Objective: To hasten drug development for facioscapulohumeral muscular dystrophy (FSHD) by validating clinical outcome assessments (COAs) and refining trial strategies.
Background: FSHD is a dominantly-inherited disease caused by de-repression of the DUX4 gene, which can lead to significant loss of motor function. As targeted drugs move into human trials, validating clinical trial tools is essential to facilitate the drug development process.
Methods: 24-month longitudinal study in genetically confirmed and clinically affected FSHD participants in the FSHD Clinical Trial Research Network (8 sites in the United States, and 3 sites in Europe). Visits occur at baseline and months 3, 12, 18, and 24. At each visit we collect: a novel FSHD functional composite (FSHD-COM) made up of 18 evaluator-administered motor tasks; Domain 1 of the Motor Function Measure (MFMD1); clinical severity (0=unaffected, 10=non ambulatory); and strength measured by quantitative myometry (14 muscles) and manual muscle testing (32 muscles). Here we present baseline characteristics and test-retest reliability of the functional composites using intraclass correlation coefficients (ICC).
Results: Two hundred forty FSHD participants were enrolled: 45% female, spanned the adult age (median 53 years, range 19-75 years), severity range (median 6, range 1-9), and the genetic spectrum (median D4Z4 repeats 6, range 2-10). The median age at symptom onset was 20 years, with a mean diagnostic delay of 10 years, and women became symptomatic 4.9 years later than men (P=0.02). The median forced vital capacity (FVC) was 90% predicted (range 34-143), with 26% having an FVC < 80% predicted. The test-retest reliability of the functional composites was excellent, with the FSHD-COM having an ICC of 0.98 (95% lower confidence bound [LCB] 0.97) and the MFMD1 0.97 (LCB 0.96).
Conclusion: ReSolve will allow evaluation of inclusion criteria and power and sample size calculations by determining FSHD progression rates as measured by standard COAs.
Funding: NINDS U01 grant U01NS101944; MDA clinical research network grant #573783; FSH Society grant # 52016; Friends of FSH Research grant; CTSA grant from NCATS (# UL1TR000001, and UL1RR024160); and a grant from AFM (SS).