Abstract
Pompe disease/glycogen storage disease type II, is a rare, lysosomal storage disorder associated with progressive proximal myopathy, causing a gradual loss of muscular function and respiratory insufficiency. Studies of patients with late-onset Pompe disease have used endpoints such as the 6-minute walking test (6MWT) and forced vital capacity (FVC) to assess muscular and respiratory function during disease progression or treatment. However, the relevance of these markers to late-onset Pompe disease and the minimal clinically important difference (MCID) for these endpoints in late-onset Pompe disease have not yet been established. A literature search was carried out to identify studies reporting the MCID (absolute and relative) for the 6MWT and FVC in other diseases. The MCIDs determined in studies of chronic respiratory diseases were used to analyze the results of clinical studies of enzyme replacement therapy in late-onset Pompe disease. In 9 of the 10 late-onset Pompe disease studies reviewed, changes from baseline in the 6MWT were above or within the MCID established in respiratory diseases. Clinical improvement was perceived by patients in 6 of the 10 studies. In 6 of the 9 late-onset Pompe disease studies that reported FVC, the changes from baseline in percentage predicted FVC were above or within the MCID established in respiratory diseases and the difference was perceived as either an improvement or stabilization by patients. However, applying the 6MWT and FVC MCIDs from studies of chronic respiratory diseases to late-onset Pompe disease has several important limitations. Outcome measures in muscular dystrophies include composite measures of muscle function and gait, as well as Rasch-designed and validated tools to assess disease-related quality of life and activities of daily living. Given that the relevance to patients with late-onset Pompe disease of the 6MWT or FVC MCIDs established for chronic respiratory diseases is unclear, these measures should be evaluated specifically in late-onset Pompe disease and alternative outcome measures more specific to neuromuscular disease considered.
Highlights
One of the key factors in the evaluation of an intervention in controlled clinical trials is the clinical relevance of the selected study endpoints or outcome measures, together with an understanding of what comprises a minimal clinically important difference (MCID) in these endpoints
In this article we determine the clinical relevance of 6-minute walking test (6MWT) distance (6MWD) and % predicted forced vital capacity (FVC), which are currently used to assess late-onset Pompe patients, to compare these with the parameters used in long-term studies in other neuromuscular disorders (NMDs) such as Duchenne/Becker muscular dystrophy (DMD/BMD), and to consider the potential clinical relevance of alternative clinical endpoints in late-onset Pompe disease
Our analysis identified the range of MCID for 6MWT and FVC in chronic respiratory disease, and extrapolated these findings to the natural history of lateonset Pompe disease and to the results of clinical studies of enzyme replacement therapy (ERT) in late-onset Pompe disease
Summary
One of the key factors in the evaluation of an intervention in controlled clinical trials is the clinical relevance of the selected study endpoints or outcome measures, together with an understanding of what comprises a minimal clinically important difference (MCID) in these endpoints. Establishing the MCID for study endpoints allows the clinical relevance of efficacy data from published trial results to be determined. This is of particular relevance in studies that investigate treatment efficacy in chronic, progressive diseases such as the lysosomal storage disorders. In this article we determine the clinical relevance of 6MWD and % predicted FVC (main outcome measures), which are currently used to assess late-onset Pompe patients, to compare these with the parameters used in long-term studies in other neuromuscular disorders (NMDs) such as Duchenne/Becker muscular dystrophy (DMD/BMD), and to consider the potential clinical relevance of alternative clinical endpoints in late-onset Pompe disease
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