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

PLoS One. 2022 Nov 21;17(11):e0269649. doi: 10.1371/journal.pone.0269649. eCollection 2022.

Abstract

Introduction: 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.

Methods: 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.

Discussion: 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.

Clinical trial registration: ClinicalTrails.gov Identifier: NCT04349514.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers
  • Brain / pathology
  • Disease Progression
  • Friedreich Ataxia* / pathology
  • Humans
  • Magnetic Resonance Spectroscopy

Substances

  • Biomarkers

Associated data

  • ClinicalTrials.gov/NCT04349514

Grants and funding

This study is funded by grants from the Friedreich’s Ataxia Research Alliance (FARA) to each of the academic sites and IXICO plc with financial support from Takeda Pharmaceuticals Company Ltd, Novartis Gene Therapies, IXICO plc and PTC Therapeutics. The Friedreich Ataxia Research Alliance does not use grant numbers. The sponsor of the study is Monash University The study sites and the site principle Investigators (main authors who received funding) are detailed below. Monash University (N.G.K) University of Minnesota (P.G.H) Children’s Hospital of Philadelphia (D.L) University of Florida (S.S) RWTH Aachen University (K.R) University of Campinas (M.C.F) McGill University (M.P) Funding bodies Friedreich's Ataxia Research Alliance (FARA): https://www.curefa.org/ IXICO plc: https://ixico.com/ Novartis Gene Therapies: https://www.novartis.com/about/innovative-medicines/novartis-pharmaceuticals Takeda Pharmaceuticals company Ltd: https://www.takeda.com/en-au/ PTC Therapeutics:https://www.ptcbio.com/ FARA plays an ongoing role in study oversight, study design, decision to publish and author J.F who is J.F. is employed by the Friedreich’s Ataxia Research Alliance (FARA) played a role in the preparation of the manuscript. Takeda Pharmaceuticals Company Ltd plays an ongoing role in study oversight, study design, decision to publish and authors R.E. and S.Z are employees of Takeda Pharmaceuticals Company Ltd and played a role in preparation of the manuscript. Additionally former employee of Takeda Pharmaceuticals A.S. also contributed to the preparation of the manuscript. PTC Therapeutics plays an ongoing role in study oversight, study design, decision to publish and authors T.S. and B.Y. who are employees of PTC Therapeutics contributed to the preparation of the manuscript. Novartis Gene Therapies plays an ongoing role in study oversight, study design, decision to publish and authors M.L.K who holds shares in Novartis Gene Therapies as indicated in the conflicts on interest played a role in the preparation of the manuscript. IXICO plc plays an ongoing role in study oversight, study design, decision to publish will perform independent quality control and data analysis of brain anatomical imaging and brain diffusion imaging data for one third of TRACK-FA participants. Authors M.L, R.J and M.P are employees of IXICO and contributed to the preparation of the manuscript.