Ten years of collecting natural history data in the International Clinical Outcome Study for Dysferlinopathy


Clinical Trials

Poster Number: 142


Volker Straub, PhD, Newcastle University, Anna Mayhew, PhD, MCSP, Newcastle University, Heather Hilsden, Newcastle University, Meredith James, BAppSci, John Walton Muscular Dystrophy Research Centre

Patients with dysferlinopathies have highly variable clinical presentations and a lack of appropriate outcome measures to define progression. This presents significant challenges for clinical trial readiness. The International Clinical Outcome Study for Dysferlinopathy (COS) was the first international, multi-centre longitudinal natural history study in dysferlinopathy. COS aimed to characterise phenotypes and determine appropriate outcome measures (OMs) across function, MRI, biomarkers and quality of life. _x000D_
Methods _x000D_
193 participants from 15 sites in eight countries attended for three years, with some sites collecting data for up to six years. The extension study, COSII, recruited 203 participants, from 16 sites globally in nine countries. Inclusion criteria was two predicted pathogenic mutations in DYSF, or one predicted pathogenic mutation plus either absent dysferlin expression on immunoblot or < 20% dysferlin monocyte expression (NCT01676077). In the absence of any dysferlinopathy specific OMs, participants completed a variety of standardised assessments of strength and function, patient reported questionnaires, qualitative and quantitative MRI and biomarker studies. _x000D_ _x000D_ Results_x000D_ The North Star Assessment for limb girdle type muscular dystrophies (NSAD), was developed, validated and allowed accurate capture of dysferlinopathy presentation and progression. Utilising NSAD and MRI, COS has confirmed that Miyoshi and LGMD2B/R2 are not two distinct phenotypes, but both dysferlinopathies, a critical finding for clinical management, clinical trial population definition and access to disease modifying treatments. Participants experienced the steepest functional decline in the first ten years after symptom onset. Qualitative MRI defined a characteristic pattern of muscle involvement. Quantitative MRI methods including MRS and fat fraction captured change over three years. Standards of care for dysferlinopathy are under development._x000D_ _x000D_ Conclusion_x000D_ COS, conducted with patient advocacy partners the Jain Foundation, has determined appropriate OMs that define the phenotype and progression of dysferlinopathy, driving the community much closer to clinical trial readiness.