Respiratory muscle training in late-onset Pompe disease: Results of a sham-controlled clinical trial
Introduction
Pompe disease is an autosomal recessive inherited progressive metabolic myopathy that results in skeletal, cardiac, and smooth muscle weakness, respiratory muscle involvement, and early death. Deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) causes tissue destruction and muscle fiber atrophy [1]. Pompe disease manifests clinically across a spectrum based on age of onset, progression rate, genetic mutation(s), and disease distribution [2]. Late-onset Pompe disease (LOPD) presents as a spectrum of disease involvement from the first year of life to patients who present in adulthood with signs and symptoms related to progressive weakness in the lower limbs, trunk, and respiratory muscles [3], [4], [5]. Despite enzyme replacement therapy (ERT) with alglucosidase alfa, (LumizymeⓇ), respiratory muscle weakness often persists and remains a primary cause of morbidity and mortality in LOPD. Respiratory weakness in LOPD leads to ineffective cough and reduced airway clearance [6], sleep-disordered breathing [7], and progressive respiratory insufficiency.
Over 18 months of treatment with ERT in LOPD, walking distance is improved and pulmonary function is stabilized based on forced vital capacity. Modest increases in respiratory strength are achieved 12 to 26 weeks after initiation of ERT in roughly two-thirds of patients [3], [8]. Thus, up to a third of patients exhibit no improvements, and, in those who do, these effects on respiratory strength either remain stable or diminish over time. Recent data from 177 LOPD patients were unable to detect the effect of ERT on the subsequent need for respiratory support [9]. While treatments such as bi-level ventilation and cough-assisting devices may improve survival, they do not modulate progressive respiratory weakness. Advanced disease progression at the time of initiation of ERT may limit the reversal of motor and pulmonary signs associated with disease phenotype [10], [11]. Therefore, despite drug therapy, respiratory muscle weakness remains an unmet medical need in LOPD. Though next generation therapies currently under development appear to hold promise [12], adjunctive treatments to prevent ongoing progression of disease severity may still provide meaningful improvements in patients’ quality of life. Counteracting respiratory weakness with resistance training offers a plausible biological mechanism to address this clinical gap. In response, we have developed a 12-week RMT program that provides calibrated, individualized, progressive pressure-threshold resistance against inspiration and expiration [13], [14], [15], [16].
Although patients with muscle disease were once discouraged from exercise, consensus guidelines now support supervised exercise programs in patients with Pompe disease [4], [17]. Whole body exercise studies involving resistance and/or aerobic training in humans with LOPD on ERT suggest that supervised exercise programs are safe and well-tolerated, benefit muscular strength and functional capacity, and improve pain and fatigue [[18], [19], [20], [21], [22]]. Therefore, supervised programs of submaximal exercise training are increasingly thought to have value as both adjunctive treatments to ERT and as part of the comprehensive treatment of LOPD.
There has also been increased interest, including our own, in the use of RMT to provide resistance training to the inspiratory and/or expiratory muscles directly in patients with LOPD on ERT [[13], [14], [15], [16],[23], [24], [25]]. Overall, these studies, albeit in relatively small groups of subjects, suggest that RMT in LOPD is safe and well-tolerated and may be a useful intervention to increase respiratory muscle strength.
Although preliminary data from our laboratory and others are promising, RMT research with a control group has not previously been conducted in LOPD. Therefore, we investigated the effects of our 12-week RMT regimen in a group of 22 adults with LOPD in an exploratory, double-blind, randomized control trial (RCT) using a parallel arm pretest-posttest design and sham-RMT as the control condition. Our aims were to: 1) determine the utility and feasibility of sham-RMT as a control condition for RMT in a double-blind RCT, and 2) determine the clinically meaningful outcomes for inclusion in future clinical trial.
Section snippets
Methods
Comprehensive, detailed information regarding the design of our trial and the methodology employed was previously published and the reader is referred to this manuscript for a full description of our methods [15]. A brief review is provided below. This study was registered in a publicly accessible clinical trials database (clinicaltrials.gov identifier: NCT02801539). The Duke University Health System Institutional Review Board approved this research and informed consent was obtained from each
Results
Twenty-eight subjects with LOPD were enrolled in the study. Six subjects withdrew before starting study procedures due to concerns about the time and/or expense of the required travel or their overall health status. Therefore 22 subjects were randomized to either RMT (n = 12) or sham-RMT (n = 10) and completed the treatment phase of the study. Baseline characteristics for these 22 participants are provided in Table 1. Data are presented as pretest-posttest mean change scores (standard
Discussion
The primary outcome for this exploratory, double-blind, sham-controlled RCT of RMT in LOPD was pretest to posttest change in MIP. Although change in MIP was greater in the treatment group versus control, these differences did not achieve statistical significance. Similarly, while pretest to posttest change in MEP was greater in the treatment group relative to control, these differences were not statistically significant. Except for pretest to posttest improvements in time to climb 4 steps on
Conclusion
Results from this exploratory, double-blind, sham-controlled RCT of RMT in LOPD show promise for treatment of respiratory weakness and warrant further investigation. With very few treatment options available for respiratory muscle weakness in this population, our findings confirm our prior experiences suggesting our 12-week RMT regimen is safe and well-tolerated in LOPD subjects. In terms of magnitude of change, changes in MIP and MEP were consistent with our pilot findings but did not achieve
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
LEC, PSK, LHW, and HNJ have received research/grant support and honoraria from Sanofi Genzyme Corporation. LEC is a member of the Pompe Registry Board of Advisors for Sanofi Genzyme. PSK has received research/grant support, honoraria, and/or consulting fees from Valerion Therapeutics, Amicus Therapeutics, Vertex Pharmaceuticals, and Asklepios BioPharmaceuticals,
Acknowledgements
This work was supported by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases [R21AR069880]. The authors would like to acknowledge Joanna Downer for her helpful discussions and editorial guidance, Emily Randolph and Tracy Boggs for their contributions to data collection, and Matt Brown for his contributions to the development and production of the RMT-related technologies described in this manuscript. Additionally, we would like to thank
References (37)
- et al.
Pompe disease diagnosis and management guideline
Genet Med
(2006) - et al.
The emerging phenotype of late-onset Pompe disease: a systematic literature review
Mol Genet Metab
(2017) - et al.
Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alpha: the EMBASSY study
Mol Genet Metab
(2016) - et al.
Pompe disease: early diagnosis and early treatment make a difference
Pediatr Neonatol
(2013) - et al.
Clinical and pathophysiological clues of respiratory dysfunction in late-onset Pompe disease: new insights from a comparative study by MRI and respiratory function assesment
Neuromuscul Disord
(2015) - et al.
Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): effects of training and detraining
Mol Genet Metab
(2016) - et al.
Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): a protocol for a sham-controlled clinical trial
Mol Genet Metab
(2019) - et al.
Increased inspiratory and expiratory muscle strength following respiratory muscle strength training (RMST) in two patients with late-onset Pompe disease
Mol Genet Metab
(2011) - et al.
Effect of aerobic and resistance exercise training on late-onset Pompe disease patients receiving enzyme replacement therapy
Mol Genet Metab
(2011) - et al.
Effects of exercise training during infusion on late-onset Pompe disease patients receiving enzyme replacement therapy
Mol Genet Metab
(2012)
Daily respiratory training with large intrathoracic pressures, but not large lung volumes, lowers blood pressure in normotensive adults
Respir Physiol Neurobiol
Role of autophagy in the pathogenesis of Pompe disease
Acta Myol
A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease
J Pediatr
A randomized study of alglucosidase alfa in late-onset Pompe's disease
N Engl J Med
Cough effectiveness and pulmonary hygiene practices in patients with Pompe disease
Lung
Sleep-related symptoms and sleep-disordered breathing in adult Pompe disease
Eur J Neurol
Enzyme replacement therapy reduces the risk for wheelchair dependency in adult Pompe patients
Orphanet J Rare Dis
Pompe disease
Medlink Neurology [Internet]
Cited by (10)
Safety and effectiveness of resistance training in patients with late onset Pompe disease - a pilot study
2022, Neuromuscular DisordersCitation Excerpt :Recently inspiratory muscle training was shown to improve MIP and thereby stabilize and decelerate the decline of the diaphragm strength and was recommended to be offered to all LOPD patients, especially those who demonstrate a progressive decline in respiratory muscle function or are unable to receive ERT [14–16]. Jones et al. (2011,2019,2020) [12,13,22] provided inspiratory and expiratory muscle strength training in small groups of patients with LOPD and showed that RMT in LOPD is safe and well-tolerated and increases respiratory muscle strength. The first study to evaluate respiratory muscle strength training used a device that provided 60% of the maximal inspiratory and expiratory strength with 25 repetitions twice a day six days a week [11] An 8 week respiratory muscle training study (both inspiratory and expiratory resistance, at 70% of MIP (for inspiratory training) and MEP, 25 repetitions) in eight patients with LOPD who were receiving ERT, was conducted revealed a significant increase in MIP in all 8 subjects, and 7 of 8 showed increases in MEP [12].
Inspiratory Muscle Training in Nemaline Myopathy
2023, Journal of Neuromuscular DiseasesSleep disorders in patients with neuromuscular diseases
2023, Somnologie