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

Nellie Georgiou-Karistianis; Louise A. Corben; Kathrin Reetz; Isaac M. Adanyeguh; Manuela Corti; Dinesh K. Deelchand; Martin B. Delatycki; Imis Dogan; Rebecca Evans; Jennifer Farmer; Marcondes C. França; William Gaetz; Ian H. Harding; Karen S. Harris; Steven Hersch; Richard Joules; James J. Joers; Michelle L. Krishnan; Michelle Lax; Eric F. Lock; David Lynch; Thomas Mareci; Sahan Muthuhetti Gamage; Massimo Pandolfo; Marina Papoutsi; Thiago J.R. Rezende; Timothy P.L. Roberts; Jens T. Rosenberg; Sandro Romanzetti; Jörg B. Schulz; Traci Schilling; Adam J. Schwarz; Sub Subramony; Bert Yao; Stephen Zicha; Christophe Lenglet; Pierre Gilles Henry

doi:10.1371/journal.pone.0269649

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

Nellie Georgiou-Karistianis, Louise A. Corben, Kathrin Reetz, Isaac M. Adanyeguh, Manuela Corti, Dinesh K. Deelchand, Martin B. Delatycki, Imis Dogan, Rebecca Evans, Jennifer Farmer, Marcondes C. França, William Gaetz, Ian H. Harding, Karen S. Harris, Steven Hersch, Richard Joules, James J. Joers, Michelle L. Krishnan, Michelle Lax, Eric F. LockDavid Lynch, Thomas Mareci, Sahan Muthuhetti Gamage, Massimo Pandolfo, Marina Papoutsi, Thiago J.R. Rezende, Timothy P.L. Roberts, Jens T. Rosenberg, Sandro Romanzetti, Jörg B. Schulz, Traci Schilling, Adam J. Schwarz, Sub Subramony, Bert Yao, Stephen Zicha, Christophe Lenglet, Pierre Gilles Henry

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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.

Original language	English (US)
Article number	e0269649
Journal	PloS one
Volume	17
Issue number	11 November
DOIs	https://doi.org/10.1371/journal.pone.0269649
State	Published - Nov 2022

Bibliographical note

Funding Information:
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. The authors gratefully thank all of the participants for their participation in the study, the Friedreich's Ataxia Research Alliance, Takeda Pharmaceuticals Company, Novartis Gene Therapies, IXICO plc and PTC Therapeutics for their help with FRDA participant recruitment. We thank Dr Andreas Deistung for providing the sequence parameters for brain QSM. Study data were collected and managed using REDCap electronic data capture tools hosted and managed by Helix (Monash University). Study data were collected, stored, and managed using XNAT, a software framework for managing neuroimaging laboratory data hosted by Monash (MXNAT) and Monash Biomedical Imaging (MBI-XNAT). The authors thank the research coordinators across all TRACK-FA sites for their assistance in participant recruitment and testing.

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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.

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Georgiou-Karistianis, N., Corben, L. A., Reetz, K., Adanyeguh, I. M., Corti, M., Deelchand, D. K., Delatycki, M. B., Dogan, I., Evans, R., Farmer, J., França, M. C., Gaetz, W., Harding, I. H., Harris, K. S., Hersch, S., Joules, R., Joers, J. J., Krishnan, M. L., Lax, M., ... Henry, P. G. (2022). A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol. PloS one, 17(11 November), Article e0269649. https://doi.org/10.1371/journal.pone.0269649

Georgiou-Karistianis, N, Corben, LA, Reetz, K, Adanyeguh, IM, Corti, M, Deelchand, DK, Delatycki, MB, Dogan, I, Evans, R, Farmer, J, França, MC, Gaetz, W, Harding, IH, Harris, KS, Hersch, S, Joules, R, Joers, JJ, Krishnan, ML, Lax, M, Lock, EF, Lynch, D, Mareci, T, Gamage, SM, Pandolfo, M, Papoutsi, M, Rezende, TJR, Roberts, TPL, Rosenberg, JT, Romanzetti, S, Schulz, JB, Schilling, T, Schwarz, AJ, Subramony, S, Yao, B, Zicha, S, Lenglet, C & Henry, PG 2022, 'A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol', PloS one, vol. 17, no. 11 November, e0269649. https://doi.org/10.1371/journal.pone.0269649

@article{0bfc5e271b8b428a89c1d53f753a2c77,

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

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.",

author = "Nellie Georgiou-Karistianis and Corben, {Louise A.} and Kathrin Reetz and Adanyeguh, {Isaac M.} and Manuela Corti and Deelchand, {Dinesh K.} and Delatycki, {Martin B.} and Imis Dogan and Rebecca Evans and Jennifer Farmer and Fran{\c c}a, {Marcondes C.} and William Gaetz and Harding, {Ian H.} and Harris, {Karen S.} and Steven Hersch and Richard Joules and Joers, {James J.} and Krishnan, {Michelle L.} and Michelle Lax and Lock, {Eric F.} and David Lynch and Thomas Mareci and Gamage, {Sahan Muthuhetti} and Massimo Pandolfo and Marina Papoutsi and Rezende, {Thiago J.R.} and Roberts, {Timothy P.L.} and Rosenberg, {Jens T.} and Sandro Romanzetti and Schulz, {J{\"o}rg B.} and Traci Schilling and Schwarz, {Adam J.} and Sub Subramony and Bert Yao and Stephen Zicha and Christophe Lenglet and Henry, {Pierre Gilles}",

note = "Funding Information: 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. The authors gratefully thank all of the participants for their participation in the study, the Friedreich's Ataxia Research Alliance, Takeda Pharmaceuticals Company, Novartis Gene Therapies, IXICO plc and PTC Therapeutics for their help with FRDA participant recruitment. We thank Dr Andreas Deistung for providing the sequence parameters for brain QSM. Study data were collected and managed using REDCap electronic data capture tools hosted and managed by Helix (Monash University). Study data were collected, stored, and managed using XNAT, a software framework for managing neuroimaging laboratory data hosted by Monash (MXNAT) and Monash Biomedical Imaging (MBI-XNAT). The authors thank the research coordinators across all TRACK-FA sites for their assistance in participant recruitment and testing. Publisher Copyright: Copyright: {\textcopyright} 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.",

year = "2022",

month = nov,

doi = "10.1371/journal.pone.0269649",

language = "English (US)",

volume = "17",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "11 November",

}

TY - JOUR

T1 - A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia

T2 - TRACK-FA study protocol

AU - Georgiou-Karistianis, Nellie

AU - Corben, Louise A.

AU - Reetz, Kathrin

AU - Adanyeguh, Isaac M.

AU - Corti, Manuela

AU - Deelchand, Dinesh K.

AU - Delatycki, Martin B.

AU - Dogan, Imis

AU - Evans, Rebecca

AU - Farmer, Jennifer

AU - França, Marcondes C.

AU - Gaetz, William

AU - Harding, Ian H.

AU - Harris, Karen S.

AU - Hersch, Steven

AU - Joules, Richard

AU - Joers, James J.

AU - Krishnan, Michelle L.

AU - Lax, Michelle

AU - Lock, Eric F.

AU - Lynch, David

AU - Mareci, Thomas

AU - Gamage, Sahan Muthuhetti

AU - Pandolfo, Massimo

AU - Papoutsi, Marina

AU - Rezende, Thiago J.R.

AU - Roberts, Timothy P.L.

AU - Rosenberg, Jens T.

AU - Romanzetti, Sandro

AU - Schulz, Jörg B.

AU - Schilling, Traci

AU - Schwarz, Adam J.

AU - Subramony, Sub

AU - Yao, Bert

AU - Zicha, Stephen

AU - Lenglet, Christophe

AU - Henry, Pierre Gilles

N1 - Funding Information: 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. The authors gratefully thank all of the participants for their participation in the study, the Friedreich's Ataxia Research Alliance, Takeda Pharmaceuticals Company, Novartis Gene Therapies, IXICO plc and PTC Therapeutics for their help with FRDA participant recruitment. We thank Dr Andreas Deistung for providing the sequence parameters for brain QSM. Study data were collected and managed using REDCap electronic data capture tools hosted and managed by Helix (Monash University). Study data were collected, stored, and managed using XNAT, a software framework for managing neuroimaging laboratory data hosted by Monash (MXNAT) and Monash Biomedical Imaging (MBI-XNAT). The authors thank the research coordinators across all TRACK-FA sites for their assistance in participant recruitment and testing. Publisher Copyright: 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.

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

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U2 - 10.1371/journal.pone.0269649

DO - 10.1371/journal.pone.0269649

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VL - 17

JO - PloS one

JF - PloS one

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M1 - e0269649

ER -

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

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