Insulin Resistance in Multiple System Atrophy

Multiple System Atrophy Clinical Trial

— IRAMS  

Official title:

Insulin Resistance in Multiple System Atrophy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04250493
• Other study ID #: CHUBX 2018/30
• Status: Recruiting
• Phase: N/A
• Start date: October 28, 2020
• Est. completion date: October 28, 2023

Study information

• Verified date: March 2022
• Source: University Hospital, Bordeaux
• Contact: Anna DELAMARRE
• Phone: 05 33 51 47 19
• Email: anna.delamarre[@]u-bordeaux.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 124
• Est. completion date: October 28, 2023
• Est. primary completion date: October 28, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 30 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrophy
• Insulin Resistance
• Multiple System Atrophy
• Shy-Drager Syndrome

Intervention

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)
• 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

Locations

Country	Name	City	State
France	CHU de Bordeaux	Bordeaux

Sponsors (4)

Lead Sponsor	Collaborator
University Hospital, Bordeaux	Centre National de la Recherche Scientifique, France, Labex Brain, University of Bordeaux

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Day 0
Secondary	IRS-1pS312 (Insulin Receptor Substrate-1, Phosphorylated at Serine 312) concentration	Mean concentration of neuronal IRS-1pS312 in plasma exosomes	Day 0
Secondary	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)	Day 0
Secondary	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)	One year
Secondary	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	Day 0
Secondary	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	One year
Secondary	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	Day 0
Secondary	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	One year
Secondary	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)	Day 0
Secondary	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)	One year
Secondary	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	Day 0
Secondary	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	One year