A Natural History Study to TRACK Brain and Spinal Cord Changes in Individuals With Friedreich Ataxia (TRACK-FA)

Friedreich Ataxia Clinical Trial

— (TRACK-FA)  

Official title:

A Natural History Study to TRACK Brain and Spinal Cord Changes in Individuals With Friedreich Ataxia (TRACK-FA)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04349514
• Other study ID #: TRACK-FA
• Status: Active, not recruiting
• Start date: February 10, 2021
• Est. completion date: August 2025

Study information

• Verified date: January 2024
• Source: Monash University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This is a natural history study prospectively investigating neuroimaging markers of disease progression in children and adults with Friedreich ataxia (FA). There will be three assessment periods (baseline, 12 and 24 months). The study will include approximately 200 individuals with FA and 100 matched controls recruited across the six international academic sites. Other assessments will include secondary clinical and cognitive markers, as well as exploratory blood markers.

Description:

Friedreich ataxia (FA) is a multi-system progressive disorder with the most prevalent and prominent symptoms relating to dysfunction in the central and peripheral nervous system, including, loss of balance and coordination, frequent falls, loss of ambulation, dysarthria, dysphagia and loss of vision and hearing. Other symptoms include cardiomyopathy, diabetes, scoliosis and fatigue. Age of onset can vary but most often presents during childhood, ages 5-15 years.

There is currently no cure and no disease-modifying treatment. Drug candidates to potentially treat FA are under development; however, there is a lack of well- characterized neuroimaging biomarkers for testing their efficacy in clinical trials, hampering this process. Establishing disease-specific neuroimaging biomarkers to track disease progression requires high-quality longitudinal data from large cohorts of patients, compared to controls. In rare diseases, such as FA, this can only be achieved through multi-site collaboration.

The aim of TRACK-FA is to develop an FA neuroimaging dataset from brain and spinal cord that is suitable for assessing the potential value of neuroimaging biomarkers and providing a basis for instituting them in clinical trials. The dataset will comprise a range of neuroimaging measures to assess changes in spinal cord and brain regions that have previously shown to be compromised in individuals with FA. In addition to neuroimaging measures, TRACK-FA will also include clinical, cognitive data and biospecimen data. The TRACK-FA dataset will provide a unique opportunity for academic researchers in collaboration with industry partners to access the images, subsidiary data, and associated clinical data for community research.

This multi-centre study is a collaborative effort across six academic institutions, together with industry partners and the Friedreich's Ataxia Research Alliance USA (FARA).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 300
• Est. completion date: August 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 5 Years and older

Eligibility

Inclusion Criteria:

• Age = 5 years

• Written informed consent provided

• Individuals with FA must have a genetic confirmation of diagnosis and be biallelic for a GAA repeat length > 55 in intron 1 of FXN and/or have a GAA repeat length > 55 in intron 1 of FXN in one allele and another type of mutation that is inferred to cause loss of function in the second FXN allele

• Individuals with FA must have an age of disease onset = 25 years

• Individuals with FA must have a disease duration = 25 years

• Individuals with FA must have a Friedreich Ataxia Rating Scale (FARS) Functional staging score of = 5 and total modified FARS (mFARS) score of = 65 on enrolment

Exclusion Criteria:

• Age < 5 years

• Unable to provide written informed consent

• Magnetic resonance contraindications (e.g. pacemaker or other metallic surgical implants)

• Presence of metallic dental braces

• Pregnancy (ascertained via a question or test as mandated at particular sites)

• Individuals with FA must not have acute or ongoing medical or other conditions that, after discussion between the Site Investigator and steering committee, is deemed to interfere with the conduct and assessments of the study

• Individuals with FA must not have another neurological condition apart from FA

• Individuals with FA must not have other neurologic conditions that, in the opinion of the Site Investigator, would interfere with the conduct and assessments of the study

• Controls must not have a diagnosed psychiatric or neurological condition

• Controls must not have acute or ongoing medical or other conditions that would interfere with the conduct and assessments of the study

• Controls must not be siblings of individuals with FA whose carrier status (i.e., confirmed carrier, confirmed non-carrier, or obligate carrier) is unknown.

Related Conditions & MeSH terms

• Ataxia
• Cerebellar Ataxia
• Friedreich Ataxia

Intervention

Other:
• Natural history
Longitudinal observation of neuroimaging, clinical, and blood markers.

Locations

Country	Name	City	State
Australia	Monash Biomedical Imaging, Monash University	Clayton	Victoria
Brazil	Lab of Neuroimaging and Dept of Neurology, University of Campinas (UNICAMP)	São Paulo
Canada	McGill University	Montréal	Quebec
Germany	Department of Neurology, RWTH Aachen University	Aachen
United States	University of Florida	Gainesville	Florida
United States	Center for Magnetic Resonance Research, University of Minnesota	Minneapolis	Minnesota
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (8)

Lead Sponsor	Collaborator
Monash University	Children's Hospital of Philadelphia, Friedreich's Ataxia Research Alliance, McGill University, RWTH Aachen University, University of Campinas, Brazil, University of Florida, University of Minnesota

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serum neurofilament light chain (NfL) level	Neurofilament light chain (NfL) is a peripherally-accessible blood biomarker of neuroaxonal destruction in various neurodegenerative diseases. It has been shown for several such diseases that blood NfL might serve as a progression biomarker as well as a treatment response biomarker. Blood samples will be collected at each of the three study visits, stored locally, and shipped to a central location for analysis of NfL levels.	Baseline to 24 months
Other	Frataxin protein level	Levels of frataxin protein in lymphocyte and serum will be measured. Frataxin is produced at reduced levels in FA as a consequence of the guanine-adenine-adenine (GAA) repeat expansion in the frataxin gene (FXN) on chromosome 9. Blood samples will be collected at each of the three study visits, stored locally, and shipped to a central location for analysis of frataxin levels.	Baseline to 24 months
Primary	Baseline dentate nuclei magnetic susceptibility	Magnetic susceptibility of the dentate nuclei will be measured using T2*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. Baseline dentate nuclei susceptibility will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in dentate nuclei magnetic susceptibility	Magnetic susceptibility of the dentate nuclei will be measured using T2*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. The within-person slope of dentate nuclei susceptibility over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline dentate volume	Volume of the dentate nuclei will be measured using T2*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. Baseline dentate nuclei volume will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in dentate volume	Volume of the dentate nuclei will be measured using T2*-weighted multiecho magnetic resonance imaging and quantitative susceptibility mapping processing. The within-person slope of dentate nuclei volume over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline total cerebellar volume	Total volume of the cerebellum will be measured using T1- and T2-weighted magnetic resonance imaging. Baseline total cerebellar volume will be compared between the Friedreich ataxia and control groups.	Baseline
Primary	Slope of change in total cerebellar volume	Total volume of the cerebellum will be measured using T1- and T2-weighted magnetic resonance imaging. The within-person slope of total cerebellar volume over the three study visits will be estimated and compared between the Friedreich ataxia and control groups.	Baseline to 24 months
Primary	Baseline superior cerebellar peduncle volume	Volume of the superior cerebellar peduncles will be measured using T1- and T2-weighted magnetic resonance imaging. Baseline superior cerebellar peduncle volume will be compared between the Friedreich ataxia and control groups.	Baseline
Primary	Slope of change in superior cerebellar peduncle volume	Volume of the superior cerebellar peduncles will be measured using T1- and T2-weighted magnetic resonance imaging. The within-person slope of superior cerebellar peduncle volume over the three study visits will be estimated and compared between the Friedreich ataxia and control groups.	Baseline to 24 months
Primary	Baseline superior cerebellar peduncle fractional anisotropy	Fractional anisotropy of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle fractional anisotropy will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in superior cerebellar peduncle fractional anisotropy	Fractional anisotropy of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle fractional anisotropy over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline superior cerebellar peduncle mean diffusivity	Mean diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle mean diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in superior cerebellar peduncle mean diffusivity	Mean diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle mean diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline superior cerebellar peduncle radial diffusivity	Radial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle radial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in superior cerebellar peduncle radial diffusivity	Radial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle radial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline superior cerebellar peduncle axial diffusivity	Axial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. Baseline superior cerebellar peduncle axial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in superior cerebellar peduncle axial diffusivity	Axial diffusivity of the superior cerebellar peduncles will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of superior cerebellar peduncle axial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline cervical spinal cord cross-sectional area	Cross-sectional area of the cervical portion of the spinal cord will be measured using T2-weighted magnetic resonance imaging. Baseline cervical spinal cord cross-sectional area will be compared between the Friedreich ataxia and control groups.	Baseline
Primary	Slope of change in cervical spinal cord cross-sectional area	Cross-sectional area of the cervical portion of the spinal cord will be measured using T2-weighted magnetic resonance imaging. The within-person slope of cervical spinal cord cross-sectional area over the three study visits will be estimated and compared between the Friedreich ataxia and control groups.	Baseline to 24 months
Primary	Baseline cervical spinal cord fractional anisotropy	Fractional anisotropy of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord fractional anisotropy will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in cervical spinal cord fractional anisotropy	Fractional anisotropy of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord fractional anisotropy over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline cervical spinal cord mean diffusivity	Mean diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord mean diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in cervical spinal cord mean diffusivity	Mean diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord mean diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline cervical spinal cord radial diffusivity	Radial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord radial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in cervical spinal cord radial diffusivity	Radial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord radial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline cervical spinal cord axial diffusivity	Axial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. Baseline cervical spinal cord axial diffusivity will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of change in cervical spinal cord axial diffusivity	Axial diffusivity of the cervical portion of the spinal cord will be measured using diffusion tensor magnetic resonance imaging. The within-person slope of cervical spinal cord axial diffusivity over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Primary	Baseline cervical spine tNAA/mIns ratio	The ratio of N-acetylaspartate (tNAA) and myo-inositol (mIns) within cervical spinal cord will be measured using sLASER magnetic resonance spectroscopy. The baseline tNAA/mIns ratio will be compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline
Primary	Slope of the cervical spine tNAA/mIns ratio	The ratio of N-acetylaspartate (tNAA) and myo-inositol (mIns) within cervical spinal cord will be measured using sLASER magnetic resonance spectroscopy. The within-person slope of the tNAA/mIns ratio over the three study visits will be estimated and compared between the Friedreich ataxia and control groups. This measurement will be obtained for participants aged 11 years and over.	Baseline to 24 months
Secondary	Modified Friedreich Ataxia Rating Scale (mFARS) score	The modified Friedreich Ataxia Rating Scale (mFARS) is a neurological rating scale comprising four subscales (bulbar, upper limb coordination, lower limb coordination, and upright stability). The total score ranges from 0 to 93, with a higher score reflecting greater neurological severity. This assessment will be administered to participants with FA only.	Baseline to 24 months
Secondary	Upright Stability (US) score	The Upright Stability (US) assessment is part of the neurological examination within the Modified Friedreich Ataxia Rating Scale (mFARS). This component comprises nine items: sitting position, stance with feet apart, stance with feet apart and eyes closed, stance with feet together, stance with feet together and eyes closed, tandem stance, stance with dominant foot, tandem walk, and gait. The score ranges from 0 to 9, with a higher score reflecting poorer upright stability (i.e., greater neurological severity). This assessment will be administered to participants with FA only.	Baseline to 24 months
Secondary	Activities of Daily Living (ADL) score	Activities of Daily Living (ADL) is a component of the Friedreich Ataxia Rating Scale (FARS), a clinical rating scale developed for FA. The ADL score aims to quantify essential and routine aspects of self-care, often reported on by a family member or caregiver of a person with FA. The ADL comprises 9 items: speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function. The score ranges from 0 to 36, with a higher score reflecting greater difficulty completing activities of daily living independently. This assessment will be administered to participants with FA only.	Baseline to 24 months
Secondary	Scale for the Assessment and Rating of Ataxia (SARA) score	The SARA is a semi-quantitative assessment of ataxia, measuring ataxia of upper limb, lower limb, gait, balance and speech. It has eight items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movement, and heel-shin slide. The total score ranges from 0 (no ataxia) to 40 (severe ataxia). This assessment will be administered to participants with FA only.	Baseline to 24 months
Secondary	9 Hole Peg Test times	The 9 Hole Peg Test (9HPT) examines finger dexterity and involves placing and removing nine pegs in a pegboard in the quickest possible time. Two consecutive trials of the dominant hand, followed immediately by two consecutive trials of the non-dominant hand, are undertaken. The average time taken to complete the task, for each of the dominant and non-dominant hand, is calculated. The 9HPT has high intra- and inter-rater reliability and is the most commonly used measure of upper limb function in FA. This assessment will be administered to participants with FA only.	Baseline to 24 months
Secondary	Speech analysis scores	A battery of speech evaluations will be administered and recorded on a laptop for analysis, using Redenlab software. This will include: reading of a phonetically-balanced passage, sustained vowel sound, listing days of the week, repeating syllables, and a monologue task. This will form a measure of dysarthria. Redenlab is a US-Australian speech-testing company, https://redenlab.com. This assessment will be administered to participants with FA and controls.	Baseline to 24 months
Secondary	Low-Contrast Sloan Letter Chart (LCSLC) test score	Contrast letter acuity for vision will be assessed using back-lit Low-Contrast Sloan Letter Charts (LCSLCs). Participants will sit at an eye distance of 2 metres from the chart. Binocular vision will be assessed using participants' normal corrective lenses where relevant. Participants are required to read each letter on the chart. Three charts will be presented, with three different visual contrast levels: 100% (equivalent to high-contrast visual acuity), 2.5%, and 1.25%. The maximum total score across the three charts (number of letters read correctly) is 240. Scores for each individual chart will also be recorded. This assessment will be administered to participants with FA only.	Baseline to 24 months
Secondary	Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) scale score	The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) Scale is a 10-item screening measure assessing attention and concentration, executive functioning, memory, language, visuospatial functioning, abstract thinking, and neuropsychiatric features. Each item has an associated raw score and pass/fail evaluation. The total raw score (maximum 120) and the total number of "failed" items (maximum 10) will be recorded. This scale is to be administered to participants who are aged 18 years and over. This assessment will be administered to participants with FA and controls.	Baseline to 24 months
Secondary	Hayling Sentence Completion Test (HSCT) scores	The Hayling Sentence Completion Test (HSCT) is an orally-administered test measuring response initiation and response suppression. In the first section, participants are asked to complete a series of incomplete sentences with a sensible word. In the second section, participants are asked to supply an unrelated word to complete each sentence. Scaled scores for total response latency in each section, a scaled score for errors in the second section, and an overall scale score are calculated. This test is to be administered to participants who are aged 18 years and over. This assessment will be administered to participants with FA and controls.	Baseline to 24 months
Secondary	Hospital Anxiety and Depression Scale (HADS) scores	The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-assessment scale designed to screen for states of depression and anxiety and measure the severity of these states. It contains a 7-item subscale for each of Anxiety (HADS-A) and Depression (HADS-D). Possible scores for each of the HADS-Anxiety and HADS-Depression scales range from 0 to 21. Higher scores indicate more severe anxiety and depression. This scale is be administered to participants who are aged 18 year and over. This assessment will be administered to participants with FA and controls.	Baseline to 24 months
Secondary	Junior Hayling Sentence Completion Test (Junior HSCT) scores	The Junior Hayling Sentence Completion Test (Junior HSCT) is an orally-administered measure of response initiation and response suppression in children. To be administered to participants who are aged at least 8 years but less than 18 years. This assessment will be administered to participants with FA and controls.	Baseline to 24 months
Secondary	Paediatric Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) scale score	The Paediatric Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) scale is an assessment of the executive, visual-spatial and linguistic components of cognitive control and affect in children. Currently under development. To be incorporated as a secondary outcome measure if available at the time of study commencement. To be administered to participants who are aged at least 8 years but less than 18 years. This assessment will be administered to participants with FA and controls.	Baseline to 24 months
Secondary	Revised Children's Anxiety and Depression scale (RCADS) scores	The Revised Child Anxiety and Depression Scale (RCADS) is a 47-item, self-report questionnaire six subscales: separation anxiety disorder, social phobia, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and major depressive disorder. It also yields a Total Anxiety Scale and a Total Internalizing Scale. A higher score indicates a higher level of the given disorder/syndrome. This scale is to be administered to participants who are aged at least 8 years but less than 18 years. This assessment will be administered to participants with FA and controls.	Baseline to 24 months