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Insulin Resistance in Multiple System Atrophy (IRAMS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04250493
Recruitment Status : Not yet recruiting
First Posted : January 31, 2020
Last Update Posted : March 31, 2020
Sponsor:
Collaborators:
Université de Bordeaux
Labex Brain
Centre National de la Recherche Scientifique, France
Information provided by (Responsible Party):
University Hospital, Bordeaux

Brief Summary:
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder. The pathologic hallmark is the accumulation of aggregated alpha-synuclein in oligodendrocytes forming glial cytoplasmic inclusions. Some symptomatic treatments are available while disease-modification remains an unmet treatment need. Post-mortem findings suggest insulin resistance, i.e. reduced insulin signaling, in the brains of MSA patients. The aim of this study is to complete the target validation of insulin resistance for future treatment trials.

Condition or disease Intervention/treatment Phase
Multiple System Atrophy Biological: Homeostasis Model Assessment of insulin resistance (HOMA) Behavioral: MOntreal Cognitive Assessment (MoCA) Behavioral: Clinical characteristics of AMS patients Procedure: Brain Magnetic Resonance Imaging (MRI) Biological: Blood sampling Not Applicable

Detailed Description:

Multiple system atrophy (MSA) patients have a poor prognosis with a median survival ranging between 6 and 10 years. MSA belongs to the synucleinopathies, which are characterized by the abnormal accumulation of alpha-synuclein. We have recently shown brain insulin resistance (i.e. reduced insulin signaling) in post-mortem brain tissue of MSA patients and transgenic MSA mice, as illustrated by increased protein levels of insulin receptor substrate-1 phosphorylated at serine 312 (IRS-1pS312). Additionally, exendin-4, an approved anti-diabetic drug targeting glucagon-like peptide-1 (GLP-1) receptors, was capable of decreasing brain levels of IRS-1pS312 and preserving dopamine neurons in transgenic MSA mice. We further observed an inverse correlation between plasma neural-derived exosomal IRS-1pS312 levels and survival of dopamine neurons in transgenic MSA mice.

The aim of this study is to further characterize peripheral and central insulin resistance in MSA patients, thereby validating this target for future treatment trials. For this purpose, fasting blood glucose and insulin levels will be determined in samples of MSA patients and healthy controls for a homeostatic model assessment of insulin resistance (HOMA). Additionally, IRS-1pS312 will be measured in neural-derived plasma exosomes of MSA patients and healthy controls.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: Insulin Resistance in Multiple System Atrophy
Estimated Study Start Date : June 15, 2020
Estimated Primary Completion Date : June 15, 2022
Estimated Study Completion Date : June 15, 2023


Arm Intervention/treatment
Experimental: MSA patient
Patients will be recruited at the French Reference Center for MSA.
Biological: Homeostasis Model Assessment of insulin resistance (HOMA)
Fasting blood sample for : glucose, insulinemia, hemoglobin and lipid test to determine the Homeostasis Model Assessment of insulin resistance (HOMA) index

Behavioral: MOntreal Cognitive Assessment (MoCA)
Cognitive evaluation with MOntreal Cognitive Assessment (MoCA)

Behavioral: Clinical characteristics of AMS patients
Severity and progression of motor disorders assessed by the UMSARS scale, severity of dysautonomia assessed by the COMPASS31 scale ; quality of life questionnaire (AMS-Qol) for the level of difficulty experienced by the patient (on activities such as : move; walk; maintain balance; talk; feed)

Procedure: Brain Magnetic Resonance Imaging (MRI)
Brain Magnetic Resonance Imaging (MRI) : putamen imaging, bridge and cerebellum; white substance hypersignals volume

Biological: Blood sampling
Optional blood sampling for the constitution of a biological collection

Control
Healthy volunteer matched for age (+/- 5years) and sex with MSA patient.
Biological: Homeostasis Model Assessment of insulin resistance (HOMA)
Fasting blood sample for : glucose, insulinemia, hemoglobin and lipid test to determine the Homeostasis Model Assessment of insulin resistance (HOMA) index

Behavioral: MOntreal Cognitive Assessment (MoCA)
Cognitive evaluation with MOntreal Cognitive Assessment (MoCA)

Procedure: Brain Magnetic Resonance Imaging (MRI)
Brain Magnetic Resonance Imaging (MRI) : putamen imaging, bridge and cerebellum; white substance hypersignals volume

Biological: Blood sampling
Optional blood sampling for the constitution of a biological collection




Primary Outcome Measures :
  1. HOMA Index [ Time Frame: Day 0 ]
    Homeostasis Model Assessment of insulin resistance (HOMA) index, calculated from a fasted blood glucose and insulin level between AMS patients and a formula-controlled group (insulinemia x glycemia)/22.5 insulinemia being expressed in mU/l and glucose in mmol/L.


Secondary Outcome Measures :
  1. IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration [ Time Frame: Day 0 ]
    Mean concentration of neuronal IRS-1pS312 in plasma exosomes

  2. Unified Multiple System Atrophy Rating Scale (UMSARS) score [ Time Frame: Day 0 ]

    UMSARS I (0=no disorder, 48=severe disorders): is an evaluation of activities of daily life via 12 items. It evaluates language, writing, autonomy (diet; dressing; hygiene), walking and the presence of possible urinary, sexual or intestinal disorders.

    UMSARS II (0=no disorder, 56=severe disorders): consists of a motor examination on the basis of 14 items that allow to evaluate including facial expression, oculomotricity, oral expression, tremors or walking.

    UMSARS III: consists of measurements of blood pressure and heart rate in the lying and standing position for 10 minutes every minute.

    UMSARS IV : disability assessment from 1 to 5 (1= completely independent; 5 = totally dependent / dependent)


  3. Unified Multiple System Atrophy Rating Scale (UMSARS) score [ Time Frame: One year ]

    UMSARS I (0=no disorder, 48=severe disorders): is an evaluation of activities of daily life via 12 items. It evaluates language, writing, autonomy (diet; dressing; hygiene), walking and the presence of possible urinary, sexual or intestinal disorders.

    UMSARS II (0=no disorder, 56=severe disorders): consists of a motor examination on the basis of 14 items that allow to evaluate including facial expression, oculomotricity, oral expression, tremors or walking.

    UMSARS III: consists of measurements of blood pressure and heart rate in the lying and standing position for 10 minutes every minute.

    UMSARS IV : disability assessment from 1 to 5 (1= completely independent; 5 = totally dependent / dependent)


  4. COMPosite Autonomic Symptoms Score (COMPASS-31) [ Time Frame: Day 0 ]
    Assessment of dysautonomia. The scale consists of 31 items in 6 domains and provides an autonomic symptom score from 0 to 100. High values represent severe symptoms

  5. COMPosite Autonomic Symptoms Score (COMPASS-31) [ Time Frame: One year ]
    Assessment of dysautonomia. The scale consists of 31 items in 6 domains and provides an autonomic symptom score from 0 to 100. High values represent severe symptoms

  6. AMS-Qol - Quality of life questionnaire [ Time Frame: Day 0 ]
    Quality of life questionnaire to collect the level of difficulty experienced by the patient (from no problem to extreme problem) during the 4 weeks preceding the interview on activities such as : move; walk; maintain balance; talk; feed. It also assesses how the patient feels about his disease

  7. AMS-Qol - Quality of life questionnaire [ Time Frame: One year ]
    Quality of life questionnaire to collect the level of difficulty experienced by the patient (from no problem to extreme problem) during the 4 weeks preceding the interview on activities such as : move; walk; maintain balance; talk; feed. It also assesses how the patient feels about his disease

  8. MOntreal Cognitive Assessment (Moca) score [ Time Frame: Day 0 ]
    Moca evaluates short-term memory, visual spatial skills, executive functions, attention, concentration, working memory, language, abstraction abilities, computing and orientation in time and space. Cognitive impairment is assessed on the score of 30 points (27-30: no cognitive impairment; 21-26: mild)

  9. MOntreal Cognitive Assessment (Moca) score [ Time Frame: One year ]
    Moca evaluates short-term memory, visual spatial skills, executive functions, attention, concentration, working memory, language, abstraction abilities, computing and orientation in time and space. Cognitive impairment is assessed on the score of 30 points (27-30: no cognitive impairment; 21-26: mild)

  10. Brain MRI volume [ Time Frame: Day 0 ]
    Imaging data (severity and progression of putamen atrophy, bridge and cerebellum in mm3; magnitude and progression of white substance hypersignals on T2-FLAIR images in mm3

  11. Brain MRI volume [ Time Frame: One year ]
    Imaging data (severity and progression of putamen atrophy, bridge and cerebellum in mm3; magnitude and progression of white substance hypersignals on T2-FLAIR images in mm3



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Ages Eligible for Study:   30 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Patients :

  • Patients suffering from "possible" or "probable" MSA according to clinical consensus criteria (Gilman et al., 2008).
  • Age > 30
  • Written informed consent
  • Patient covered by the national health system

Controls:

  • Patients not suffering from a neurologic disorder
  • Age > 30
  • Written informed consent
  • Patient covered by the national health system

Exclusion Criteria:

For patients and controls:

  • Presence of a diabetes
  • Treatment with corticosteroids, estrogen, atypical antipsychotics, and anti-retroviral agents
  • Patient under tutelage
  • Patient unable to give consent
  • Any other neurologic disorder
  • Pregnancy and breastfeeding
  • MOCA ≤21
  • Contraindication to perform an MRI

Information from the National Library of Medicine

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): NCT04250493


Contacts
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Contact: Anna DELAMARRE 05 33 51 47 19 anna.delamarre@u-bordeaux.fr

Locations
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France
CHU de Bordeaux
Bordeaux, France, 33 076
Contact: Anna DELAMARRE    05 33 51 47 19    anna.delamarre@u-bordeaux.fr   
Sponsors and Collaborators
University Hospital, Bordeaux
Université de Bordeaux
Labex Brain
Centre National de la Recherche Scientifique, France
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Responsible Party: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT04250493    
Other Study ID Numbers: CHUBX 2018/30
First Posted: January 31, 2020    Key Record Dates
Last Update Posted: March 31, 2020
Last Verified: March 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 University Hospital, Bordeaux:
Multiple system atrophy
Neurodegenerative disease
Alpha synuclein
Insulin resistance
Additional relevant MeSH terms:
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Multiple System Atrophy
Shy-Drager Syndrome
Insulin Resistance
Atrophy
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Pathological Conditions, Anatomical
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs