Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study

Abstract

Background Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process. Methods/design The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials. Discussion To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics. Trial registration clinicaltrials.gov NCT03458832; Date of registration: 1/11/2018

Designed U7 snRNAs inhibit DUX4 expression and improve FSHD-associated outcomes in DUX4 overexpressing cells and FSHD patient myotubes

“…With the emergence of prospective FSHD therapies came a need in the FSHD field to develop clinical outcome measures and biomarkers that could be used to establish therapeutic efficacy. 41 , 42 , 43 , 44 Although DUX4 expression is the most direct measure of target engagement by a prospective drug or gene therapy, it is difficult to detect and relatively scarce in FSHD muscle biopsies. Thus, DUX4 expression in human muscle biopsies is currently not a reliable outcome measure for FSHD clinical trials, and several groups have now turned to examining DUX4-activated biomarkers as an indirect measure of DUX4 expression.…”

Therapeutic Strategies Targeting DUX4 in FSHD

“…One of the most critical points will be the identification of outcome measures of clinical efficacy. Several have been proposed such as clinical severity score (CSS) [92], the reachable work space (RWS) [93], and muscle MRI [94,95], or are under development such as the FSHD-COM [96]. While these techniques are informative, they suffer from several limitations as they are often costly, laborious, low through-put, or allow the assessment of a limited number of muscles.…”

Current Therapeutic Approaches in FSHD

“…Nevertheless, both outcome measures showed a slight 12-month decline in strength. A large, multi-national, natural history study, the ReSolve study, is currently in its third year and will exam a change in a variety of outcome measures over a span of 24 months [ 81 ]. These outcome measures include, in addition to strength testing, a composite functional outcome measure (FSHD-COM), reachable workspace as a quantitative measure of shoulder function an FSHD-specific patient reported health index (FSHD HI) (90, 91, 92, 93).…”