Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). METHODS: To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models. The chosen statistical model was re-fitted in order to estimate parameters and predict disease progression. Median time-to-change and rate of score progression were estimated using the Kaplan-Meier method and weighted linear regression models, respectively. RESULTS: SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4-year follow-up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one-point score increase of 1 to 2 years. INTERPRETATION: Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials

Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

Introduction: Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown. Methods: The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1–4) to the individually highest tolerated dose of 2–4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5–104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician’s and patient’s global impression-change scales as well as the upregulation of the frataxin protein level, safety and survival/death. Perspective: The NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia

Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study

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

Quantifiable evaluation of cerebellar signs in children

Objective: To validate, examine the internal validity, and adapt to children the electronic version of the composite cerebellar functional severity (CCFS) score. Methods: In this multicenter study, we compared the validated manual device with the new electronic version (n 46) and analyzed its kinetics in 146 patients with Friedreich ataxia through the EFACTS (European Friedreich's Ataxia Consortium for Translational Studies) network, 77 patients with spinocerebellar ataxia, and 48 controls. We validated the CCFS in cerebellar ataxias in healthy children (n 120) and children with Friedreich ataxia through the EFACTS network (n 33). Results: We showed that the electronic CCFS is a reliable replacement for the manual version (intraclass correlation coefficient: 0.98 [0.97-0.99]), and that the electronic CCFS is consistent when performed several times (0.92 [0.84-0.97]). Analysis of kinetics data showed an acceleration and irregularity that is not relevant compared with total speed. The CCFS was tested after modification in a population of patients with Friedreich ataxia between 8 and 19 years old, and showed similar values as adult patients with Friedreich ataxia (1.203 ± 0.125 vs 1.228 ± 0.167) and significantly higher values than controls of the same age (0.863 ± 0.042). Conclusions: The electronic CCFS is a quantified measurement of cerebellar ataxia independent of age, usable in individuals aged from 7 to 80 years. The automated nature of the electronic test device makes it reproducible between operators and centers, as well as easy to use.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Nonataxia symptoms in Friedreich Ataxia

Objective To provide a systematic evaluation of the broad clinical variability in Friedreich ataxia (FRDA), a multisystem disorder presenting mainly with afferent ataxia but also a complex phenotype of nonataxia symptoms.Methods From the large database of the European Friedreich’s Ataxia Consortium for Translational Studies, 650 patients with genetically confirmed FRDA were included. Detailed data of medical history documentation, questionnaires, and reports on clinical features were analyzed to provide in-depth description of the clinical profile and frequency rates of phenotypical features with a focus on differences between typical-onset and late-onset FRDA. Logistic regression modeling was used to identify predictors for the presence of the most common clinical features.Results The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems.Conclusions This joint European effort demonstrates the multisystem nature of this neurodegenerative disease encompassing most the central nervous, neuromuscular, cardiologic, and sensory systems. A distinct and deeper knowledge of this rare and chronic disease is highly relevant for clinical practice and designs of clinical trials

Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study

Background The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich's ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. Methods We enrolled patients with genetically confirmed Friedreich's ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits—baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. Findings Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreich's ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (–0·02 points per year [0·01] per year of age) and lower SARA baseline scores (–0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, −0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and −0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. Interpretation Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreich's ataxia. Funding European Commission.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

Introduction: Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown. Methods: The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1-4) to the individually highest tolerated dose of 2-4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5-104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician's and patient's global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death. Perspective: The NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia. Trial registration: EudraCT-No.: 2017-002163-17, ClinicalTrials.gov NCT03761511

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset.

Funder: Christina FoundationFunder: EuroAtaxiaFunder: Voyager Therapeutics; doi: http://dx.doi.org/10.13039/100018556BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). METHODS: To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models. The chosen statistical model was re-fitted in order to estimate parameters and predict disease progression. Median time-to-change and rate of score progression were estimated using the Kaplan-Meier method and weighted linear regression models, respectively. RESULTS: SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4-year follow-up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one-point score increase of 1 to 2 years. INTERPRETATION: Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

Abstract Background The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). Methods To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical‐onset FA (<25 years) participating in the 4‐year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed‐effects regression models. The chosen statistical model was re‐fitted in order to estimate parameters and predict disease progression. Median time‐to‐change and rate of score progression were estimated using the Kaplan–Meier method and weighted linear regression models, respectively. Results SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4‐year follow‐up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one‐point score increase of 1 to 2 years. Interpretation Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials