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

Samantha Lorusso, Nicholas E. Johnson, Michael P. McDermott, Katy Eichinger, Russell J. Butterfield, Elena Carraro, Kiley Higgs, Leann Lewis, Karlien Mul, Sabrina Sacconi, Valeria A. Sansone, Perry Shieh, Baziel Van Engelen, Kathryn Wagner, Leo Wang, Jeffrey M. Statland, Rabi Tawil, Mazen Dimachkie, Mamatha Pasnoor, Katherine RoathAyla McCalley, Melissa Currence, Laura Herbelin, Johanna Hamel, W. David Arnold, Tabitha Alexander, Matthew Yankie, Kristina Kelly, Brittney Holmberg, Liz Diaz, Aileen Jones, Amanda Butler, Sarah Moldt, Amelia Wilson, Melissa McIntyre, Doris Leung, Genila Bibat, Mary Yep, Nikia Stinson, Andrea Jaworek, Laura Sissons-Ross, Laura Johnstone, Christy Skura, Dianne Deguzman, Yvonne Cornelissen, Luisa Villa, Angela Puma, Manuela Gambella, Ying Shi, Jeremy Garcia, Fatmira Beshiri, Luca Mauro

Research output: Contribution to journalArticle

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

Original languageEnglish (US)
Article number224
JournalBMC neurology
Volume19
Issue number1
DOIs
StatePublished - Sep 10 2019

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Keywords

  • Biomarkers
  • Clinical trial
  • Electrical impedance Myography
  • Facioscapulohumeral muscular dystrophy
  • Functional testing
  • Muscular dystrophy
  • Outcome measures

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Lorusso, S., Johnson, N. E., McDermott, M. P., Eichinger, K., Butterfield, R. J., Carraro, E., Higgs, K., Lewis, L., Mul, K., Sacconi, S., Sansone, V. A., Shieh, P., Van Engelen, B., Wagner, K., Wang, L., Statland, J. M., Tawil, R., Dimachkie, M., Pasnoor, M., ... Mauro, L. (2019). Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): Protocol of a large, international, multi-center prospective study. BMC neurology, 19(1), [224]. https://doi.org/10.1186/s12883-019-1452-x