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

BMC Neurology

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[1] 0000 0000 9632 6718, grid.19006.3e, Department of Neurology, University of California, Los Angeles, 300 Medical Plaza, Suite B-200, 90095, Los Angeles, CA, USA;0000 0001 1545 0811, grid.412332.5, Department of Neurology, Ohio State University Wexner Medical Center, 395 W. 12th Ave., 7th Floor, 43210, Columbus, OH, USA;0000 0001 2177 6375, grid.412016.0, Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 2012, 66160, Kansas City, KS, USA;0000 0001 2193 0096, grid.223827.e, Department of Pediatrics and Neurology, University of Utah, Eccles Institute of Human Genetics, Room 2260A, 15 N 2030 E, 84112, Salt Lake City, UT, USA;0000 0001 2322 4179, grid.410528.a, Université Côte d’Azur, Peripheral Nervous System, Centre Hospitalier Universitaire de Nice, Muscle & ALS Department, Pasteur 2 Hospital, 30 Voie Romaine, 06001, Nice Cedex 1, France;0000 0004 0427 667X, grid.240023.7, Center for Genetic Muscle Disorders, Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD, USA;0000 0004 0444 9382, grid.10417.33, Department of Neurology, Radboud University Medical Center, Reinier Postlaan 4 (935), 6525, Nijmegen, GC, The Netherlands;0000 0004 0458 8737, grid.224260.0, Department of Neurology, Virginia Commonwealth University, 1101 East Marshall St, PO Box 980599, 23298, Richmond, VA, USA;0000 0004 1757 2822, grid.4708.b, The NEMO Clinical Center, Neurorehabilitation Unit, University of Milan, Piazza dell’Ospedale Maggiore, 3, 20162, Milan, Italy;0000 0004 1936 9166, grid.412750.5, Department of Biostatistics and Computational Biology and Department of Neurology, University of Rochester Medical Center, 265 Crittenden Blvd., CU 420630, 14642, Rochester, NY, USA;0000 0004 1936 9166, grid.412750.5, Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Ave, 14642, Rochester, NY, USA;0000000122986657, grid.34477.33, Department of Neurology, University of Washington, 1959 NE Pacific St, 98195, Seattle, WA, USA;

关键词: Facioscapulohumeral muscular dystrophy;    Muscular dystrophy;    Outcome measures;    Clinical trial;    Functional testing;    Electrical impedance Myography;    Biomarkers;   

DOI  :  10.1186/s12883-019-1452-x

来源: publisher

【 摘 要 】

BackgroundFacioscapulohumeral 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/designThe 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.DiscussionTo 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 registrationclinicaltrials.gov NCT03458832; Date of registration: 1/11/2018

【 授权许可】

CC BY