A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. ClinicalTrails.gov Identifier: NCT04349514.

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Copyright: © 2022 Georgiou-Karistianis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Déclaration de conflit d'intérêts

I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.E. and S.Z. are employed by Takeda Pharmaceutical Company Ltd with both authors receiving salary and S.Z. holds stocks in the company. A.S. was employed by Takeda Pharmaceutical Company Ltd at the time of his contribution to the TRACK-FA project. Takeda Pharmaceutical Company Ltd remains committed to FRDA research and will help develop translational tools to monitor patient disease and share with the FRDA community. T.S. and B.Y. are both employees of PTC Therapeutics. D.L. is a grant recipient from the National Institute of Health (NIH), Muscular Dystrophy Association (MDA), Friedreich’s Ataxia Research Alliance (FARA), Reata Pharmaceuticals Inc, Retrotope Inc, Voyager Therapeutics, Novartis Gene Therapies, Audentes Therapeutics (Astellas Gene Therapies) and Minoryx Therapeutics S.L. T.P.L.R. has equity interest in PRISM Clinical Imaging and Proteus Neurodynamics and consulting/advisory board engagement with CTF MEG International Services LP, Ricoh Company Ltd, Spago Nanomedical AB, Avexis (Novartis Gene Therapies) and Acadia Pharmaceuticals Inc. P.G.H. is a grant recipient from the Friedreich’s Ataxia Research Alliance (FARA), GoFAR, Ataxia UK, the Bob Allison Ataxia Research Centre, and the National Institute of Health (NIH). CMRR is supported by NIH grants P41EB027061 and P30NS076408. P.G.H. reports grants from Minoryx Therapeutics for activities outside this study. M.P. and R.J. and M.L. are employed by IXICO plc, ML is a shareholder for IXICO plc. M.C.F. is a grant recipient from PTC Therapeutics and has taken part in advisory board for PTC Therapeutics and Avexis (Novartis Gene Therapies). T.R. is a grant recipient from the Friedreich’s Ataxia Research Alliance (FARA). C.L. is a research grant recipient from the Friedreich’s Ataxia Research Alliance (FARA), GoFAR, Ataxia UK, the Bob Allison Ataxia Research Center, and National Institute of Health (NIH) grants P41. EB027061 and P30 NS076408. C.L. reports research grants from Minoryx Therapeutics and Biogen Inc. for activities outside this study. S.S. is a broad member of the Research Advisory Board for National Ataxia Foundation (USA), a research grant recipient from the Friedreich’s Ataxia Research Alliance (FARA), Wyck Foundation, National Ataxia Foundation, Muscular Dystrophy Association (MDA), National Institute of Health (NIH), FDA and receives industry support from Reata Pharmaceutical Inc, Retrotope Inc, PTC Therapeutics, Biohaven Pharmaceuticals, Avidity Biosciences Inc, and Strides Pharma Science Limited. M.L.K. holds shares in Novartis Gene Therapies. K.R. has received grants from the German Federal Ministry of Education and Research (BMBF 01GQ1402, 01DN18022), the German Research Foundation (IRTG 2150, ZUK32/1), Alzheimer Forschung Initiative e.V. (AFI 13812, NL-18002CB) and honoraria for presentations or advisory boards from Biogen and Roche. J.F. is employed by the Friedreich’s Ataxia Research Alliance (FARA) and receives a salary from this institution. L.C. is a research grant recipient from the Friedreich Ataxia Research Alliance (FARA), Ataxia UK, Medical Research Future Fund and is funded by a Medical Research Futures Fund Next Generation Career Development Fellowship.