From Long‐Term to Trial‐Ready: 1.5‐Year Follow‐Up in an Established FSHD Cohort Highlights Limitations of Current Outcome Measures

INTRODUCTION/AIMS: Identifying endpoints that are sensitive to change is crucial for clinical trial design in facioscapulohumeral muscular dystrophy (FSHD). This study adds follow-up data to a previously published 5-year natural history study in the same cohort, aiming to correlate short-term disease progression to longer term follow-up. METHODS: Adult FSHD patients were reassessed 1.5 years after their 5-year visit. A subgroup underwent trimonthly assessments for 1 year following the 1.5-year visit. Disease severity scores, motor function measure (MFM), 6-min walk test (6MWT), antigravity tests (AGTs), and muscle strength by manual muscle testing (MMT) were assessed to determine change over time. Sample sizes were calculated for a hypothetical trial assuming stabilization of the disease as treatment aim. RESULTS: Eighty-six patients completed both assessments, 30 of whom underwent trimonthly assessments. Over 1.5 years, a small decline was observed in the mean MMT score (median change: -0.2, p < 0.001), and the 6MWT (median change: -14 m, p = 0.009). In the trimonthly subgroup, individual mean MMT scores were variable between visits. Sample size estimates ranged from 16 (MMT of specific muscles) to 1824 participants (MFM) per group depending on the used clinical outcome measure and patient selection. DISCUSSION: This study provides clinically relevant data on short-term progression in FSHD. The findings confirm the limited responsiveness of clinical outcome measures resulting in large sample size estimates, demonstrate variability of MMT, and highlight the need for multimodal or biomarker-based endpoints to enable feasible and sensitive clinical trial design.