Clinical trial NCT02357225: 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
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Pompe Disease
Keywords: Pompe disease
Pyridostigmine
Lead sponsor: University of Florida
Sponsor class: OTHER
First posted: 2015-02-06
Enrollment: 2
Sex: ALL
Minimum age (years): 8
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Change in skeletal muscle function (6 Minute Walk Test)(QMT)
timeFrame: Baseline, Day 90
measure: Change in respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and vital capacity)
timeFrame: Baseline, Day 90
measure: Change in quality of life [short form 36 (SF-36)]
timeFrame: Baseline, Day 90
measure: Evaluate the acute effects of pyridostigmine on neuromuscular junction transmission (Single-fiber EMG)
timeFrame: Baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida Clinical Research Center
state: Florida
Study officials:
affiliation: University of Florida
name: Barry J Byrne, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.