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Trial record 1 of 1 for:    2019-A01931-56
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The Energetic Origin of Neurodegeneration in MS (ENERGYSEP)

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ClinicalTrials.gov Identifier: NCT04532944
Recruitment Status : Not yet recruiting
First Posted : August 31, 2020
Last Update Posted : August 31, 2020
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

Brief Summary:

In multiple sclerosis (MS), the sequence of events leading to irreversible neuro-axonal degeneration, which is a major determinant of clinical disability, is poorly understood. Recently, the key role of neuronal energy dysfunction in driving axonal degeneration has been highlighted. In the neuronal injury pathway triggered by inflammation and myelin disruption, multiple adaptive changes force the neuron to a temporary condition of "virtual hypoxia", characterized by a mismatch between energy demand and supply. If this condition of energy dysregulation is not reversed within an appropriate time-window, neurons enter an irreversible axonal degeneration.

Two key questions on the relationship between early energy dysregulation and neurodegeneration remain unanswered:

i) whether brain energy dysfunction measured at a given time point can predict the subsequent occurrence of neurodegeneration; ii) to what extent and for how long neurons can bear this "virtual hypoxia" before undergoing structural damage.

Tracking the "energetic signature" of MS and defining its temporal distance from irreversible damage is essential for the development of neuroprotective therapies.The recent optimization of innovative magnetic resonance (MR)-based techniques such as sodium (23Na) MRI, phosphorus MR spectroscopy (31P-MRS), and diffusion-weighted 1H MRS (DW-MRS) has allowed the generation of promising in vivo data on cellular energy dysregulation in MS.

The main objective of this project is to explore whether MR-derived metrics of energy dysregulation predict MR-derived parameters of cortical neurodegeneration developing over 2 years, as reflected by cortical atrophy. To address this key question, the Investigators will use a combination of 23Na MRI, 31P MRS, and DW-MRS associated with advanced MRI sequences to explore energy dysregulation in the sensorimotor region, and measurements of cortical atrophy in the same area after 24 months in 40 patients with either relapsing-remitting or progressive MS and 15 age- and gender-matched healthy controls.

The Investigators will also test whether MR-derived metrics of energy dysregulation at study entry correlate, both cross-sectionally and longitudinally, with: i) global cortical atrophy; ii) functional cortical reorganization resulting from the condition of energy dysregulation, which precedes the occurrence of structural damage; iii) cortical demyelination and remyelination; iv) clinical, neuropsychological and biological measures.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Diagnostic Test: imaging of energy dysfunction Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 40 patients with MS and 15 healthy controls
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Exploring in Vivo the Energetic Origin of Neurodegeneration in Multiple Sclerosis: a Ultra-high Field Sodium Imaging, Phosphorus Spectroscopy and Diffusion-weighted Spectroscopy Study.
Estimated Study Start Date : September 15, 2020
Estimated Primary Completion Date : September 15, 2022
Estimated Study Completion Date : March 15, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
patients with MS
20 relapsing-remitting and 20 progressive MS patients
Diagnostic Test: imaging of energy dysfunction
7T sodium imaging, phosphorus spectroscopy and 3T diffusion-weighted spectroscopy

healthy controls
15 age- and sex-matched healthy controls
Diagnostic Test: imaging of energy dysfunction
7T sodium imaging, phosphorus spectroscopy and 3T diffusion-weighted spectroscopy




Primary Outcome Measures :
  1. Energy dysregulation in the whole brain with sodium imaging [ Time Frame: 0-12 months ]
    Evaluation of the levels of total, intracellular and extracellular sodium quantified through 23Na MRI in the whole brain.

  2. Energy dysregulation in the motor-sensory region (MSR) with phosphorus spectroscopy [ Time Frame: 0-12 months ]
    Evaluation of ATP and PCr concentrations measured through 31P MRS in a voxel centred on the left MSR

  3. Energy dysregulation in the motor-sensory region with diffusion-weighted spectroscopy [ Time Frame: 0-12 months ]
    Evaluation of the ADC of tCr (Cr + PCr) measured through DW-MRS in a voxel centred on the left MSR.

  4. Neurodegeneration in the MSR after 24 months [ Time Frame: 0-24 months ]

    Neurodegeneration after 24 months will be evaluated by the measurements of the following parameters:

    Evaluation of MSR cortical thickness after 24 months and relative change in MSR cortical thickness between study entry and 24 months measured with Freesurfer (https://surfer.nmr.mgh.harvard.edu).



Secondary Outcome Measures :
  1. Patient-specific profiles of energy dysregulation [ Time Frame: 0-12 months ]
    The difference of MRI-derived metrics of energy dysregulation between patients and controls at study entry will be evaluated with 23Na MRI in the whole brain, and with 23Na MRI, 31P MRS and DW-MRS in the MSR

  2. cortical demyelination and remyelination [ Time Frame: 0-12 months ]
    Cortical demyelination at study entry will be measured by cross-sectional cortical magnetisation transfer ratio (MTR), and cortical remyelination after 12 months will be evaluated by the measurement of cortical MTR change over 12 months

  3. neuro-axonal damage over time [ Time Frame: 0-12-24 months ]
    Early axonal damage will be quantified through the NODDI-derived metrics

  4. functional changes in brain connectivity [ Time Frame: 0-12-24 months ]
    Changes in brain connectivity at study entry and after 12 and 24 months will be measured by resting-state functional MRI

  5. serum markers of tissue damage [ Time Frame: 0-12-24 months ]
    Serum neurofilaments, measured at study entry and at 12 and 24 months, will be used as a biomarker of acute and chronic neuronal lesions

  6. physical and cognitive dysfunction [ Time Frame: 0-12-24 months ]
    Neurologic disability will be evaluated by EDSS

  7. physical and cognitive dysfunction [ Time Frame: 0-12-24 months ]
    Neurologic disability will be evaluated by MFIS

  8. physical and cognitive dysfunction [ Time Frame: 0-12-24 months ]
    Neurologic disability will be evaluated by BICAMS



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria for MS:

  1. RR-MS patients with a disease duration of less than 10 years:

    • 18-55 years
    • clinically defined RR-MS according to the 2017 revised McDonald's criteria (MS diagnostic criteria 2017)
    • disease duration <10 years
    • ability to understand the research objectives and the procedure details, and to sign the informed consent
    • affiliation with the French National Health Insurance, Universal Medical Coverage (CMU) or any equivalent
  2. Patients with progressive MS (primary or secondary) of less than 10 years:

    • 18-55 years
    • clinically defined progressive MS according to the 2017 revised McDonald's criteria
    • disease duration <10 years from the beginning of the progressive phase
    • ability to understand the research objectives and the procedure details, and to sign the informed consent
    • affiliation with the French National Health Insurance, Universal Medical Coverage (CMU) or any equivalent

Inclusion Criteria for healthy controls:

  • 18-55 years (matched with patients)
  • no known general pathologies
  • ability to understand the research objectives and the procedure details, and to sign the informed consent
  • affiliation with the French National Health Insurance, Universal Medical Coverage (CMU) or any equivalent

Exclusion Criteria for MS:

  • Pregnant or breastfeeding women
  • Last infusion of cyclophosphamide, mitoxantrone or methylprednisolone realized less than 1 month before inclusion
  • last clinical relapse less than one month before inclusion
  • severe cardiac, pulmonary, hepatic, hematologic renal, gastrointestinal disease, or cancer
  • contraindications to MRI: claustrophobia, pace-maker implant, any surgical ferromagnetic clips, ocular implants, any intraocular or intracranial metallic fragments, any metallic objects able to concentrate the radiofrequency field, cochlear implants, cardiac or brain stimulators, any tattoos or permanent makeup on the face, renal failure (exclusion criterion for gadolinium injection) patients not willing to be informed of any possible cerebral malformations incidentally discovered at the MRI exam
  • severe renal failure (clearance of creatinine < 30ml/min)
  • history of allergic reactions to gadolinium salts
  • any other chronic neurological disorders associated
  • persons deprived of liberty by law or by administrative decision
  • Persons under legal protection

Exclusion Criteria for healthy controls:

  • Pregnant or breastfeeding women
  • severe cardiac, pulmonary, hepatic, hematologic renal, gastrointestinal disease, or cancer
  • contraindications to MRI : claustrophobia, pace-maker implant, any surgical magnetic clips, ocular implants, any intraocular or intracranial metallic fragments, any metallic objects able to concentrate the radiofrequency field, cochlear implants, cardiac or brain stimulators, any tattoos or permanent makeup on the face
  • person not willing to be informed of any possible cerebral malformations incidentally discovered at the MRI exam
  • associated chronic neurological disorders
  • persons deprived of liberty by law or by administrative decision
  • Persons under legal protection
  Study Documents (Full-Text)

Documents provided by Institut National de la Santé Et de la Recherche Médicale, France:
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Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT04532944    
Other Study ID Numbers: C19-20
2019-A01931-56 ( Registry Identifier: ID RCB )
First Posted: August 31, 2020    Key Record Dates
Last Update Posted: August 31, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
energy dysfunction
neurodegeneration
7 T MRI
sodium imaging
phosphorus spectroscopy
diffusion-weighted spectroscopy
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Nerve Degeneration
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases