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

Overview

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.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: August 2025

Detailed 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).

Interventions

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

Arms, Groups and Cohorts

  • Friedreich ataxia
    • Individuals with a diagnosis of Friedreich ataxia.
  • Control
    • Individuals without a diagnosis of Friedreich ataxia.

Clinical Trial Outcome Measures

Primary Measures

  • Baseline dentate nuclei magnetic susceptibility
    • Time Frame: Baseline
    • 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.
  • Slope of change in dentate nuclei magnetic susceptibility
    • Time Frame: Baseline to 24 months
    • 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 dentate volume
    • Time Frame: Baseline
    • 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.
  • Slope of change in dentate volume
    • Time Frame: Baseline to 24 months
    • 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 total cerebellar volume
    • Time Frame: Baseline
    • 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.
  • Slope of change in total cerebellar volume
    • Time Frame: Baseline to 24 months
    • 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 superior cerebellar peduncle volume
    • Time Frame: Baseline
    • 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.
  • Slope of change in superior cerebellar peduncle volume
    • Time Frame: Baseline to 24 months
    • 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 superior cerebellar peduncle fractional anisotropy
    • Time Frame: Baseline
    • 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.
  • Slope of change in superior cerebellar peduncle fractional anisotropy
    • Time Frame: Baseline to 24 months
    • 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 superior cerebellar peduncle mean diffusivity
    • Time Frame: Baseline
    • 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.
  • Slope of change in superior cerebellar peduncle mean diffusivity
    • Time Frame: Baseline to 24 months
    • 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 superior cerebellar peduncle radial diffusivity
    • Time Frame: Baseline
    • 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.
  • Slope of change in superior cerebellar peduncle radial diffusivity
    • Time Frame: Baseline to 24 months
    • 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 superior cerebellar peduncle axial diffusivity
    • Time Frame: Baseline
    • 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.
  • Slope of change in superior cerebellar peduncle axial diffusivity
    • Time Frame: Baseline to 24 months
    • 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 cervical spinal cord cross-sectional area
    • Time Frame: Baseline
    • 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.
  • Slope of change in cervical spinal cord cross-sectional area
    • Time Frame: Baseline to 24 months
    • 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 cervical spinal cord fractional anisotropy
    • Time Frame: Baseline
    • 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.
  • Slope of change in cervical spinal cord fractional anisotropy
    • Time Frame: Baseline to 24 months
    • 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 cervical spinal cord mean diffusivity
    • Time Frame: Baseline
    • 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.
  • Slope of change in cervical spinal cord mean diffusivity
    • Time Frame: Baseline to 24 months
    • 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 cervical spinal cord radial diffusivity
    • Time Frame: Baseline
    • 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.
  • Slope of change in cervical spinal cord radial diffusivity
    • Time Frame: Baseline to 24 months
    • 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 cervical spinal cord axial diffusivity
    • Time Frame: Baseline
    • 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.
  • Slope of change in cervical spinal cord axial diffusivity
    • Time Frame: Baseline to 24 months
    • 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 cervical spine tNAA/mIns ratio
    • Time Frame: Baseline
    • 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.
  • Slope of the cervical spine tNAA/mIns ratio
    • Time Frame: Baseline to 24 months
    • 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.

Secondary Measures

  • Modified Friedreich Ataxia Rating Scale (mFARS) score
    • Time Frame: Baseline to 24 months
    • 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.
  • Upright Stability (US) score
    • Time Frame: Baseline to 24 months
    • 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.
  • Activities of Daily Living (ADL) score
    • Time Frame: Baseline to 24 months
    • 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.
  • Scale for the Assessment and Rating of Ataxia (SARA) score
    • Time Frame: Baseline to 24 months
    • 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.
  • 9 Hole Peg Test times
    • Time Frame: Baseline to 24 months
    • 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.
  • Speech analysis scores
    • Time Frame: Baseline to 24 months
    • 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.
  • Low-Contrast Sloan Letter Chart (LCSLC) test score
    • Time Frame: Baseline to 24 months
    • 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.
  • Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) scale score
    • Time Frame: Baseline to 24 months
    • 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.
  • Hayling Sentence Completion Test (HSCT) scores
    • Time Frame: Baseline to 24 months
    • 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.
  • Hospital Anxiety and Depression Scale (HADS) scores
    • Time Frame: Baseline to 24 months
    • 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.
  • Junior Hayling Sentence Completion Test (Junior HSCT) scores
    • Time Frame: Baseline to 24 months
    • 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.
  • Paediatric Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) scale score
    • Time Frame: Baseline to 24 months
    • 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.
  • Revised Children’s Anxiety and Depression scale (RCADS) scores
    • Time Frame: Baseline to 24 months
    • 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.

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 5 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Monash University
  • Collaborator
    • University of Minnesota
  • Provider of Information About this Clinical Study
    • Principal Investigator: Nellie Georgiou-Karistianis, Professor Nellie Georgiou-Karistianis – Monash University
  • Overall Official(s)
    • Nellie Georgiou-Karistianis, PhD, Principal Investigator, Monash University

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