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A Pilot Study of Pyridostigmine in Pompe Disease

Primary Purpose

Pompe Disease

Status
Terminated
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pyridostigmine Bromide
Sponsored by
University of Florida
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pompe Disease focused on measuring Pompe disease, Pyridostigmine

Eligibility Criteria

8 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Florida Clinical Research Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Acute Dose of Pyridostigmine

Prolonged Use of Pyridostigmine

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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
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
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.

Secondary Outcome Measures

Full Information

First Posted
January 23, 2015
Last Updated
May 9, 2018
Sponsor
University of Florida
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1. Study Identification

Unique Protocol Identification Number
NCT02357225
Brief Title
A Pilot Study of Pyridostigmine in Pompe Disease
Official Title
Evaluation of Respiratory and Skeletal Muscle Functions in Response to Acetylcholinesterase Inhibitors in Pompe Disease
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Terminated
Why Stopped
The drug was ineffective in improving function in Pompe's disease
Study Start Date
August 2015 (Actual)
Primary Completion Date
January 1, 2018 (Actual)
Study Completion Date
January 1, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Florida

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pompe Disease
Keywords
Pompe disease, Pyridostigmine

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Acute Dose of Pyridostigmine
Arm Type
Experimental
Arm Description
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.
Arm Title
Prolonged Use of Pyridostigmine
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Pyridostigmine Bromide
Other Intervention Name(s)
Mestinon
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in skeletal muscle function (6 Minute Walk Test)(QMT)
Description
Quantitative muscle testing and the 6 Minute Walk Test will be used to evaluate skeletal muscle function.
Time Frame
Baseline, Day 90
Title
Change in respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and vital capacity)
Description
Pulmonary function tests, including maximal inspiratory pressure, maximal expiratory pressure, and vital capacity, will be used to evaluate respiratory function
Time Frame
Baseline, Day 90
Title
Change in quality of life [short form 36 (SF-36)]
Description
The short form 36 health survey (SF-36) will be used to evaluate quality of life
Time Frame
Baseline, Day 90
Title
Evaluate the acute effects of pyridostigmine on neuromuscular junction transmission (Single-fiber EMG)
Description
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.
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barry J Byrne, MD, PhD
Organizational Affiliation
University of Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Florida Clinical Research Center
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
21518733
Citation
Byrne BJ, Falk DJ, Pacak CA, Nayak S, Herzog RW, Elder ME, Collins SW, Conlon TJ, Clement N, Cleaver BD, Cloutier DA, Porvasnik SL, Islam S, Elmallah MK, Martin A, Smith BK, Fuller DD, Lawson LA, Mah CS. Pompe disease gene therapy. Hum Mol Genet. 2011 Apr 15;20(R1):R61-8. doi: 10.1093/hmg/ddr174. Epub 2011 Apr 25.
Results Reference
background
PubMed Identifier
25217571
Citation
Falk DJ, Todd AG, Lee S, Soustek MS, ElMallah MK, Fuller DD, Notterpek L, Byrne BJ. Peripheral nerve and neuromuscular junction pathology in Pompe disease. Hum Mol Genet. 2015 Feb 1;24(3):625-36. doi: 10.1093/hmg/ddu476. Epub 2014 Sep 12.
Results Reference
background
PubMed Identifier
25186912
Citation
Corti M, Smith BK, Falk DJ, Lawson LA, Fuller DD, Subramony SH, Byrne BJ, Christou EA. Altered activation of the tibialis anterior in individuals with Pompe disease: Implications for motor unit dysfunction. Muscle Nerve. 2015 Jun;51(6):877-83. doi: 10.1002/mus.24444. Epub 2015 Apr 24.
Results Reference
background
PubMed Identifier
21440438
Citation
Robb SA, Sewry CA, Dowling JJ, Feng L, Cullup T, Lillis S, Abbs S, Lees MM, Laporte J, Manzur AY, Knight RK, Mills KR, Pike MG, Kress W, Beeson D, Jungbluth H, Pitt MC, Muntoni F. Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies. Neuromuscul Disord. 2011 Jun;21(6):379-86. doi: 10.1016/j.nmd.2011.02.012. Epub 2011 Mar 25.
Results Reference
background
PubMed Identifier
21815707
Citation
Maggi L, Mantegazza R. Treatment of myasthenia gravis: focus on pyridostigmine. Clin Drug Investig. 2011 Oct 1;31(10):691-701. doi: 10.2165/11593300-000000000-00000.
Results Reference
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A Pilot Study of Pyridostigmine in Pompe Disease

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