Clinical trial NCT05177809: RFC1 Natural History Study
Official title: RFC1 Natural History Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Ataxia
Keywords: RFC1
CANVAS
Natural History Study
Biomarker
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2022-01-05
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study enrolls probands with clinically manifest and genetically confirmed RFC1 repeat expansion disease, as well as healthy unrelated controls to contrast unspecific, age- or sex-related findings to disease-related specific findings.

Brief summary: This international, multi-center, multi-modal and prospective observational study aims to determine the phenotypic spectrum and the natural progression of the RFC1 repeat expansion disease, and to seek and validate digital, imaging, and molecular biomarkers that aid in diagnosis and serve as outcome measures in future clinical trials of this novel, but frequent ataxia with late adult-onset.

Detailed description: The investigators will perform an international, multi-center, multi-modal, and registry-based standardized prospective Natural History Study (NHS) in RFC1 repeat expansion disease. Participants will be assessed annually. Study visits with a standardized clinical examination will apply several clinical rating scales, and data will be entered into a clinical database (ARCA Registry; www.ARCA-registry.org) customized to the requirements of this specific study. At all study visits, patients will be asked to donate biosamples; biomaterial collection is optional, and participants can elect to participate in sampling of blood, urine, CSF, and/or a skin biopsy.

Optionally, and depending on local availability at each participating site, additional examinations may be performed including imaging, quantitative movement and speech analysis, vestibular testing, a neuropsychological examination, or examination of swallowing function, all to fully capture the multisystemic presentation of the RFC1 repeat expansion disease.

This study will delineate variable phenotypes of this relatively novel disease, and systematically characterize the longitudinal progression of multi-model biomarkers to determine the most sensitive, comprehensive, and reliable outcomes measures for future therapeutic trials. Here, longitudinal validation of targeted fluid biomarker candidates will be an important part. The multi-modal longitudinal design of the study and its comprehensive assessment will also provide mechanistic insights into the multisystemic evolution of the disease, which will especially allow to track and understand selective as well as overlapping dysfunction of the cerebellum, sensory peripheral nerves, the vestibular system, and additional systems known to be involved in RFC1 disease or 'CANVAS' as its related syndrome.

Eligibility criteria: Inclusion Criteria:

* RFC1: genetic diagnosis of bi-allelic pathogenic repeat expansions in RFC1
* Unrelated healthy controls: no signs or history of neurological or psychiatric disease AND
* Written informed consent AND
* Participants are willing and able to comply with study procedures

Exclusion Criteria:

* RFC1: Missing informed consent
* Controls: evidence of neuropathy, neurodegenerative disease, or movement disorder; inability to give informed consent

Primary outcomes:
measure: Change of Scale for the Assessment and Rating of Ataxia (SARA) from baseline to 2-year follow-up.
timeFrame: 24 months
Secondary outcomes:
measure: Friedreich Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Charcot-Marie-Tooth Examination Score Version 2 (CMTESv2) from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Nine-Hole Peg Test (9HPT) from baseline to 2-year follow-up.
timeFrame: 24 months
Other outcomes:
measure: Composite Autonomic Symptom Score (COMPASS-31) at baseline, and eventually from baseline to 2-year follow-up if baseline data supports further use.
timeFrame: 24 months
measure: Cerebellar cognitive-affective syndrome scale (CCAS) from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Clinical Assessment of Dysphagia in Neurodegeneration (CADN) from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Video Head Impulse Test (vHIT) from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Digital gait and balance assessment from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Digital assessment of limb function from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Digital Speech Assessment from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Magnetic resonance imaging (MRI) from baseline to 2-year follow-up.
timeFrame: 24 months
measure: Patient-reported outcomes of chronic cough from baseline to 2-year follow-up.
timeFrame: 24 months
Locations:
city: Melbourne
country: Australia
facility: Department of Neuroscience, Central Clinical School, Monash University
state: Victoria
city: São Paulo
country: Brazil
facility: Department of Neurology, Ataxia Unit, Universidade Federal de São Paulo
state: State Of São Paulo
city: Strasbourg
country: France
facility: Service de Neurologie, Hôpitaux Universitaires de Strasbourg
city: Tübingen
country: Germany
facility: Center for Neurology & Hertie-Institute for Clinical Brain Research, Dept. for Neurodegenerative Diseases
state: Baden-Württemberg
city: Bonn
country: Germany
facility: German Center for Neurodegenerative Diseases (DZNE)
state: Nordrhein-Westfalen
city: Lübeck
country: Germany
facility: Department of Neurology University Hospital Schleswig Holstein
state: Schleswig-Holstein
city: Napoli
country: Italy
facility: Università degli Studi di Napoli 'Federico II', c/o AOU Federico II
city: Pisa
country: Italy
facility: IRCCS Fondazione Stella Maris
city: Auckland
country: New Zealand
facility: Centre of Brain Research Neurogenetics Research Clinic, University of Auckland
city: Istanbul
country: Turkey
facility: Koç University Hospital, KUTTAM-NDAL
Study officials:
affiliation: University Hospital Tübingen
name: Matthis Synofzik, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Tübingen
name: Andreas Traschütz, Dr. Dr.
role: PRINCIPAL_INVESTIGATOR
References: