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Natural History and Disease Progression Biomarkers of Multiple System Atrophy (ASPIRE-MSA)

Primary Purpose

Multiple System Atrophy

Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
MRI acquisition
DAT-SPECT
blood sample, cerebrospinal fluid (optional)
Evaluations about motor abilities, depression, cognition and lifestyle
Evaluation about depression cognition
Sponsored by
University Hospital, Toulouse
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Multiple System Atrophy focused on measuring MSA, MRI, Dat spect, Atrophy, Biomarkers

Eligibility Criteria

30 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

INCLUSION CRITERIA:

Applicable to MSA patients:

  • Patients with possible or probable MSA according to consensus diagnosis criteria [Gilman et al., 2008]
  • Patients aged between 30 and 80 years
  • Patients at the early stages of the disease, defined as maximum 5 years since the onset of one of the following symptoms associated to MSA:

Parkinsonism Ataxia Orthostatic hypotension and/or urinary dysfunction - Patients with an anticipated survival of at least 3 years on the basis of Investigators' clinical judgment

Applicable to healthy controls:

  • Participants with a similar age (+/- 5 years) and gender distribution compared to MSA patients
  • Participants with absence of neurological pathology
  • Patients aged between 25 and < 80 years

Applicable to both patients and healthy controls:

- Participants who voluntarily sign the written informed consent form, indicating that they understand the purpose of and procedures required for the study and are willing to participate in it Participants affiliated to the French social security health system

EXCLUSION CRITERIA:

Applicable to MSA patients:

  • Speech impairment (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 1);
  • Impairment in ambulation (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 7)
  • Falling more frequently than once per week (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 8)

Applicable to both MSA patients and healthy controls:

  • Participants with significant cognitive impairment (MoCA score <21)
  • Any major medical or psychiatric condition which may compromise participation in the study or the safety, at the discretion of the Investigator
  • Contraindications for MRI imaging, including claustrophobia and presence of metallic implants such as cardiac or auditory prostheses, pacemakers or cerebral clips
  • Contraindications to obtain a FP-CIT SPECT(Single Photon Emission Computed Tomography) (i.e. known hypersensitivity to the active substance or to any of the excipients, or to iodine)
  • Current pharmacological treatments that may alter the DAT(dopamine transporter ) SPECT (Single Photon Emission Computed Tomography) reading, including amphetamines, benzatropine, buproprion (amfebutamone), cocaine, mazindol, methylphenidate, phentermine or sertraline
  • Females who are pregnant, breast feeding or of child bearing age without effective contraception
  • Participants who lack the capacity to give informed consent
  • Participants taking any investigational products within 3 months before baseline assessment
  • Participant under adult autonomy protection system, legal guardianship or incapacitation.

Additional exclusion criteria concerning only patients consenting to the lumbar puncture:

  • Coagulopathy and/or anticoagulant treatment
  • Thrombocytopenia
  • Intracranial hypertension
  • Severe degenerative arthritis of the lumbar spine Patients failing to meet these criteria can still participate in the study and all other study assessments (with the exception of lumbar puncture) as appropriate.

Sites / Locations

  • CHU de Bordeaux
  • Hôpital Neurologique Pierre Wertheimer
  • Chu Clermont Ferrand
  • CHU Lille
  • Hôpital de La Timone
  • CHU de Nancy
  • Clinique neurologique - Hôpital Laennec
  • Hôpital Pitié-Salpêtrière
  • Hôpital de Hautepierre
  • CHU

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

MSA patients

Healthy volunteers

Arm Description

Patients with multiple system atrophy will be examined at baseline, 6 months and 12 months via the following procedures performed at all 3 visits: a clinical examination; blood and cerebrospinal fluid (CSF) (optional) sampling for the assessment of selected fluid biomarkers; MRI for the assessment of brain volume, white matter integrity and cerebral iron deposition; DAT-SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography) for the assessment of presynaptic dopaminergic function

healthy. Controls will undergo an MRI scan at baseline, 6 months and 12 months, and a DAT-SPECT(Dopamine Transporter, Single Photon Emission Computed Tomography) scan at baseline and 12 months.

Outcomes

Primary Outcome Measures

Change putamen, cerebellum and brainstem volume measured on MRI
volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2* (s-1), diffusion: mean diffusivity (mm2s-1)

Secondary Outcome Measures

Effect of disease progression on other measures of brain structural integrity and iron accumulation
volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2* (s-1), diffusion: mean diffusivity (mm2s-1)
Effect of disease progression on the loss of presynaptic dopaminergic terminals in the striatum integrity and iron accumulation
volume measured with DAT SPECT (Single Photon Emission Computed Tomography), unit : binding potential (e.g ratio striatum/brain activity)
Effect of disease progression on axonal damage as evidenced in biofluids
biomarkers dosages in blood and Cerebral Spinal Fluid total Concentration unit : pg/ml.

Full Information

First Posted
November 28, 2019
Last Updated
June 19, 2023
Sponsor
University Hospital, Toulouse
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1. Study Identification

Unique Protocol Identification Number
NCT04229173
Brief Title
Natural History and Disease Progression Biomarkers of Multiple System Atrophy
Acronym
ASPIRE-MSA
Official Title
Natural History and Disease Progression Biomarkers of Multiple System Atrophy
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
May 26, 2020 (Actual)
Primary Completion Date
May 30, 2022 (Actual)
Study Completion Date
October 28, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Toulouse

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease characterised by a variable combination of parkinsonism, cerebellar impairment and autonomic dysfunction. The neuropathological hallmark is the accumulation of alpha-synuclein in oligodendrocytes. While some symptomatic treatments exist, neuroprotective treatments for MSA remain an urgent, unmet need. Moreover, at present there is not a single surrogate biomarker of MSA which could be used to inform clinical trials. This study seeks to characterise the natural history of MSA on a panel of candidate biomarkers, pre-selected for being putative surrogates of the underlying neurodegenerative process
Detailed Description
Surrogate biomarkers are objectively measured characteristics of a disease which act as indicators of the underlying pathophysiological processes responsible for disease progression. Reduced grey matter volume in putamen, cerebellum and brainstem as measured with MRI have been consistently reported to differentiate MSA from other parkinsonian disorders. However, to date, there are no longitudinal studies examining the natural history of MSA on these structural neuroimaging markers over time. The magnitude of the abnormalities observed cross-sectionally in MSA compared to other parkinsonian disorders and the fast clinical progression of the disease make it very likely that structural changes can be observed even over short periods of time. There is also a strong scientific rationale for the potential of measures reflecting white matter integrity, cerebral iron deposition and presynaptic dopaminergic dysfunction, as well as levels of neurofilament light chain (NfL), alpha-synuclein and other proteins involved in the neurodegenerative process in MSA, to serve as progression biomarkers of the disease, although supporting evidence remains limited. A better understanding of the natural history of MSA over 6 and 12 months on a panel of candidate surrogate biomarkers is needed to better understand the disease, help optimise future trial designs in terms of patient selection, sample size and trial duration, and improve the ability to measure the therapeutic effects of novel treatments. In evaluating potential progression markers of a neurodegenerative disease such as MSA, it is important to control for the normal effects of aging. Studies in healthy volunteers have shown regionally distinct effects of aging on both brain volume and dopamine transporter density, justifying the inclusion of healthy controls with a similar age and gender distribution than patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple System Atrophy
Keywords
MSA, MRI, Dat spect, Atrophy, Biomarkers

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
61 (Actual)

8. Arms, Groups, and Interventions

Arm Title
MSA patients
Arm Type
Other
Arm Description
Patients with multiple system atrophy will be examined at baseline, 6 months and 12 months via the following procedures performed at all 3 visits: a clinical examination; blood and cerebrospinal fluid (CSF) (optional) sampling for the assessment of selected fluid biomarkers; MRI for the assessment of brain volume, white matter integrity and cerebral iron deposition; DAT-SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography) for the assessment of presynaptic dopaminergic function
Arm Title
Healthy volunteers
Arm Type
Other
Arm Description
healthy. Controls will undergo an MRI scan at baseline, 6 months and 12 months, and a DAT-SPECT(Dopamine Transporter, Single Photon Emission Computed Tomography) scan at baseline and 12 months.
Intervention Type
Diagnostic Test
Intervention Name(s)
MRI acquisition
Intervention Description
MRI acquisition
Intervention Type
Diagnostic Test
Intervention Name(s)
DAT-SPECT
Intervention Description
Imaging with DAT SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography)
Intervention Type
Diagnostic Test
Intervention Name(s)
blood sample, cerebrospinal fluid (optional)
Intervention Description
blood sample, cerebrospinal fluid
Intervention Type
Behavioral
Intervention Name(s)
Evaluations about motor abilities, depression, cognition and lifestyle
Intervention Description
Evaluations about motor abilities (UMSAR scale), depression (BDI scale), cognition (MoCA scale) and lifestyle (MSA- QoL)
Intervention Type
Behavioral
Intervention Name(s)
Evaluation about depression cognition
Intervention Description
Evaluations about depression (BDI scale), cognition (MoCA scale)
Primary Outcome Measure Information:
Title
Change putamen, cerebellum and brainstem volume measured on MRI
Description
volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2* (s-1), diffusion: mean diffusivity (mm2s-1)
Time Frame
at 12 month
Secondary Outcome Measure Information:
Title
Effect of disease progression on other measures of brain structural integrity and iron accumulation
Description
volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2* (s-1), diffusion: mean diffusivity (mm2s-1)
Time Frame
6 month and 12 month
Title
Effect of disease progression on the loss of presynaptic dopaminergic terminals in the striatum integrity and iron accumulation
Description
volume measured with DAT SPECT (Single Photon Emission Computed Tomography), unit : binding potential (e.g ratio striatum/brain activity)
Time Frame
6 month and 12 month
Title
Effect of disease progression on axonal damage as evidenced in biofluids
Description
biomarkers dosages in blood and Cerebral Spinal Fluid total Concentration unit : pg/ml.
Time Frame
6 month and 12 month

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
INCLUSION CRITERIA: Applicable to MSA patients: Patients with possible or probable MSA according to consensus diagnosis criteria [Gilman et al., 2008] Patients aged between 30 and 80 years Patients at the early stages of the disease, defined as maximum 5 years since the onset of one of the following symptoms associated to MSA: Parkinsonism Ataxia Orthostatic hypotension and/or urinary dysfunction - Patients with an anticipated survival of at least 3 years on the basis of Investigators' clinical judgment Applicable to healthy controls: Participants with a similar age (+/- 5 years) and gender distribution compared to MSA patients Participants with absence of neurological pathology Patients aged between 25 and < 80 years Applicable to both patients and healthy controls: - Participants who voluntarily sign the written informed consent form, indicating that they understand the purpose of and procedures required for the study and are willing to participate in it Participants affiliated to the French social security health system EXCLUSION CRITERIA: Applicable to MSA patients: Speech impairment (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 1); Impairment in ambulation (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 7) Falling more frequently than once per week (score of ≥3 on UMSARS (Unified Multiple System Atrophy Rating Scale) question 8) Applicable to both MSA patients and healthy controls: Participants with significant cognitive impairment (MoCA score <21) Any major medical or psychiatric condition which may compromise participation in the study or the safety, at the discretion of the Investigator Contraindications for MRI imaging, including claustrophobia and presence of metallic implants such as cardiac or auditory prostheses, pacemakers or cerebral clips Contraindications to obtain a FP-CIT SPECT(Single Photon Emission Computed Tomography) (i.e. known hypersensitivity to the active substance or to any of the excipients, or to iodine) Current pharmacological treatments that may alter the DAT(dopamine transporter ) SPECT (Single Photon Emission Computed Tomography) reading, including amphetamines, benzatropine, buproprion (amfebutamone), cocaine, mazindol, methylphenidate, phentermine or sertraline Females who are pregnant, breast feeding or of child bearing age without effective contraception Participants who lack the capacity to give informed consent Participants taking any investigational products within 3 months before baseline assessment Participant under adult autonomy protection system, legal guardianship or incapacitation. Additional exclusion criteria concerning only patients consenting to the lumbar puncture: Coagulopathy and/or anticoagulant treatment Thrombocytopenia Intracranial hypertension Severe degenerative arthritis of the lumbar spine Patients failing to meet these criteria can still participate in the study and all other study assessments (with the exception of lumbar puncture) as appropriate.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Olivier RASCOL, MD, PhD
Organizational Affiliation
University Hospital, Toulouse
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU de Bordeaux
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
Hôpital Neurologique Pierre Wertheimer
City
Bron
ZIP/Postal Code
69677
Country
France
Facility Name
Chu Clermont Ferrand
City
Clermont Ferrand
ZIP/Postal Code
63003
Country
France
Facility Name
CHU Lille
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Hôpital de La Timone
City
Marseille
ZIP/Postal Code
13000
Country
France
Facility Name
CHU de Nancy
City
Nancy
ZIP/Postal Code
54035
Country
France
Facility Name
Clinique neurologique - Hôpital Laennec
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Hôpital Pitié-Salpêtrière
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Hôpital de Hautepierre
City
Strasbourg
ZIP/Postal Code
67098
Country
France
Facility Name
CHU
City
Toulouse
ZIP/Postal Code
31000
Country
France

12. IPD Sharing Statement

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Natural History and Disease Progression Biomarkers of Multiple System Atrophy

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