Christian Rummey1, Louise A Corben2,3, Martin Delatycki2,3, George Wilmot4, Sub H Subramony5, Manuela Corti5, Khalaf Bushara6, Antoine Duquette7, Christopher Gomez8, J Chad Hoyle9, Richard Roxburgh10, Lauren Seeberger11, Grace Yoon12, Katherine Mathews13, Theresa Zesiewicz14, Susan Perlman15, David R Lynch16. 1. Clinical Data Science GmbH, Basel, Switzerland. 2. Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, 3052, Victoria. Australia. 3. Department of Paediatrics, University of Melbourne. Parkville, 3052, Victoria. Australia. 4. Emory University, Atlanta. 5. Department of Neurology, McKnight Brain Institute, Room L3-100, 1149 Newell Drive, Gainesville, Florida 32611. 6. University of Minnesota. 7. Service de Neurologie, Département de Médecine, Unité de Troubles du Mouvement André-Barbeau, Centre Hospitalier de l'Université de Montréal (CHUM) and CRCHUM, 900 rue Saint-Denis, Montreal, QC, Canada, H2X 0A9. 8. University of Chicago. 9. Ohio State University. 10. University of Auckland. 11. University of Colorado. 12. Divisions of Neurology and Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 13. University of Iowa, Carver College of Medicine, Iowa City, Iowa, USA. 14. University of South Florida. 15. University of California Los Angeles. 16. Division of Neurology, Children's Hospital of Philadelphia lynchd@pennmedicine.upenn.edu.
Abstract
BACKGROUND: - The understanding of the natural history of Friedreich's ataxia has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this work was to acknowledge the broad genetic diversity of the population, especially with respect to younger individuals and to provide analyses stratified by age to guide population selection in future studies. METHODS: - Based on a large natural history study, the Friedreich's Ataxia Clinical Outcome Measures study (FACOMS) that at the current data cut enrolled 1115 participants, followed up for 5287 yearly visits, we present results from the modified Friedreich's Ataxia Rating Scale and its sub scores. Secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk and the 9-hole peg test. Long-term progression was modeled using slope analyses within Early, Typical, Intermediate and Late Onset Friedreich's Ataxia. To reflect recruitment in clinical trials, short term changes were analyzed within age-based sub-populations. All analyses were stratified by ambulation status. FINDINGS: - Long term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages of onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability sub score of the mFARS. The analyses of short-term changes showed slower progression with increasing population age, as a result of decreasing genetic severity. Future clinical studies could reduce population diversity, inter-patient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification. INTERPRETATION: - Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.
BACKGROUND: - The understanding of the natural history of Friedreich's ataxia has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this work was to acknowledge the broad genetic diversity of the population, especially with respect to younger individuals and to provide analyses stratified by age to guide population selection in future studies. METHODS: - Based on a large natural history study, the Friedreich's Ataxia Clinical Outcome Measures study (FACOMS) that at the current data cut enrolled 1115 participants, followed up for 5287 yearly visits, we present results from the modified Friedreich's Ataxia Rating Scale and its sub scores. Secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk and the 9-hole peg test. Long-term progression was modeled using slope analyses within Early, Typical, Intermediate and Late Onset Friedreich's Ataxia. To reflect recruitment in clinical trials, short term changes were analyzed within age-based sub-populations. All analyses were stratified by ambulation status. FINDINGS: - Long term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages of onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability sub score of the mFARS. The analyses of short-term changes showed slower progression with increasing population age, as a result of decreasing genetic severity. Future clinical studies could reduce population diversity, inter-patient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification. INTERPRETATION: - Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.
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