A Pilot Study of Pyridostigmine in Pompe Disease

Study Overview
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Brief Summary
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Pyridostigmine is an acetylcholinesterase inhibitor, which degrades acetylcholine at the neuromuscular junction. Based on recent studies, pyridostigmine may be an effective adjuvant treatment for people with Pompe disease, as it increases the functional impact of this neurotransmitter. Hypothesis: the use of pyridostigmine in Pompe disease will improve transmission of acetylcholine across the neuromuscular junction, skeletal muscle function, respiratory function, and quality of life.

Detailed Description
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Pompe is a rare disease, which occurs in approximately 1 per 40,000 births. It is a progressive and often fatal neuromuscular disorder resulting from mutation in the gene for acid alpha-glucosidase (GAA), an enzyme necessary to degrade glycogen. Accumulation of glycogen in multiple tissues results in cardiac, respiratory and skeletal muscle dysfunction. Enzyme replacement therapy (ERT) is currently the only treatment available, and although it prolongs survival, adjuvant therapies are needed to help alleviate the dire symptoms of Pompe disease. Recent data has revealed that degradation of the neuromuscular junction (NMJ) occurs in Pompe disease. Acetylcholinesterase inhibitors (AChEI) are substances that inhibit the AChE enzyme from degrading acetylcholine at the NMJ, and thus increase the functional impact of this neurotransmitter. AChEI are established as a beneficial therapy for individuals with primary diseases of the NMJ, such as myasthenia gravis. Recently, administration of an AChEI was demonstrated to improve NMJ pathology in both mice and individuals affected by other congenital myopathies, including autosomal centronuclear myopathies (CNM), X-linked myotubular myopathy (XLMTM) and mutation of tropomyosin 3 (TPM3). Specifically, both NMJ transmission and motor function were improved. These studies demonstrate that AChEI can be beneficial in myopathy associated with NMJ pathology. In this study, we will study the acute effects of pyridostigmine on neuromuscular transmission, as well as the prolonged effects on respiratory function, skeletal muscle function and quality of life over a 90 day treatment period. This project focuses on developing an adjuvant treatment to ERT that targets dysfunction at the NMJ. Our ultimate goal is to reduce the deleterious consequences of Pompe disease and improve the overall quality and duration of life in affected individuals.

Official Title
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Evaluation of Respiratory and Skeletal Muscle Functions in Response to Acetylcholinesterase Inhibitors in Pompe Disease

Conditions
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Pompe Disease

Intervention / Treatment
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* Drug: Pyridostigmine Bromide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between 8 and 60 years of age; Diagnosis of Pompe disease (protein assay, genotyping, and positive clinical signs) No contraindication to pyridostigmine Exclusion Criteria: Already receive pyridostigmine as part of their normal clinical care at screening Are pregnant - participants will receive a urine pregnancy test at screening Have received acute administration of antibiotic, corticosteroid, or neuromuscular blockade medications within 30 days prior to screening Any other concurrent medical condition which, in the opinion of the study team, would make the subject inappropriate to participate in the assessments

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute Dose of Pyridostigmine<br>Subjects will receive an acute administration of pyridostigmine bromide, calculated on their body weight at clinical exam (1 mg/kg, 60mg max starting dose), and will be monitored for 2 hours post administration. Subjects will also receive a pre- and post-administration single-fiber EMG, respiratory tests and strength tests in order to evaluate the function of the neuromuscular junction. All study subjects will be enrolled in this arm. | Drug: Pyridostigmine Bromide<br>* Pyridostigmine is an acetylcholinesterase inhibitor, which increases the amount of acetylcholine at the neuromuscular junction. It will be taken orally, either as a tablet or as a syrup.<br>* Other names: Mestinon;|
| Experimental: Prolonged Use of Pyridostigmine<br>This arm will evaluate the impact of pyridostigmine bromide on respiratory and skeletal muscle function during a 90-day administration period. On Days 1 - 7 subjects will receive 0.5mg/kg of the study drug every 4 hours while awake. On Days 8 - 90 subjects will receive 1.0 mg/kg every 4 hours while awake. Quality of life will also be measured with the SF-36 health survey. Data collection will occur at multiple time points (Days 30 and 90) throughout the study. Subjects will also be contacted at least weekly via telephone. All study subjects will be enrolled in this arm. | Drug: Pyridostigmine Bromide<br>* Pyridostigmine is an acetylcholinesterase inhibitor, which increases the amount of acetylcholine at the neuromuscular junction. It will be taken orally, either as a tablet or as a syrup.<br>* Other names: Mestinon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in skeletal muscle function (6 Minute Walk Test)(QMT) | Quantitative muscle testing and the 6 Minute Walk Test will be used to evaluate skeletal muscle function. | Baseline, Day 90 | 
| Change in respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and vital capacity) | Pulmonary function tests, including maximal inspiratory pressure, maximal expiratory pressure, and vital capacity, will be used to evaluate respiratory function | Baseline, Day 90 | 
| Change in quality of life [short form 36 (SF-36)] | The short form 36 health survey (SF-36) will be used to evaluate quality of life | Baseline, Day 90 | 
| Evaluate the acute effects of pyridostigmine on neuromuscular junction transmission (Single-fiber EMG) | Single-fiber EMG will be performed on the tibialis anterior pre- and 2 hour post-administration of pyridostigmine. MIP and hand grip will also be tested before and after receiving the study drug. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pompe disease, Pyridostigmine