Principal Investigator: Russell Butterfield
Keywords: FSHD , EIM , Clinical Trial , UPIN , Muscular Dystrophy Department: Pediatric Administration
IRB Number: 00114058 Co Investigator: Russell Butterfield
Specialty: Neurology
Sub Specialties: Neurodegenerative Disorders
Recruitment Status: Active, not recruiting

Contact Information

Sarah Moldt
(801) 585-9399

Brief Summary

The overall aim of this proposal is to hasten drug development for facioscapulohumeral muscular dystrophy (FSHD) by validating new clinical outcome assessments (COAs) and refining trial planning strategies.  FSHD is caused by the aberrant expression of a normally silenced gene, DUX4, which causes disease by a toxic gain-of-function, identifying for the first time disease-specific targets for therapy. The key abnormality in FSHD is particularly amenable molecular knock-down or silencing of DUX4, making strategies like the use of RNA antisense oligonucleotide drugs possible, similar to clinical trials already underway for spinal muscular atrophy, Duchenne muscular dystrophy, and myotonic dystrophy.  Several pharmaceutical companies have active programs for targeted treatments in FSHD, with time-frames for first-in-human trials starting in the next 5 years, and two early-phase clinical trials of drugs designed to ameliorate downstream FSHD pathology are underway now, or planned to start in the next year (e.g. muscle inflammation or muscle atrophy and fibrosis).  Meetings with industry, advocacy groups, and FSHD researchers have identified several gaps that need to be addressed to accelerate efficient drug development and confirmatory drug trials.  A drug industry panel at the 2015 FSHD International Workshop identified a strong need for biomarkers for early phase studies, functional COAs for registration studies, and a better understanding of factors that could influence progression in order to define trial eligibility criteria.  Rationale: As drugs move from preclinical planning into human trials, it is essential that we validate clinical trial tools and methodology to hasten the drug development process. In preliminary single site studies we determined the reliability and convergent validity of an evaluator-administered functional composite COA (FSHD-COM) composed of disease-relevant standard functional tasks, and electrical impedance myography (EIM), a non-invasive physiological biomarker for measuring changes in muscle composition. In addition, in cross-sectional studies we identified likely genetic and demographic determinants of disease progression.  Such clinical work has prepared the existing FSHD Clinical Trial Research Network (CTRN) to conduct a longitudinal study to test the multi-site reliability of the COAs, and define subgroups more likely to have consistent disease progression.  The FSHD CTRN has leveraged support from the FSH Society and private philanthropy and existing data and statistical infrastructure from the Muscle Study Group to build a network of 7 academic centers with considerable experience in neuromuscular diseases.  The primary goal of this proposal is to hasten drug development by validating the FSHD-COM and EIM in 160 participants in an 18-month longitudinal study.  This large prospective study will simultaneously allow us to reassess the rate of disease progression of FSHD in light of specific demographic and genetic factors that may influence how to define criteria for trial eligibility. We propose the following specific aims.

Aim 1: Determine the Multi-Site Reliability and Validity of New COAs.  We hypothesize that both the FSHD-COM and EIM will be reliable across multiple sites and reflect disease severity.  We will utilize a comprehensive multi-site training plan to optimize reliability between study personnel at CTRN sites. Having already established single site reliability and convergent validity compared to other FSHD outcomes like strength and function of our new COAs, we will confirm these findings in a large multi-site study.

Aim 2: Compare the Responsiveness of New COAs to Other FSHD Outcomes and Determine the Minimal Clinically Important Change. We hypothesize that our new COAs will be sensitive to disease progression, and minimal clinically meaningful changes will reflect patient-reported changes in disease burden.  We will determine the responsiveness of our COAs to disease progression over 3, 12, and 18 months and compare to other FSHD outcomes, including strength and patient-reported motor disability.  We will confirm the variability in our COAs in a large cohort for future power and sample size calculations. We will use a variety of techniques to determine what change in the FSHD-COM would be of minimal clinical importance.

Aim 3: Establish FSHD Cohort Characteristics Useful for Determining Clinical Trial Eligibility Criteria. We hypothesize that known genetic and demographic determinants of disease severity will account for some of the variability in disease progression, and can help refine trial eligibility criteria.  We will determine the relationships between D4Z4 residual fragment size, baseline functional status, age, and gender and disease progression in our new COAs and standard FSHD outcomes like strength and functional tasks.  We will implement statistical methods such as regression trees to determine specific subgroups of people with FSHD who are more or less likely to progress over 12-18 months and use this information to establish eligibility criteria for future clinical trials.

Inclusion Criteria

Inclusion criteria:

Genetically confirmed FSHD1 or clinical diagnosis of FSHD with characteristic findings on exam and an affected parent or offspring [64}
Age 18-75 years
Symptomatic limb weakness
Able to walk 30 feet without the support of another person (canes, walking sticks, and braces allowed; no walker).
If taking over the counter supplements willing to remain consistent with supplement regimen throughout the course of the study

We have not included FSHD2 as they represent only about 5% of the FSHD population and recruitment of a sufficient number of these patients to obtain meaningful results is not practical. The inclusion criteria may inadvertently enroll individuals who will subsequently be found to have FSHD2, or an alternative diagnosis. However, the expectation is that this will be less than 5% of individuals without genetic confirmation prior to enrollment. If genetic testing performed as part of this study fails to confirm the genetic diagnosis, the results of the genetic test will be shared with the participant, and their participation in the study will end.  


Exclusion Criteria

Exclusion criteria:

Cardiac or respiratory dysfunction (deemed clinically unstable, or would interfere with safe testing in the opinion of the Investigator)

Orthopedic conditions that preclude safe testing of muscle function

Regular use of available muscle anabolic/catabolic agents such as corticosteroids, oral testosterone or derivatives, or oral beta agonists

Use of an experimental drug in an FSHD clinical trial within the past 30 days