Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by mutation of the dystrophin gene with resultant progressive muscle weakness, leading to death usually by young adulthood. It is the most common childhood neuromuscular disorder affecting about 1 in 3,500 males across all ethnic groups. Disabling weakness, loss of ambulation and self-care, and cardiopulmonary failure, create tremendous psychological and emotional stress on patients, caregivers, and family;and considerable health, education, and community resources are required for management. The disease prevalence, seriousness, and the combined emotional and financial cost make DMD a significant public health concern. Although no effective treatment for DMD is available at this time, promising and novel therapeutic treatments have emerged for DMD that will require well-designed clinical trials. Critical in this effort is the development of practical, cost-effective, and easily administered outcome measures that are clinically meaningful and sensitive to changes due to disease progression and treatment. In addition, a more detailed natural history data is needed to optimize clinical trial design. Currently, our group of twenty international centers is collecting serial measures of strength, range of motion, motor functional ability, pulmonary function, and patient-reported health-related quality of life in a cohort of 348 males with DMD between 2 and 28 years of age. In this proposed ancillary study, we will administer novel objective clinical outcome measures (6-minute walk test [6MWT], 9-hole peg test and Motor Function Measure [MFM]) and assessments of patient-reported health-related quality of life (Neuromuscular Module of the PedsQL [NMM] and NIH PROMIS Network Quality of Life in Neurological Disease [NeuroQoL] assessment) at baseline and annually for two years.
Specific aims of the project are:
Specific Aim 1 : To assess the reliability, validity, and responsiveness of novel objective clinical outcome measures in DMD: including the 6MWT, the 9-hole peg test (9-HPT), and the Motor Function Measure (MFM).
Specific Aim 2 : To assess the reliability, validity, and responsiveness of novel patient-reported outcome (PRO) measures in DMD: including the NeuroQoL and Neuromuscular module of the PedsQL (NMM).
Specific Aim 3 : To assess the clinical meaningfulness of novel objective outcome measures (6MWT, 9-HPT, and MFM) by assessing their ability to predict milestones of loss of ambulation and loss of ability to self-feed. 7 We hypothesize that in DMD, the 6MWT, 9-HPT, and MFM will be reliable, valid as determined by association with appropriate patient-reported outcome domains, responsive to disease-related progression, and clinically meaningful as determined by ability to predict important disease-related milestones. The proposal is significant for DMD patients and the research community because the study will document the utility, clinical meaningfulness and responsiveness of newly developed outcome measures that will be used as primary clinical endpoints by industry and academics in future therapeutic trials of promising new treatments.

Public Health Relevance

Duchenne muscular dystrophy (DMD) is the most common neuromuscular disease of childhood and is the neuromuscular disorder with the greatest annual per capita cost for outpatient rehabilitative treatment. The combination of the disease's prevalence, seriousness, cross-cultural presentation, and the combined emotional and financial expense make DMD a significant public health concern. One of the critical issues identified by the DMD research community, industry, and federal agencies is the development of practical, cost-effective, easily administered endpoints that are clinically meaningful and sensitive to changes in disease progression as well as those produced by treatments. Our proposal is significant for DMD patients because we will document the utility, clinical meaningfulness, and responsiveness of newly developed outcome measures that will be used as primary clinical endpoints by industry in future therapeutic trials of promising novel agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR061875-04
Application #
8735608
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Boyce, Amanda T
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
Anderson, Julia; Seol, Haeri; Gordish-Dressman, Heather et al. (2017) Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy. Pediatr Cardiol 38:1606-1612
Hathout, Yetrib; Conklin, Laurie S; Seol, Haeri et al. (2016) Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children. Sci Rep 6:31727
Boca, Simina M; Nishida, Maki; Harris, Michael et al. (2016) Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study. PLoS One 11:e0153461
Bello, Luca; Morgenroth, Lauren P; Gordish-Dressman, Heather et al. (2016) DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study. Neurology 87:401-9
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Bello, Luca; Kesari, Akanchha; Gordish-Dressman, Heather et al. (2015) Genetic modifiers of ambulation in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study. Ann Neurol 77:684-96
Shinnar, Shlomo; Cnaan, Avital; Hu, Fengming et al. (2015) Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial. Neurology 85:1108-14
Bello, Luca; Gordish-Dressman, Heather; Morgenroth, Lauren P et al. (2015) Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study. Neurology 85:1048-55
Hathout, Yetrib; Marathi, Ramya L; Rayavarapu, Sree et al. (2014) Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients. Hum Mol Genet 23:6458-69

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