Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective

Klockgether, Thomas; Ashizawa, Tetsuo; Brais, Bernard; Chuang, Rosalind; Dürr, Alexandra; Fogel, Brent L.; Greenfield, Julie; Hagen, Sue; Jardim, Laura Bannach; Jiang, Hong; Onodera, Osamu; Pedroso, José Luiz; Soong, Bin‐Weng; Szmulewicz, David J.; Graeßner, Holm; Synofzik, Matthis

doi:10.1002/mds.29032

Cited by 26 publications

(48 citation statements)

References 41 publications

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“…The smaller sample size in SCA1 coupled with a conservative type I error correction could have limited several MR metrics to reach statistical significance. Future studies need to collect trial readiness data with larger sample sizes in global efforts such as the Ataxia Global Initiative 61 . A technical limitation was the use of scanners from a single vendor.…”

Section: Discussionmentioning

confidence: 99%

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Chandrasekaran

Petit

Park

et al. 2022

Annals of Neurology

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This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. Methods: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses.

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Section: Discussionmentioning

confidence: 99%

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Chandrasekaran

Petit

Park

et al. 2022

Annals of Neurology

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“…With disease‐modifying drugs on the horizon for degenerative ataxias, 1‐3 sensitive motor biomarkers are highly warranted. Gait measures including step variability and body sway have shown their sensitivity to ataxia severity in multiple cross‐sectional studies, correlating with clinical ataxia scores 4‐16 .…”

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confidence: 99%

Digital Gait Biomarkers Allow to Capture 1‐Year Longitudinal Change in Spinocerebellar Ataxia Type 3

et al. 2022

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Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross‐sectional studies. However, to serve as a valid progression biomarker, these gait measures have to prove their sensitivity to robustly capture longitudinal change, ideally within short time frames (eg, 1 year). We present the first multicenter longitudinal gait analysis study in spinocerebellar ataxias. We performed a combined cross‐sectional (n = 28) and longitudinal (1‐year interval, n = 17) analysis in Spinocerebellar Ataxia type 3 subjects (including seven preataxic mutation carriers). Longitudinal analysis showed significant change in gait measures between baseline and 1‐year follow‐up, with high effect sizes (stride length variability: P = 0.01, effect size rprb = 0.66; lateral sway: P = 0.007, rprb = 0.73). Sample size estimation for lateral sway indicates a required cohort size of n = 43 for detecting a 50% reduction of natural progression, compared with n = 240 for the clinical ataxia score Scale for the Assessment and Rating of Ataxia (SARA). These measures thus present promising motor biomarkers for upcoming interventional studies. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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“…This finding extends recent findings limited to SCA3 15 to a large across-genotype cohort, thus demonstrating their general applicability to genetic ataxias. In combination with the suggested metric optimizations, such a rank-optimized SARA might help to facilitate its regulatory qualification for upcoming trials 42 .…”

Section: Discussionmentioning

confidence: 99%

“…While modifications to optimize the SARA are thus now being discussed (e.g. the modified SARA score f-SARA 19 ), the underlying data evidence and validation of such modifications has remained scarce 16 . Extensive real-world data from ataxia registries, with prospective SARA assessments across many years and ataxia genotypes, may in turn provide the opportunity for statistical modeling and data-driven optimization of its responsiveness as a generic COA of ataxia.…”

Section: Introductionmentioning

confidence: 99%

Capturing clinical progression in multisystemic genetic ataxias: lessons from a prospective study of 884 patients with autosomal recessive or early-onset ataxia

Traschuetz

Adarmes‐Gómez

Anheim

et al. 2022

Preprint

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Objective: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. Methods: Subitem-level correlation- and distribution-based analysis of 1637 SARA assessments in 884 patients with autosomal-recessive/early-onset ataxia (370 with 2-8 longitudinal assessments), complemented by linear mixed-effects modeling to estimate progression and sample sizes. Results: While SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA<25). Responsiveness was diminished by incomplete sub-scale use at intermediate or upper levels, non-transitions ('static periods'), and fluctuating decreases/increases. All subitems -except nose-finger- showed moderate-to-strong correlations to activities of daily living, indicating that metric properties -not content validity- limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes, e.g., SYNE1-ataxia: 0.55 points/year, AOA2: 1.14, POLG-ataxia: 1.56; but no change in others (ARSACS, COQ8A-ataxia). While sensitivity to change was optimal in mild ataxia (SARA≤10), it substantially deteriorated in advanced ataxia (SARA>25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20-25%. Interpretation: This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design.

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Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective

Cited by 26 publications

References 41 publications

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3

Digital Gait Biomarkers Allow to Capture 1‐Year Longitudinal Change in Spinocerebellar Ataxia Type 3

Capturing clinical progression in multisystemic genetic ataxias: lessons from a prospective study of 884 patients with autosomal recessive or early-onset ataxia

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