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

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ClinicalTrials.gov Identifier: NCT04229173
Recruitment Status : Active, not recruiting
First Posted : January 18, 2020
Last Update Posted : October 12, 2021
Sponsor:
Information provided by (Responsible Party):
University Hospital, Toulouse

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


Condition or disease Intervention/treatment Phase
Multiple System Atrophy Diagnostic Test: MRI acquisition Diagnostic Test: DAT-SPECT Diagnostic Test: blood sample, cerebrospinal fluid (optional) Behavioral: Evaluations about motor abilities, depression, cognition and lifestyle Behavioral: Evaluation about depression cognition Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Natural History and Disease Progression Biomarkers of Multiple System Atrophy
Actual Study Start Date : May 26, 2020
Estimated Primary Completion Date : May 30, 2022
Estimated Study Completion Date : September 2022


Arm Intervention/treatment
MSA patients

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
Diagnostic Test: MRI acquisition
MRI acquisition

Diagnostic Test: DAT-SPECT
Imaging with DAT SPECT (Dopamine Transporter, Single Photon Emission Computed Tomography)

Diagnostic Test: blood sample, cerebrospinal fluid (optional)
blood sample, cerebrospinal fluid

Behavioral: Evaluations about motor abilities, depression, cognition and lifestyle
Evaluations about motor abilities (UMSAR scale), depression (BDI scale), cognition (MoCA scale) and lifestyle (MSA- QoL)

Healthy volunteers
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.
Diagnostic Test: MRI acquisition
MRI acquisition

Behavioral: Evaluation about depression cognition
Evaluations about depression (BDI scale), cognition (MoCA scale)




Primary Outcome Measures :
  1. Change putamen, cerebellum and brainstem volume measured on MRI [ Time Frame: at 12 month ]
    volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2* (s-1), diffusion: mean diffusivity (mm2s-1)


Secondary Outcome Measures :
  1. Effect of disease progression on other measures of brain structural integrity and iron accumulation [ Time Frame: 6 month and 12 month ]
    volume measured with T1-3D MRI, unit : Volume (mm3), Fer: R2* (s-1), diffusion: mean diffusivity (mm2s-1)

  2. Effect of disease progression on the loss of presynaptic dopaminergic terminals in the striatum integrity and iron accumulation [ Time Frame: 6 month and 12 month ]
    volume measured with DAT SPECT (Single Photon Emission Computed Tomography), unit : binding potential (e.g ratio striatum/brain activity)

  3. Effect of disease progression on axonal damage as evidenced in biofluids [ Time Frame: 6 month and 12 month ]
    biomarkers dosages in blood and Cerebral Spinal Fluid total Concentration unit : pg/ml.



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

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): NCT04229173


Locations
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France
CHU de Bordeaux
Bordeaux, France, 33076
Hôpital Neurologique Pierre Wertheimer
Bron, France, 69677
Chu Clermont Ferrand
Clermont Ferrand, France, 63003
CHU Lille
Lille, France, 59037
Hôpital de La Timone
Marseille, France, 13000
CHU de Nancy
Nancy, France, 54035
Clinique neurologique - Hôpital Laennec
Nantes, France, 44093
Hôpital Pitié-Salpêtrière
Paris, France, 75013
Hôpital de Hautepierre
Strasbourg, France, 67098
CHU
Toulouse, France, 31000
Sponsors and Collaborators
University Hospital, Toulouse
Investigators
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Principal Investigator: Olivier RASCOL, MD, PhD University Hospital, Toulouse
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Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT04229173    
Other Study ID Numbers: RC31/19/0161
First Posted: January 18, 2020    Key Record Dates
Last Update Posted: October 12, 2021
Last Verified: October 2021

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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, Toulouse:
MSA
MRI
Dat spect
Atrophy
Biomarkers
Additional relevant MeSH terms:
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Multiple System Atrophy
Shy-Drager Syndrome
Disease Progression
Atrophy
Disease Attributes
Pathologic Processes
Pathological Conditions, Anatomical
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases