A Pilot Study of Pyridostigmine in Pompe Disease

Pompe Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02357225
• Other study ID #: IRB201200154
• Status: Terminated
• Phase: Early Phase 1
• Start date: August 2015
• Est. completion date: January 1, 2018

Study information

• Verified date: May 2018
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: January 1, 2018
• Est. primary completion date: January 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Glycogen Storage Disease Type II
• Pompe Disease

Intervention

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.

Locations

Country	Name	City	State
United States	University of Florida Clinical Research Center	Gainesville	Florida

Sponsors (1)

Lead Sponsor	Collaborator
University of Florida

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. Review. — View 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. — View 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. — View 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. Review. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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