Kathrin Reetz1, Imis Dogan2, Ralf-Dieter Hilgers3, Paola Giunti4, Michael H Parkinson4, Caterina Mariotti5, Lorenzo Nanetti5, Alexandra Durr6, Claire Ewenczyk6, Sylvia Boesch7, Wolfgang Nachbauer7, Thomas Klopstock8, Claudia Stendel9, Francisco Javier Rodríguez de Rivera Garrido10, Christian Rummey11, Ludger Schöls12, Stefanie N Hayer13, Thomas Klockgether14, Ilaria Giordano15, Claire Didszun16, Myriam Rai17, Massimo Pandolfo17, Jörg B Schulz2. 1. Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich and RWTH Aachen University, Aachen, Germany. Electronic address: kreetz@ukaachen.de. 2. Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich and RWTH Aachen University, Aachen, Germany. 3. Department of Medical Statistics, RWTH Aachen University, Aachen, Germany. 4. Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL-Queen Square Institute of Neurology, London, UK. 5. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 6. Sorbonne Universite, Paris Brain Institute, ICM Institut du Cerveau, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France. 7. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. 8. Department of Neurology, Friedrich Baur Institute, University Hospital, LMU, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany. 9. Department of Neurology, Friedrich Baur Institute, University Hospital, LMU, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany. 10. Reference Unit of Hereditary Ataxias and Paraplegias, Department of Neurology, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain. 11. Clinical Data Science, Basel, Switzerland. 12. Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases, Tübingen, Germany. 13. Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 14. Department of Neurology, University Hospital of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases, Bonn, Germany. 15. Department of Neurology, University Hospital of Bonn, Bonn, Germany. 16. Department of Neurology, RWTH Aachen University, Aachen, Germany. 17. Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium.
Abstract
BACKGROUND: The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia. METHODS: EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov, NCT02069509. FINDINGS: Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included. INTERPRETATION: Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia. FUNDING: European Commission, Voyager Therapeutics, and EuroAtaxia.
BACKGROUND: The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia. METHODS: EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov, NCT02069509. FINDINGS: Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included. INTERPRETATION: Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia. FUNDING: European Commission, Voyager Therapeutics, and EuroAtaxia.
Authors: Christian Rummey; Louise A Corben; Martin Delatycki; George Wilmot; Sub H Subramony; Manuela Corti; Khalaf Bushara; Antoine Duquette; Christopher Gomez; J Chad Hoyle; Richard Roxburgh; Lauren Seeberger; Grace Yoon; Katherine Mathews; Theresa Zesiewicz; Susan Perlman; David R Lynch Journal: Neurology Date: 2022-07-11 Impact factor: 11.800
Authors: Marie Beaudin; Mario Manto; Jeremy D Schmahmann; Massimo Pandolfo; Nicolas Dupre Journal: Nat Rev Neurol Date: 2022-03-24 Impact factor: 42.937
Authors: María Jesús Valero; Jose L Muñoz-Blanco; Alejandro Garrido Sanchez; Gregorio Cuerpo; Javier Castrodeza; Paula Navas; Iago Sousa; Adolfo Villa; Francisco Fernández-Avilés; Manuel Martínez-Sellés Journal: J Cardiovasc Dev Dis Date: 2022-03-09