RFC1 Natural History Study

Ataxia Clinical Trial

— RFC1-NHS  

Official title:

RFC1 Natural History Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05177809
• Other study ID #: RFC1-NHS
• Status: Recruiting
• Start date: December 14, 2021
• Est. completion date: December 2025

Study information

• Verified date: June 2024
• Source: University Hospital Tuebingen
• Contact: Matthis Synofzik, Prof. Dr.
• Phone: +49 7071 29
• Email: matthis.synofzik[@]uni-tuebingen.de
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: December 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Ataxia

Intervention

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.

Locations

Country	Name	City	State
Australia	Department of Neuroscience, Central Clinical School, Monash University	Melbourne	Victoria
Brazil	Department of Neurology, Ataxia Unit, Universidade Federal de São Paulo	São Paulo	State Of São Paulo
France	Service de Neurologie, Hôpitaux Universitaires de Strasbourg	Strasbourg
Germany	German Center for Neurodegenerative Diseases (DZNE)	Bonn	Nordrhein-Westfalen
Germany	Department of Neurology University Hospital Schleswig Holstein	Lübeck	Schleswig-Holstein
Germany	Center for Neurology & Hertie-Institute for Clinical Brain Research, Dept. for Neurodegenerative Diseases	Tübingen	Baden-Württemberg
Italy	Università degli Studi di Napoli 'Federico II', c/o AOU Federico II	Napoli
Italy	IRCCS Fondazione Stella Maris	Pisa
New Zealand	Centre of Brain Research Neurogenetics Research Clinic, University of Auckland	Auckland
Turkey	Koç University Hospital, KUTTAM-NDAL	Istanbul

Sponsors (1)

Lead Sponsor	Collaborator
Prof. Dr. Matthis Synofzik

Countries where clinical trial is conducted

Australia,  Brazil,  France,  Germany,  Italy,  New Zealand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Composite Autonomic Symptom Score (COMPASS-31) at baseline, and eventually from baseline to 2-year follow-up if baseline data supports further use.	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
Other	Cerebellar cognitive-affective syndrome scale (CCAS) from baseline to 2-year follow-up.	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
Other	Clinical Assessment of Dysphagia in Neurodegeneration (CADN) from baseline to 2-year follow-up.	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
Other	Video Head Impulse Test (vHIT) from baseline to 2-year follow-up.	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
Other	Digital gait and balance assessment from baseline to 2-year follow-up.	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
Other	Digital assessment of limb function from baseline to 2-year follow-up.	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
Other	Digital Speech Assessment from baseline to 2-year follow-up.	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
Other	Magnetic resonance imaging (MRI) from baseline to 2-year follow-up.	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
Other	Patient-reported outcomes of chronic cough from baseline to 2-year follow-up.	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
Primary	Change of Scale for the Assessment and Rating of Ataxia (SARA) from baseline to 2-year follow-up.	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	Friedreich Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) from baseline to 2-year follow-up.	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
Secondary	Charcot-Marie-Tooth Examination Score Version 2 (CMTESv2) from baseline to 2-year follow-up.	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
Secondary	Nine-Hole Peg Test (9HPT) from baseline to 2-year follow-up.	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

External Links

•   Website of the ARCA Registry