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Insulin Resistance in Multiple System Atrophy (IRAMS)

Primary Purpose

Multiple System Atrophy

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Homeostasis Model Assessment of insulin resistance (HOMA)
MOntreal Cognitive Assessment (MoCA)
Clinical characteristics of AMS patients
Brain Magnetic Resonance Imaging (MRI)
Blood sampling
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional health services research trial for Multiple System Atrophy focused on measuring Multiple system atrophy, Neurodegenerative disease, Alpha synuclein, Insulin resistance

Eligibility Criteria

30 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • CHU de BordeauxRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

MSA patient

Control

Arm Description

Patients will be recruited at the French Reference Center for MSA.

Healthy volunteer matched for age (+/- 5years) and sex with MSA patient.

Outcomes

Primary Outcome Measures

HOMA Index
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

IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration
Mean concentration of neuronal IRS-1pS312 in plasma exosomes
Unified Multiple System Atrophy Rating Scale (UMSARS) score
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)
Unified Multiple System Atrophy Rating Scale (UMSARS) score
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)
COMPosite Autonomic Symptoms Score (COMPASS-31)
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
COMPosite Autonomic Symptoms Score (COMPASS-31)
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
AMS-Qol - Quality of life questionnaire
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
AMS-Qol - Quality of life questionnaire
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
MOntreal Cognitive Assessment (Moca) score
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)
MOntreal Cognitive Assessment (Moca) score
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)
Brain MRI volume
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
Brain MRI volume
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

Full Information

First Posted
January 29, 2020
Last Updated
March 29, 2022
Sponsor
University Hospital, Bordeaux
Collaborators
University of Bordeaux, Labex Brain, Centre National de la Recherche Scientifique, France
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1. Study Identification

Unique Protocol Identification Number
NCT04250493
Brief Title
Insulin Resistance in Multiple System Atrophy
Acronym
IRAMS
Official Title
Insulin Resistance in Multiple System Atrophy
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
October 28, 2020 (Actual)
Primary Completion Date
October 28, 2023 (Anticipated)
Study Completion Date
October 28, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Bordeaux
Collaborators
University of Bordeaux, Labex Brain, Centre National de la Recherche Scientifique, 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
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple System Atrophy
Keywords
Multiple system atrophy, Neurodegenerative disease, Alpha synuclein, Insulin resistance

7. Study Design

Primary Purpose
Health Services Research
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
124 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
MSA patient
Arm Type
Experimental
Arm Description
Patients will be recruited at the French Reference Center for MSA.
Arm Title
Control
Arm Type
Other
Arm Description
Healthy volunteer matched for age (+/- 5years) and sex with MSA patient.
Intervention Type
Biological
Intervention Name(s)
Homeostasis Model Assessment of insulin resistance (HOMA)
Intervention Description
Fasting blood sample for : glucose, insulinemia, hemoglobin and lipid test to determine the Homeostasis Model Assessment of insulin resistance (HOMA) index
Intervention Type
Behavioral
Intervention Name(s)
MOntreal Cognitive Assessment (MoCA)
Intervention Description
Cognitive evaluation with MOntreal Cognitive Assessment (MoCA)
Intervention Type
Behavioral
Intervention Name(s)
Clinical characteristics of AMS patients
Intervention Description
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)
Intervention Type
Procedure
Intervention Name(s)
Brain Magnetic Resonance Imaging (MRI)
Intervention Description
Brain Magnetic Resonance Imaging (MRI) : putamen imaging, bridge and cerebellum; white substance hypersignals volume
Intervention Type
Biological
Intervention Name(s)
Blood sampling
Intervention Description
Optional blood sampling for the constitution of a biological collection
Primary Outcome Measure Information:
Title
HOMA Index
Description
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.
Time Frame
Day 0
Secondary Outcome Measure Information:
Title
IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration
Description
Mean concentration of neuronal IRS-1pS312 in plasma exosomes
Time Frame
Day 0
Title
Unified Multiple System Atrophy Rating Scale (UMSARS) score
Description
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)
Time Frame
Day 0
Title
Unified Multiple System Atrophy Rating Scale (UMSARS) score
Description
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)
Time Frame
One year
Title
COMPosite Autonomic Symptoms Score (COMPASS-31)
Description
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
Time Frame
Day 0
Title
COMPosite Autonomic Symptoms Score (COMPASS-31)
Description
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
Time Frame
One year
Title
AMS-Qol - Quality of life questionnaire
Description
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
Time Frame
Day 0
Title
AMS-Qol - Quality of life questionnaire
Description
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
Time Frame
One year
Title
MOntreal Cognitive Assessment (Moca) score
Description
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)
Time Frame
Day 0
Title
MOntreal Cognitive Assessment (Moca) score
Description
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)
Time Frame
One year
Title
Brain MRI volume
Description
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
Time Frame
Day 0
Title
Brain MRI volume
Description
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
Time Frame
One year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anna DELAMARRE
Phone
05 33 51 47 19
Email
anna.delamarre@u-bordeaux.fr
Facility Information:
Facility Name
CHU de Bordeaux
City
Bordeaux
ZIP/Postal Code
33 076
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anna DELAMARRE
Phone
05 33 51 47 19
Email
anna.delamarre@u-bordeaux.fr

12. IPD Sharing Statement

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Insulin Resistance in Multiple System Atrophy

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