Abstract
To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = −0.615), while the PST medial–lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = −0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of −2.59 (95% CI −3.52 to −1.66, p < 0.001, SRM = −1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.
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Data not published within this article will be shared after approval by the Friedreich’s Ataxia Research Alliance, USA, and ethics review boards.
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Acknowledgements
We wish to thank all the participants who have given their time for this project. The authors would also like to thank the Kingston Centre Physiotherapy Department, Monash Health, Melbourne, and the Clinical Research Center for Movement Disorders and Gait, University of South Florida, Tampa, for their support during the study. We wish to thank Lucretia Campbell and Mary Freeman, University of South Florida Ataxia Research Center, for their assistance with data collection.
Funding
This study was supported by the Friedreich’s Ataxia Research Alliance (USA) (FARA), PTC Therapeutics and Voyager Therapeutics, as a part of FARA's Biomarker Consortium.
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Sarah C Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Eppie Yiu, Nellie Georgiou-Karistianis, Theresa Zesiewicz, Martin B Delatycki and Louise A Corben contributed to the study conception and design. Material preparation and data collection were performed by Sarah C Milne, Seok Hun Kim, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli and Geneieve Tai. Analysis was performed by Sarah C Milne. The first draft of the manuscript was written by Sarah C Milne, and all authors revised the manuscript for intellectual content. All authors read and approved the final manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Monash Health Human Research Ethics Committee (15035A) and the USF Institutional Review Board (Pro00021414).
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All participants (or their parents/guardians if aged under 18 years) provided informed consent as per the Declaration of Helsinki.
Conflict of Interest
This study was sponsored by the Friedreich’s Ataxia Research Alliance (USA) (FARA), PTC Therapeutics and Voyager Therapeutics, as a part of FARA’s Biomarker Consortium. S. C. Milne received a National Health and Medical Research Council of Australia Postgraduate Scholarship (APP1093259). E. M. Yiu is a National Health and Medical Research Council Early Career Fellow (APP 1073323). L. A. Corben is a Medical Research Futures Fund Career Development Fellow (APP1143098). J. Larkindale was employed by the Friedreich’s Ataxia Research Alliance. J. Farmer is employed by the Friedreich’s Ataxia Research Alliance. S. H. Kim, A. Murphy, R. Malapira, M. Danoudis, J. Shaw, T. Ramakrishnan, F. Rasouli, N. Georgiou-Karistianis, G. Tai, T. Zesiewicz and M.B. Delatycki declare they have no financial or non-financial interests to disclose.
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Milne, S.C., Kim, S.H., Murphy, A. et al. The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia. Cerebellum 21, 963–975 (2022). https://doi.org/10.1007/s12311-021-01348-2
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DOI: https://doi.org/10.1007/s12311-021-01348-2