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Integrated Functional Evaluation of the Cerebellum (CERMOI)

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ClinicalTrials.gov Identifier: NCT04288128
Recruitment Status : Recruiting
First Posted : February 28, 2020
Last Update Posted : June 5, 2020
Sponsor:
Collaborators:
Biogen
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

Study Description
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Brief Summary:
One of the main objectives of this project is to validate potential biological, clinical and/or imaging biomarkers in SCA patients through a multimodal assessment, for future ASOs trials.

Condition or disease Intervention/treatment
Spinocerebellar Ataxia Type 2 Spinocerebellar Ataxia Type 7 Procedure: Lumbar puncture Other: Magnetic Resonance Imaging (MRI)

Detailed Description:

Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited neurological disorders, characterized by a predominant atrophy of the cerebellum and the brainstem. The most common forms are caused by abnormal CAG repeat expansions, encoding elongated polyglutamine (polyQ).

Nowadays, no preventive or curative treatments are available but different therapeutic approaches are ongoing. Antisense oligonucleotides (ASOs) therapy showed promising results in Huntington disease (HD), a disease that shares with the SCAs the same mutational mechanism. ASOs are currently under development for SCAs.

However, in SCAs, clinical scales as an only criteria to monitor a treatment are not appropriate because of the lack of sensitivity of change and the small number of patients available. The importance to dispose of outcome measures to inform about the efficacy of a treatment is fundamental as well as of new alternative designs to conduct a clinical trial in rare diseases with small sample sizes.

A comprehensive, multimodal approach is hence needed to provide a translational and integrated overview of cerebellar dysfunction in polyQ SCAs over a year.

Study Design
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Study Type : Observational
Estimated Enrollment : 40 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Integrated Functional Evaluation of the Cerebellum
Actual Study Start Date : May 28, 2020
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2022

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
SCA early-manifest and premanifest patients
This cohort is defined by individuals with a SARA score between 0 and 15 (both values included).
 Procedure: Lumbar puncture
Each participant will undergo lumbar puncture at first visit (M0) and last visit (M12)

Other: Magnetic Resonance Imaging (MRI)
Each participant will undergo scanning at 3 visits (M0, M6 and M12)
Control participants
This cohort is defined by individuals with a SARA score less than 5 and no significant neurological symptoms.
 Procedure: Lumbar puncture
Each participant will undergo lumbar puncture at first visit (M0) and last visit (M12)

Other: Magnetic Resonance Imaging (MRI)
Each participant will undergo scanning at 3 visits (M0, M6 and M12)


Outcome Measures
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Primary Outcome Measures :
  1. Identification of biological, clinical and/or imaging biomarkers in SCA2 and SCA7 patients mutations carriers and patients through a multimodal assessment over one year to prepare therapeutic trials [ Time Frame: Over one year ]

Secondary Outcome Measures :
  1. To determine the cross-sectional and longitudinal variability of SARA (Scale for the Assessment and Rating of Ataxia) and CCFS (Composite Cerebellar Functional Score) scores in SCA 2 and SCA 7 gene mutation carriers and healthy controls over one [ Time Frame: Over one year ]
  2. Determine the cross-sectional and longitudinal variability of volumetric MRI and NMR-proto spectroscopy in SCA 2 and SCA 7 gene mutation carriers and healthy controls [ Time Frame: Over one year ]
  3. Delineate a specific pattern of frontal-like cognitive deficit in SCAs gene carriers [ Time Frame: Over one year ]
    Evolution of neuropsychological scores and Cerebellar Cognitive Affective/Schmahmann Syndrome Scale. The neuropsychological data collected has to evaluate the cerebellar cognitive affective syndrome (CCAS). The CCAS consisting of cognitive and affective deficits due to cerebellar disease.

  4. To determine the cross-sectional and longitudinal variability of CSF, blood and urine biomarkers in SCAs gene mutation carriers and controls [ Time Frame: Over one year ]
    eg. specific mutant protein dosage in CSF sample for each genotype over 1 year, if available

  5. To explore the relationship of CSF, blood and urine biomarker levels in relation to clinical and imaging markers of disease progression [ Time Frame: Over one year ]
  6. To assess the feedback of individuals for the disease (Most bothersome symptoms) [ Time Frame: Over one year ]
    Evolution of a Most Bothersome Symptom (MBS) questionnaire will be performed by the physician in order to determine patients' most bothersome symptoms. This qualitative report investigating the subjective complaint and feedback of patients

  7. To assess the feedback of individuals for the disease thanks to quality of life questionnaires [ Time Frame: Over one year ]

    Evolution of quality of life self-administrated questionnaires :

    Patient global impression: is a global index that may be used to rate the response of a condition EQ-5D is a standardized instrument which measures health-related quality of life that can be used in a wide range of health conditions and treatments Patient Health Questionnaire (PHQ 9) is a self-administered depression module, which scores each of the nine DSM-IV criteria as "0" (not at all) to "3" (nearly every day).


  8. To determine the cross-sectional and longitudinal variability of quantitative measures of postural stability, free walking and turning in SCA 2 and SCA 7 mutation carriers and healthy controls [ Time Frame: Over one year ]
    Evolution of postural sway measures from the sternum and the lumbar spine by wearable APDM® sensors and evolution of cerebellar instability by Fitbit® smartwatch

  9. To determine the cross-sectional and longitudinal variability of quantitative measures of oculomotor recording in SCA 2 and SCA 7 gene mutations carriers and healthy controls. [ Time Frame: Over one year ]
  10. To determine the cross-sectional and longitudinal variability of optical coherence tomography in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]
  11. To determine the cross-sectional and longitudinal variability of adaptative optics in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]
  12. To determine the cross-sectional and longitudinal variability of autofluorescence, visual acuity, in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]
  13. To determine the cross-sectional and longitudinal variability of visual field in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]
  14. To determine the cross-sectional and longitudinal variability of colour contrast sensitivity in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]
  15. To determine the cross-sectional and longitudinal variability of electroretinogram in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]
  16. To determine the cross-sectional and longitudinal variability of static perimetry in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]
  17. To determine the cross-sectional and longitudinal variability of visual evoked potential in SCA 2 and SCA 7 gene mutations carriers [ Time Frame: Over one year ]

Biospecimen Retention:   Samples With DNA
Whole blood collected for DNA analysis

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
  1. Early stage subjects and premanifest mutation carriers refer to individuals who tested positive for the SCA 2 or 7 gene mutation and SARA score between 0 and 15 (both values included)
  2. Control participants refer to individuals with non-mutation carriers.
Criteria

Common inclusion criteria for all participants:

  • Ability to walk independently 30 foot without an assistive device
  • Able to stand unassisted for 30 seconds
  • Affiliated with the French social security, or a social security equivalent, if they are not French.
  • Capacity to consent
  • Signed Informed Consent by the subject
  • Ability to undergo MRI scanning

Inclusion criteria for SCA patients:

  • Genetic diagnosis of SCA 2 or 7 (available CAG repeat length)
  • SARA score ≤15

Inclusion criteria for control participants:

  • Negative Genetic diagnosis of SCA2/SCA7 available
  • No significant neurological symptoms
  • SARA score < 5

Common inclusion criteria for elective participant for CSF sampling:

• Ability to undergo a lumbar puncture

Exclusion criteria

  • Subjects currently receiving, or having received within 2 months prior to enrolment into this study, any investigational drug
  • Pregnancy or breastfeeding
  • Genotype consistent with other inherited ataxias
  • Changes in coordinative physical and occupational therapy for ataxia 2 months prior to study participation
  • Concomitant disorder(s) or condition(s) that affects assessment of ataxia or severity of ataxia during this study
  • Contra-indications to MRI examination
  • Person deprived of their liberty by judicial or administrative decision
Contacts and Locations
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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): NCT04288128


Contacts
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Contact: Alexandra DURR, PU-PH 01 57 27 46 91 alexandra.durr@icm-institute.org
Contact: Rania HILAB 01 57 27 46 91 rania.hilab@icm-institute.org

Locations
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France
Institut du Cerveau - Paris Brain Institute Recruiting
Paris, France, 75013
Contact: Rania Hilab    01.57.27.46.91    rania.hilab@icm-institute.org   
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Biogen
Ionis Pharmaceuticals, Inc.
Investigators
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Principal Investigator: Alexandra DURR Institut du Cerveau - Paris Brain Institute
More Information
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Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT04288128    
Other Study ID Numbers: C18-29
2018-A02563-52 ( Registry Identifier: Secondary ID )
First Posted: February 28, 2020    Key Record Dates
Last Update Posted: June 5, 2020
Last Verified: June 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 Institut National de la Santé Et de la Recherche Médicale, France:
Spinocerebellar ataxia
Multimodal approach
Biomarker
Antisense oligonucleotides (ASOs) therapy
Additional relevant MeSH terms:
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Ataxia
Cerebellar Ataxia
Spinocerebellar Ataxias
Spinocerebellar Degenerations
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
 Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Spinal Cord Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn