Clinical trial NCT04288128: Integrated Functional Evaluation of the Cerebellum
Official title: Integrated Functional Evaluation of the Cerebellum
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Spinocerebellar Ataxia Type 2
Spinocerebellar Ataxia Type 7
Keywords: Spinocerebellar ataxia
Multimodal approach
Biomarker
Antisense oligonucleotides (ASOs) therapy
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: Biogen
name: Ionis Pharmaceuticals, Inc.
First posted: 2020-02-28
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: Over one year
Secondary outcomes:
measure: 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
timeFrame: Over one year
measure: 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
timeFrame: Over one year
measure: Delineate a specific pattern of frontal-like cognitive deficit in SCAs gene carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of CSF, blood and urine biomarkers in SCAs gene mutation carriers and controls
timeFrame: Over one year
measure: To explore the relationship of CSF, blood and urine biomarker levels in relation to clinical and imaging markers of disease progression
timeFrame: Over one year
measure: To assess the feedback of individuals for the disease (Most bothersome symptoms)
timeFrame: Over one year
measure: To assess the feedback of individuals for the disease thanks to quality of life questionnaires
timeFrame: Over one year
measure: 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
timeFrame: Over one year
measure: 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.
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of optical coherence tomography in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of adaptative optics in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of autofluorescence, visual acuity, in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of visual field in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of colour contrast sensitivity in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of electroretinogram in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of static perimetry in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
measure: To determine the cross-sectional and longitudinal variability of visual evoked potential in SCA 2 and SCA 7 gene mutations carriers
timeFrame: Over one year
Other outcomes:
Locations:
city: Paris
country: France
facility: Institut du Cerveau - Paris Brain Institute
Study officials:
affiliation: Institut du Cerveau - Paris Brain Institute
name: Alexandra DURR
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nassisi M, Coarelli G, Blanchard B, Dubec-Fleury C, Drine K, Kitic N, Sancho S, Hilab R, Tezenas du Montcel S, Junge C, Lane R, Arnold HM, Durr A, Audo I. ATXN7-Related Cone-Rod Dystrophy: The Integrated Functional Evaluation of the Cerebellum (CERMOI) Study. JAMA Ophthalmol. 2024 Apr 1;142(4):301-308. doi: 10.1001/jamaophthalmol.2024.0001.