Elsevier

Neuromuscular Disorders

Volume 30, Issue 11, November 2020, Pages 904-914
Neuromuscular Disorders

Respiratory muscle training in late-onset Pompe disease: Results of a sham-controlled clinical trial

https://doi.org/10.1016/j.nmd.2020.09.023Get rights and content

Highlights

  • First controlled trial of respiratory muscle training in late-onset Pompe disease.

  • Respiratory muscle training is safe and well-tolerated.

  • Increases in respiratory muscle strength larger in treatment vs sham subjects though not statistically significant.

  • Sham respiratory muscle training may not be an optimal control condition.

  • A larger sample stratified by disease severity is needed in future research.

Abstract

To address progressive respiratory muscle weakness in late-onset Pompe disease (LOPD), we developed a 12-week respiratory muscle training (RMT) program. In this exploratory, double-blind, randomized control trial, 22 adults with LOPD were randomized to RMT or sham-RMT. The primary outcome was maximum inspiratory pressure (MIP). Secondary and exploratory outcomes included maximum expiratory pressure (MEP), peak cough flow, diaphragm ultrasound, polysomnography, patient-reported outcomes, and measures of gross motor function. MIP increased 7.6 cmH2O (15.9) in the treatment group and 2.7 cmH2O (7.6) in the control group (P = 0.4670). MEP increased 14.0 cmH2O (25.9) in the treatment group and 0.0 cmH2O (12.0) in the control group (P = 0.1854). The only statistically significant differences in secondary/exploratory outcomes were improvements in time to climb 4 steps (P = 0.0346) and daytime sleepiness (P = 0.0160). The magnitude of changes in MIP and MEP in the treatment group were consistent with our pilot findings but did not achieve statistical significance in comparison to controls. Explanations for this include inadequate power and baseline differences in subject characteristics between groups. Additionally, control group subjects appeared to exhibit an active response to sham-RMT and therefore sham-RMT may not be an optimal control condition for RMT in LOPD.

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

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