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A Pilot Study of Pyridostigmine in Pompe Disease

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ClinicalTrials.gov Identifier: NCT02357225
Recruitment Status : Terminated (The drug was ineffective in improving function in Pompe's disease)
First Posted : February 6, 2015
Last Update Posted : May 15, 2018
Sponsor:
Information provided by (Responsible Party):
University of Florida

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Pompe Disease Drug: Pyridostigmine Bromide Early Phase 1

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of Respiratory and Skeletal Muscle Functions in Response to Acetylcholinesterase Inhibitors in Pompe Disease
Actual Study Start Date : August 2015
Actual Primary Completion Date : January 1, 2018
Actual Study Completion Date : January 1, 2018


Arm Intervention/treatment
Experimental: Acute Dose of Pyridostigmine
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
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.
Other Name: Mestinon

Experimental: Prolonged Use of Pyridostigmine
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
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.
Other Name: Mestinon




Primary Outcome Measures :
  1. Change in skeletal muscle function (6 Minute Walk Test)(QMT) [ Time Frame: Baseline, Day 90 ]
    Quantitative muscle testing and the 6 Minute Walk Test will be used to evaluate skeletal muscle function.

  2. Change in respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and vital capacity) [ Time Frame: Baseline, Day 90 ]
    Pulmonary function tests, including maximal inspiratory pressure, maximal expiratory pressure, and vital capacity, will be used to evaluate respiratory function

  3. Change in quality of life [short form 36 (SF-36)] [ Time Frame: Baseline, Day 90 ]
    The short form 36 health survey (SF-36) will be used to evaluate quality of life

  4. Evaluate the acute effects of pyridostigmine on neuromuscular junction transmission (Single-fiber EMG) [ Time Frame: Baseline ]
    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.



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Ages Eligible for Study:   8 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males or females between 8 and 60 years of age;
  2. Diagnosis of Pompe disease (protein assay, genotyping, and positive clinical signs)
  3. No contraindication to pyridostigmine

Exclusion Criteria:

  1. Already receive pyridostigmine as part of their normal clinical care at screening
  2. Are pregnant - participants will receive a urine pregnancy test at screening
  3. Have received acute administration of antibiotic, corticosteroid, or neuromuscular blockade medications within 30 days prior to screening
  4. Any other concurrent medical condition which, in the opinion of the study team, would make the subject inappropriate to participate in the assessments

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02357225


Locations
United States, Florida
University of Florida Clinical Research Center
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Investigators
Principal Investigator: Barry J Byrne, MD, PhD University of Florida

Publications:
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02357225     History of Changes
Other Study ID Numbers: IRB201200154
First Posted: February 6, 2015    Key Record Dates
Last Update Posted: May 15, 2018
Last Verified: May 2018

Keywords provided by University of Florida:
Pompe disease
Pyridostigmine

Additional relevant MeSH terms:
Glycogen Storage Disease Type II
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Glycogen Storage Disease
Carbohydrate Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Bromides
Pyridostigmine Bromide
Cholinesterase Inhibitors
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs