Progression Characteristics in Friedreich's Ataxia: A 4-Year Observational Study

Abstract

Background: The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich’s ataxia (FRDA) in a prospective multinational registry study. We aimed to assess progression and metric characteristics of clinical rating scales based on longitudinal 4-year data. Methods: Patients with genetically confirmed FRDA from 11 European sites were seen on a yearly basis at five visits. Our primary endpoints were the clinical Scale for the Assessment and Rating of Ataxia (SARA) and the functional activities of daily living (ADL) scale. Secondary endpoints were the Spinocerebellar Ataxia Functional Index (SCAFI), the Inventory of Non-Ataxia Signs (INAS), and the quality of life measure EQ-5D-3L index. Annual disease progression was analysed with linear mixed effect models and additional regression statistics for detailed subgroup characterization. . Findings: 602 FRDA patients were seen between 29-Oct-2010 and 05-Mar-2018. 552 patients (92%) 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 ambulatory (1·12 [0·07]) compared to non-ambulatory (0·50 [0·07]) patients. Subitem analyses revealed high rates of progression for the lower limb components in ambulatory patients. ADL worsened with 0·93 (0·05) points per year, with the subitem falls showing strongest effects over time. Annual worsening of INAS was 0·09 (0·02) points, for SCAFI -0·05 (0·01) and for EQ-5D-3L -0·02 (0·003). For a two-year parallel-group clinical trial, about 118 (59 per group) ambulatory patients are required to detect a 50% reduction in SARA progression at 80% power. Less patients are needed using ADL as a functional outcome in a similar design and including only early-onset ambulatory individuals. Interpretation: EFACTS 4-year longitudinal data analysis provides reliable outcome measures and tailored sample size calculation for upcoming clinical trial designs in FRDA. Trial Registration: This study is registered at https://clinicaltrials.gov (NCT02069509) Funding Statement: FP7 Grant from the European Commission (HEALTH-F2-2010- 242193), Voyager Therapeutics and Euro-Ataxia. Declaration of Interests: The authors declare no potential conflicts of interests. Ethics Approval Statement: All patients and/or their authorized surrogates provided written informed consent upon enrolment into EFACTS. This study was approved by the local ethics committees of each participating centre.