Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): A protocol for a sham-controlled clinical trial.



Morbidity and mortality in adults with late-onset Pompe disease (LOPD) results primarily from persistent progressive respiratory muscle weakness despite treatment with enzyme replacement therapy (ERT). To address this need, we have developed a 12-week respiratory muscle training (RMT) program that provides calibrated, individualized, and progressive pressure-threshold resistance against inspiration and expiration. Our previous results suggest that our RMT regimen is safe, well-tolerated, and results in large increases in respiratory muscle strength. We now conduct an exploratory double-blind, randomized control trial (RCT) to determine: 1) utility and feasibility of sham-RMT as a control condition, 2) the clinically meaningful outcome measures for inclusion in a future efficacy trial. This manuscript provides comprehensive information regarding the design and methods used in our trial and will aid in the reporting and interpretation of our future findings.


Twenty-eight adults with LOPD will be randomized (1:1) in blocks of 4 to RMT (treatment) or sham-RMT (control). Assessments will be conducted at pretest, posttest, 3-months detraining, and 6-months detraining. The primary outcome is maximum inspiratory pressure (MIP). Secondary outcomes include maximum expiratory pressure (MEP), 6-min walk test (6MWT), Gait, Stairs, Gowers, and Chair test (GSGC), peak cough flow (PCF), and patient-reported life activity/social participation (Rasch-built Pompe-specific Activity scale [R-Pact]). Exploratory outcomes include quantitative measures from polysomnography; patient reported measures of fatigue, daytime sleepiness, and sleep quality; and ultrasound measures of diaphragm thickness. This research will use a novel tool to provide automated data collection and user feedback, and improve control over dose.

Ethics and dissemination

The results of this clinical trial will be promptly analyzed and submitted for publication. Results will also be made available on NCT02801539, R21AR069880.





Published Version (Please cite this version)


Publication Info

Jones, Harrison N, Maragatha Kuchibhatla, Kelly D Crisp, Lisa D Hobson Webb, Laura Case, Milisa T Batten, Jill A Marcus, Richard M Kravitz, et al. (2019). Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): A protocol for a sham-controlled clinical trial. Molecular genetics and metabolism, 127(4). pp. 346–354. 10.1016/j.ymgme.2019.05.001 Retrieved from

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Harrison N. Jones

Associate Professor of Head and Neck Surgery & Communication Sciences

Laura Elizabeth Case

Associate Professor in Orthopaedic Surgery

Laura E Case, PT, DPT, MS, PhD, PCS, C/NDT is a board-certified clinical specialist in pediatric physical therapy. She has dedicated her career to teaching, research in childhood-onset neuromusculoskeletal disorders, and to the lifelong treatment of people with childhood-onset neurological and neuromuscular disorders such as cerebral palsy, traumatic brain injury, Duchenne muscular dystrophy, spinal muscular atrophy, Pompe disease, myelodysplasia, juvenile rheumatoid arthritis, and brachial plexus injury.

She has been involved in numerous clinical trials for the treatment of disorders including Pompe disease and other metabolic disorders, cerebral palsy, Duchenne muscular dystrophy, and spinal muscular atrophy. Dr. Case has participated in the development of international guidelines for the management of Duchenne muscular dystrophy, Pompe disease, and other glycogen storage diseases.

She teaches and consults internationally, has worked on a number of Center for Disease Control (CDC) task forces, has served on numerous committees and task forces in the pediatric section of APTA, served two terms as NC State Representative to the APTA Section on Pediatrics, and is a member of the North American Pompe Registry Board of Advisors.


Priya Sunil Kishnani

Chen Family Distinguished Professor of Pediatrics


A multidisciplinary approach to care of individuals with genetic disorders in conjunction with clinical and bench research that contributes to:
1) An understanding of the natural history and delineation of long term complications of genetic disorders  with a special focus on liver Glycogen storage disorders, lysosomal disorders with a special focus on Pompe disease, Down syndrome and hypophosphatasia
2) ) The development of new therapies such as AAV gene therapy, enzyme therapy, small molecule and other approaches for genetic disorders through translational research

3) The development and execution of large multicenter trials to confirm safety and efficacy of potential therapies
4) Role of antibodies/immune response in patients on therapeutic proteins and AAV gene therapy

. Glycogen Storage Disease (GSD): We are actively following subjects with all types of Glycogen Storage Disease, with particular emphasis on types I, II, III, IV, VI and IX. The goal of the treatment team is to better determine the clinical phenotype and long term complications of these diseases. Attention to disease manifestations observed in adulthood, such as adenomas and risk for HCC, is of paramount importance in monitoring and treating these chronic illnesses. We are establishing clinical algorithms for managing adenomas, and the overall management of these patients including cardiac, bone, muscle and liver issues. A special focus is biomarker discovery, an Omics approach including metabolomics and immune phenotyping. We are working on AAV gene therapy for several hepatic GSDs

.Lysosomal Storage Disease: The Duke Lysosomal Storage Disease (LSD) treatment center follows and treats patients with Pompe, Gaucher, Fabry, Mucopolysaccharidosis, Niemann Pick, LAL-D and other LSD's. The Duke Metabolism Clinical Research Team is exploring many aspects of enzyme replacement therapy (ERT), including impact on different systems, differential response, and long term effects. Other symptomatic and treatment interventions for this category of diseases are also being explored in the context of clinical care.

. Pompe Disease: The care team has extensive experience in the care of infants and adults with Pompe disease and was instrumental in conducting clinical trials and the bench to bedside work that led to the 2006 FDA approval of alglucosidase alfa, the first treatment for this devastating disease. We are currently focusing on role of antibodies/immune response on patient outcome and role of immune modulation/immune suppression as an adjunct to ERT. Our team is also working on AAV gene therapy for Pompe disease. A focus is on newborn screening (NBS) and understanding the clinical phenotype and management approaches for babies identified via NBS

.  Hypophosphatasia: We follow a large cohort of patients with HPP. The goal is to understand the features of the disease beyond bone disease, development of biomarkers, role of ERT and immune responses in HPP

. Neuromuscular disorders: We are collaborating with neurologists, cardiologists and neuromuscular physicians to serve as a treatment site for clinical trials in these diseases. We are currently involved in trials of DMD and are working closely on setting up collaborations for studies in SMA.

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