Facioscapulohumeral muscular dystrophy functional composite outcome measure

Eichinger, Katy; Heatwole, Chad; Iyadurai, Stanley; King, Wendy; Baker, Lindsay B.; Heininger, Susanne; Bartlett, Amy; Dilek, Nuran; Martens, William; McDermott, Michael P.; Kissel, John T.; Tawil, Rabi; Statland, Jeffrey

doi:10.1002/mus.26088

Cited by 22 publications

(26 citation statements)

References 41 publications

(100 reference statements)

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“…A recently developed functional facioscapulohumeral muscular dystrophy composite outcome measure (FSHD-COM) combines several assessments of patient-identified areas of functional burden [80]. The FSHD-COM correlates well with disease severity, duration, and strength.…”

Section: Trial Preparednessmentioning

confidence: 99%

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Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Hamel

Tawil

2018

Neurotherapeutics

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A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.

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Section: Trial Preparednessmentioning

confidence: 99%

“…The FSHD-COM correlates well with disease severity, duration, and strength. However, the FSHD-COM still needs to be validated in multicenter trials and demonstrate sensitivity to disease change [80]. A patient-reported outcome tool, the FSHD Health Index (FSHD-HI), is currently being evaluated in a prospective study [81].…”

Section: Trial Preparednessmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Hamel

Tawil

2018

Neurotherapeutics

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“…In all of these ways, the reachable workspace outcome has the ability to become an extremely useful tool for the FSHD field. Indeed, it would be complementary to newly developed imaging biomarker outcomes (18), functional composite scales (19), and other novel biomarker outcomes (20) currently under development.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal study of upper extremity reachable workspace in fascioscapulohumeral muscular dystrophy

Hatch¹,

Kim

Kurillo

et al. 2019

Neuromuscular Disorders

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Facioscapulohumeral Dystrophy (FSHD) results in slowly progressive strength impairment, especially the upper extremities. Recent discoveries regarding pathophysiology have led to exciting novel therapeutic strategies. To further facilitate drug development, improved FSHD outcome measures that are functionally-relevant and sensitive to longitudinal change will be critical. Recently, a motion sensor (Kinect)-based upper extremity outcome called 'reachable workspace' that provides a quantitative reconstruction of an individual's reachability was developed. In this study, changes in reachable workspace were tracked upwards for 5-years in 18 FSHD subjects. Results show −1.63%/year decline in total reachable workspace (p=0.144); with most notable decline in the above-the-shoulder level quadrants (upper-lateral Q3: −9.5%/year, p<0.001 and upper-medial Q1: −6.8%/year, p=0.063) with no significant changes in the lower quadrants (Q2,Q4). Reachable workspace declined more significantly if the subjects were challenged with 500g wrist weights: total reachable workspace: −1.82%/year, p=0.039; Q1: −7.20%/year, p=0.041; Q3: −8.09%/year, p=0.001. Importantly, reachable workspace outcome was also able to distinguish subgroups in FSHD: mildlyand severely-affected with essentially unchanging reachability over years, and moderately-affected who demonstrate the most detectable changes longitudinally. The study demonstrates utility for measuring declines in upper quadrant

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“…The FSHD-COM is an 18-item evaluator-administered instrument comprised of individually validated functional motor tasks (Table 2) [21]. The body regions represented match areas of importance identified by patients and include: leg function, shoulder and arm function, trunk function, hand function, and balance.…”

Section: Methodsmentioning

confidence: 99%

“…A functional FSHD composite outcome measure (FSHD-COM) was recently developed and is novel in that the selected motor tasks reflect patient-reported significant domains of functional impairment [4, 20]. It has shown high test-retest reliability and strong cross-sectional associations with disease duration, clinical severity, and strength, but multi-site reliability and sensitivity to disease progression are yet to be demonstrated [21].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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

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Facioscapulohumeral muscular dystrophy functional composite outcome measure

Cited by 22 publications

References 41 publications

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Longitudinal study of upper extremity reachable workspace in fascioscapulohumeral muscular dystrophy

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

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