Recruitment Status
    Unknown status
    Study Start Date
    February 1, 2019 (Anticipated)
    Primary Completion Date
    April 1, 2021 (Anticipated)
    Study Completion Date
    April 1, 2021 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France

    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
    Beyond white matter pathology, grey matter damage is considered as a key player in disability onset and progression in Multiple Sclerosis (MS). The underlying substratum of grey matter damage is complex and pluriform, ranging from cortical demyelinating lesions, synapse and dendrite disappearance to neuronal cell death. Current Magnetic Resonance Imaging MRI techniques fail to fully assess and quantify grey matter pathology in this disease. The development of a quantitative marker of neurodegeneration for MS patients would allow: (i) to better understand the pathophysiological mechanisms underlying the distinct forms of MS; (ii) to stratify patients according to their prognosis; and (iii) to evaluate new therapies aimed at promoting neuroprotection. would allow to better understand the mechanisms underlying the distinct forms of MS, to stratify patients according to their prognosis, and to evaluate new therapies aimed at promoting neuroprotection.
    Detailed Description
    The investigators have recently shown that PET (Tomographie par Émission de Positrons) with [11C]Flumazenil ([11C]FMZ), that binds to the benzodiazepine site of GABA-A receptors, allowed to quantify and map neuronal damage in MS patients. In the present project, the investigators will assess neuronal damage in MS using PET with [18F]Flumazenil ([18F]FMZ), at the early phase of either relapsing or primary progressive MS, and investigate the pathophysiological meaning of this neuronal damage by combining PET with Flumazenil with MRI at 7T and 3T. The main objective will be to quantify and map [18F]FMZ binding changes in the grey matter of MS patients compared to controls, both at the group and the individual level. Secondary and exploratory objectives will be to investigate the relationship between Flumazenil binding changes and: i) cortical demyelinating lesions identified by several 7T MRI sequences ; ii) dendritic arborisation assessed by 3T DWI; ii) available MRI metrics obtained on a clinical 3T scan (grey matter atrophy MTR modifications, resting state connectivity); iv) clinical metrics. This study will develop and assess a new imaging biomarker that has the potential to be used as an index of neurodegeneration in MS.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis
    Keywords
    Patients,, Multiple Sclerosis,, Relapsing-Remitting

    7. Study Design

    Primary Purpose
    Diagnostic
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    45 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Patients with multiple sclerosis
    Arm Type
    Other
    Arm Description
    The multiple sclerosis group (n=30) will be subdivided in two subgroups: 15 patients with a relapsing remmitting MS (RRMS), and 15 patients with a primary progressive MS (PPMS).
    Arm Title
    healthy subjects
    Arm Type
    Other
    Arm Description
    15 healthy subjects will be included. Among them 7 to 8 subjects will be matched for age and gender with the RRMS subgroup, and 7 to 8 will be matched for age and gender with the PPMS subgroup.
    Intervention Type
    Diagnostic Test
    Intervention Name(s)
    PET with [11C]Flumazenil
    Other Intervention Name(s)
    7T and 3T MRI
    Intervention Description
    7T MRI sequences : TSE, T2w FLAIR GRE-T2* and DIR 3T MRI sequences: T1, T2, T1 with gadolinium, magnetization transfer, diffusion weighted, resting state fMRI.
    Primary Outcome Measure Information:
    Title
    Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding in different groups
    Description
    11C -Flumazenil binding in the grey matter : Concentration of benzodiazepine receptors (BZR) measured from 11C -Flumazenil binding kinetic analysis, and expressed as a Bmax estimation, in the cortex and deep grey matter of subjects.
    Time Frame
    [0-2] MONTHS
    Secondary Outcome Measure Information:
    Title
    individual maps of neurodegeneration: changes in individual mapping of Flumazenil binding in different groups
    Description
    Individual mapping of Flumazenil binding changes in the grey matter of patients with MS compared to healthy controls at the voxel level
    Time Frame
    [0-2] MONTHS
    Title
    volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume
    Description
    volume of cortical lesions assessed on 7T MRI in different groups assessed in Cortical lesion volume
    Time Frame
    [0-2] MONTHS
    Title
    volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load
    Description
    volume of white matter lesions segmented on 3T T2 sequences: white matter lesion load
    Time Frame
    [0-2] MONTHS
    Title
    Volume of gadolinium-enhanced white matter lesions on T1 sequence
    Description
    Volume of gadolinium-enhanced white matter lesions assessed on T1 sequence
    Time Frame
    [0-2] MONTHS
    Title
    Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups
    Description
    Voxel wise assessment of Magnetization transfer ratio (MTR) to assess changes in the grey and in the white matter in different groups
    Time Frame
    [0-2] MONTHS
    Title
    functional connectivity changes in patients
    Description
    functional connectivity assessed on resting state fMRI
    Time Frame
    [0-2] 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: Patient group: Aged 18-55 years old Diagnosis of RRMS or PPMS according to the 2010 Mc Donald criteria Disease duration < 10 years Able to understand the study objective and procedure Efficient contraception for women of potential child-bearing Inscription to the national health care system Having signed the written consent form No current benzodiazepine or other GABAA-interacting drug (that have to be stopped 15 days before inclusion) Accept to be informed of any incidental finding on imaging acquisitions Healthy subjects Aged 18-55 years old No evolutive pathology Able to understand the study objective and procedure Efficient contraception for women of potential child-bearing Inscription to the national health care system Having signed the written consent form No concurrent benzodiazepine or other GABAA-interacting drug treatment (that have to be stopped 15 days before inclusion) Accept to be informed of any incidental finding on imaging acquisitions Exclusion Criteria: Any reason, which does not allow to perform MRI, including claustrophobia, the implant of a pace-maker or the presence of an intra-ocular foreign body. For women: pregnancy, lactation, lack of efficient contraception. A positive pregnancy test conducted at visit 2 will lead to the immediate exclusion of the subject. Current symptoms of severe or uncontrolled renal, hepatic, hematological, gastrointestinal pulmonary or cardiac disease. Radiation exposure during the last year before inclusion due to prior participations to other research protocols Other chronic neurological diseases.

    12. IPD Sharing Statement

    Learn more about this trial

    PET With [18F]Flumazenil as an Index of Neurodegeneration in MS

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