Pompe DiseaseEarly Phase 1NCT02357225
A Pilot Study of Pyridostigmine in Pompe Disease
A Early Phase 1 study testing Pyridostigmine Bromide in people with Pompe Disease, run by University of Florida at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 8 to 60 years
- Conditions the study is for
- Pompe Disease
- What is being tested?
- Pyridostigmine Bromide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2015to 1 Jan 2018
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 to 60 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Florida Clinical Research Center
Gainesville, Florida, 32610
About this study
Official title: Evaluation of Respiratory and Skeletal Muscle Functions in Response to Acetylcholinesterase Inhibitors in Pompe Disease
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.
Read the 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.
- Conditions
- Pompe Disease
- Being tested
- Pyridostigmine Bromide
- Keywords
- Pompe disease, Pyridostigmine
- Medical subject headings
- Glycogen Storage Disease Type II
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pyridostigmine BromideDrug
Also called Mestinon
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.
| Study group | Role | What they receive |
|---|---|---|
| Acute Dose of Pyridostigmine | Experimental | 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. Receives: Drug: Pyridostigmine Bromide |
| Prolonged Use of Pyridostigmine | Experimental | 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. Receives: Drug: Pyridostigmine Bromide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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
Measured: 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.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2015 (estimated)
- Study startAug 2015
- Primary completion1 Jan 2018
- Study completion1 Jan 2018
Why it stopped: The drug was ineffective in improving function in Pompe's disease
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Pompe DiseaseStudies of the same condition, open and under way.
- More trials run by University of FloridaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Florida
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Barry J Byrne, MD, PhD, Principal investigator, University of Florida
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02357225
- Sponsor's protocol ID
- IRB201200154
- Status last verified
- May 2018
- First submitted
- 23 Jan 2015
- Last updated
- 15 May 2018
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 21518733Falk 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.
PubMed 25217571Corti 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.
PubMed 25186912Robb 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.
PubMed 21440438Maggi 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.
PubMed 21815707
Study at a glance
From the registry record, last updated by the sponsor on 15 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of Respiratory and Skeletal Muscle Functions in Response to Acetylcholinesterase Inhibitors in Pompe Disease
- ClinicalTrials.gov ID
- NCT02357225
- Acronym / sponsor ID
- IRB201200154
- Conditions
- Pompe Disease
- Keywords
- Pompe disease, Pyridostigmine
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The drug was ineffective in improving function in Pompe's disease
- Enrolment
- 2 participants (actual)
- Lead sponsor
- University of FloridaUniversity, hospital or other
- Study start
- Aug 2015 (actual)
- Primary completion
- 1 Jan 2018 (actual)
- Study completion
- 1 Jan 2018 (actual)
- First posted
- 6 Feb 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Acute Dose of Pyridostigmine | Experimental | Drug: Pyridostigmine BromideSubjects 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. |
| Prolonged Use of Pyridostigmine | Experimental | Drug: Pyridostigmine BromideThis 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. |
Who may qualify
- Ages
- 8 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pyridostigmine BromideAlso: MestinonPyridostigmine 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. | Drug | Acute Dose of Pyridostigmine, Prolonged Use of Pyridostigmine |
Primary outcome
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.
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
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
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.
Results and safety
The study was stopped early (reason given: The drug was ineffective in improving function in Pompe's disease). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 May 2018.
- Background: PubMed 21518733Byrne 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.
- Background: PubMed 25217571Falk 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.
- Background: PubMed 25186912Corti 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.
- Background: PubMed 21440438Robb 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.
- Background: PubMed 21815707Maggi 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Barry J Byrne, MD, PhD principal investigator
University of Florida
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Pyridostigmine Bromide in people with Pompe Disease, run by University of Florida at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 15 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: The drug was ineffective in improving function in Pompe's disease). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in skeletal muscle function (6 Minute Walk Test)(QMT) (time frame: Baseline, Day 90). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02357225, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 May 2018.