RFC1 Natural History Study (RFC1-NHS)

March 30, 2026 updated by: Prof. Dr. Matthis Synofzik
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Estimated)

150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • Victoria
      • Melbourne, Victoria, Australia, 3004
        • Recruiting
        • Department of Neuroscience, Central Clinical School, Monash University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Ian Harding, PhD
        • Principal Investigator:
          • Adam Vogel, PhD
        • Principal Investigator:
          • David Szmulewicz, MD, PhD
  • Brazil
    • State of São Paulo
      • São Paulo, State of São Paulo, Brazil, 04040-003
        • Recruiting
        • Department of Neurology, Ataxia Unit, Universidade Federal de São Paulo
        • Contact:
        • Contact:
        • Principal Investigator:
          • José Luiz Pedroso, MD
        • Principal Investigator:
          • Orlando Graziani Povoas Barsottini, MD
  • France
    • Strasbourg
      • Strasbourg, Strasbourg, France, 67000
        • Recruiting
        • Service de Neurologie, Hôpitaux Universitaires de Strasbourg
        • Contact:
        • Principal Investigator:
          • Mathieu Anheim, Prof.
        • Sub-Investigator:
          • Thomas Wirth, Dr.
  • Germany
    • Baden-Wurttemberg
      • Tübingen, Baden-Wurttemberg, Germany, 72076
        • Recruiting
        • Center for Neurology & Hertie-Institute for Clinical Brain Research, Dept. for Neurodegenerative Diseases
        • Contact:
        • Contact:
        • Principal Investigator:
          • Matthis Synofzik, Prof. Dr.
        • Principal Investigator:
          • Andreas Traschütz, Dr. Dr.
    • North Rhine-Westphalia
      • Bonn, North Rhine-Westphalia, Germany, 53127
        • Recruiting
        • German Center for Neurodegenerative Diseases (DZNE)
        • Contact:
        • Principal Investigator:
          • Jennifer Faber, Dr.
        • Sub-Investigator:
          • Thomas Klockgether, Prof. Dr.
    • Schleswig-Holstein
      • Lübeck, Schleswig-Holstein, Germany, 23562
        • Recruiting
        • Department of Neurology University Hospital Schleswig Holstein
        • Contact:
        • Principal Investigator:
          • Norbert Brüggemann, Prof. Dr.
        • Sub-Investigator:
          • Max Borsche, Dr.
  • Italy
      • Pisa, Italy, 56128
        • Recruiting
        • IRCCS Fondazione Stella Maris
        • Principal Investigator:
          • Filippo M. Santorelli, MD
        • Contact:
        • Contact:
    • Napoli
      • Naples, Napoli, Italy, 80131
        • Recruiting
        • Università degli Studi di Napoli 'Federico II', c/o AOU Federico II
        • Contact:
        • Principal Investigator:
          • Francesco Saccà, Prof.
        • Sub-Investigator:
          • Chiara Pane, Dr.
  • New Zealand
      • Auckland, New Zealand, 1142
        • Recruiting
        • Centre of Brain Research Neurogenetics Research Clinic, University of Auckland
        • Contact:
        • Principal Investigator:
          • Richard Roxburgh, Prof.
  • Turkey (Türkiye)
      • Istanbul, Turkey (Türkiye), 34010
        • Recruiting
        • Koç University Hospital, KUTTAM-NDAL
        • Principal Investigator:
          • Nazli BAŞAK, PhD
        • Contact:
        • Contact:
        • Principal Investigator:
          • Atay Vural, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
RFC1
Participants with genetically confirmed RFC1 repeat expansion disease (ORPHA: 504476; OMIM 102579) will be recruited. Target sample size for the RFC1 cohort is 100 participants.
Other: Clinical rating scale to measure ataxia disease severity and progression
SARA is a clinical scale developed by Schmitz-Hübsch et al which assesses a range of different impairments in cerebellar ataxia. The scale is made up of 8 items related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements and heel-shin test.
Other Names:
  • Scale for the Assessment and rating of Ataxia (SARA)
Unrelated healthy controls
Unrelated healthy controls Healthy controls may undergo the same study procedures as the RFC1 cohort. Target sample size for the control cohort is 50.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of Scale for the Assessment and Rating of Ataxia (SARA) from baseline to 2-year follow-up.
Time Frame: 24 months
Severity of ataxia in the RFC1 cohort will be assessed by application of the Scale for the Assessment and Rating of Ataxia (SARA). The total score is calculated as the sum of 8 items, yielding a total score between 0 and 40. Hereby, higher SARA scores indicate more severe disease.
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Friedreich Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) from baseline to 2-year follow-up.
Time Frame: 24 months
Impairment in activities of daily living by ataxia, neuropathy, vestibular impairment or other disease features will be assessed in the RFC1 cohort by application of the Activities of Daily Living part of the Friedreich Ataxia Rating Scale (FARS-ADL). The total score is calculated as the sum of 9 items, yielding a total score between 0 and 36. Hereby, higher FARS-ADL scores indicate more severe functional impairment.
24 months
Charcot-Marie-Tooth Examination Score Version 2 (CMTESv2) from baseline to 2-year follow-up.
Time Frame: 24 months
Severity of neuropathy in the RFC1 cohort will be assessed by application of the Charcot-Marie-Tooth Examination Score Version 2 (CMTESv2). The total score is calculated as the sum of 7 items, yielding a total score between 0 and 28. Hereby, higher CMTESv2 scores indicate more severe neuropathy.
24 months
Nine-Hole Peg Test (9HPT) from baseline to 2-year follow-up.
Time Frame: 24 months
Upper limb function in the RFC1 cohort will be quantified by application of the Nine-Hole Peg Test (9HPT). This performance measure yields the mean duration of 2 trials to complete the task with the dominant and non-dominant hand, respectively, with an upper limit of 5 minutes (300 seconds).
24 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Composite Autonomic Symptom Score (COMPASS-31) at baseline, and eventually from baseline to 2-year follow-up if baseline data supports further use.
Time Frame: 24 months
Severity of dysautonomia will be assessed by application of the Composite Autonomic Symptom Score (COMPASS-31). The total score is calculated as the weighted sum of 31 questions items, yielding a total autonomic symptom score between 0 and 100. Hereby, higher COMPASS-31 cores indicate more severe dysautonomia. This module is optional in the RFC1 cohort and unrelated healthy controls.
24 months
Cerebellar cognitive-affective syndrome scale (CCAS) from baseline to 2-year follow-up.
Time Frame: 24 months
Severity of cognitive impairment will be assessed by application of the Cerebellar cognitive-affective syndrome scale (CCAS). The total score of 15 items comprises the number of failed items (with 3 or more failed items indicating definite cerebellar cognitive-affective syndrome), and a raw total score between 0 and 120. Hereby, lower CCAS raw cores indicate more severe cognitive impairment. This module is optional in the RFC1 cohort and unrelated healthy controls.
24 months
Clinical Assessment of Dysphagia in Neurodegeneration (CADN) from baseline to 2-year follow-up.
Time Frame: 24 months
Severity of dysphagia will be assessed by application of the Clinical Assessment of Dysphagia in Neurodegeneration (CADN), comprising a history part and an examination with consumption. The total score is calculated as the weighted sum of 11 items, yielding a total score between 0 and 10. Hereby, higher CADN scores indicate more severe dysphagia. This module is optional in the RFC1 cohort.
24 months
Video Head Impulse Test (vHIT) from baseline to 2-year follow-up.
Time Frame: 24 months
Vestibular function will be quantified by application of the Video Head Impulse Test (vHIT) of the horizontal semicircular canals, and eventually the vertical semicircular canals. This test yields the gain (ratio of eye velocity to head velocity) as a measure of vestibular function, yielding total scores between 0 and 1. Hereby, lower gains indicate more severe vestibular impairment. This module is optional in the RFC1 cohort and unrelated healthy controls.
24 months
Digital gait and balance assessment from baseline to 2-year follow-up.
Time Frame: 24 months
Gait and balance will be assessed digitally with body-worn sensors (inertial measurement units), which record acceleration or rotational movements during specific gait and balance tasks. This module is optional in the RFC1 cohort and unrelated healthy controls.
24 months
Digital assessment of limb function from baseline to 2-year follow-up.
Time Frame: 24 months
Motor skills of the upper and lower limb will we assessed digitally with a quantitative motor examination (Q-Motor), which measures contact pressure and position in space during specific motor tasks. This module is optional in the RFC1 cohort and unrelated healthy controls.
24 months
Digital Speech Assessment from baseline to 2-year follow-up.
Time Frame: 24 months
Dysarthria will be assessed using Redenlab audio capture and analysis software. Speakers will complete connected speech, syllable repetition and sustained vowel tasks. Data will be analyzed for measures of voice quality, articulation, breath support, resonance, and prosody. This module is optional in the RFC1 cohort and unrelated healthy controls.
24 months
Magnetic resonance imaging (MRI) from baseline to 2-year follow-up.
Time Frame: 24 months
Structural integrity of the brain and cervical spine will be assessed by application of Magnetic Resonance Imaging (MRI), with a core dataset of T1-weighted, T2-weighted, and diffusion-weighted imaging sequences. This module is optional in the RFC1 cohort and unrelated healthy controls.
24 months
Patient-reported outcomes of chronic cough from baseline to 2-year follow-up.
Time Frame: 24 months
The presence and severity of chronic cough will be assessed with the Cough Severity Visual Analogue Scale and the Leicester Cough Questionnaire as validated patient-reported outcomes and trial endpoints of chronic cough.
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Prof. Dr. Matthis Synofzik

Investigators

  • Principal Investigator: Matthis Synofzik, Prof. Dr., University Hospital Tübingen
  • Principal Investigator: Andreas Traschütz, Dr. Dr., University Hospital Tübingen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 14, 2021

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

December 14, 2021

First Submitted That Met QC Criteria

December 14, 2021

First Posted (Actual)

January 5, 2022

Study Record Updates

Last Update Posted (Actual)

March 31, 2026

Last Update Submitted That Met QC Criteria

March 30, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RFC1-NHS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Ataxia

Clinical Trials on Clinical rating scale to measure ataxia disease severity and progression

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Croatia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe