Safety Study of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase to Treat Pompe Disease

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT00976352
First received: July 13, 2009
Last updated: June 24, 2014
Last verified: June 2014
  Purpose

Pompe disease is an inherited condition of acid alpha-glucosidase (GAA) deficiency resulting in lysosomal accumulation of glycogen in all tissues. Glycogen accumulation leads to muscle dysfunction and profound muscle weakness. A wide spectrum of disease is characteristic and the most severe patients have cardiorespiratory failure, often fatal in the first two years of life. Researchers have developed a way to introduce the normal GAA gene into muscle cells with the expectation that the GAA protein will be produced at levels sufficient to reduce glycogen accumulation. This study will evaluate the safety of the experimental gene transfer procedure in individuals with GAA deficiency. The study will also determine what dose may be required to achieve improvement in measures of respiratory function.


Condition Intervention Phase
Pompe Disease
Drug: Study Agent Administration
Other: Safety Labs
Other: Pulmonary Function Testing
Other: RMST
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Diaphragm Delivery of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase (rAAV1-CMV-GAA) Gene Vector in Patients With Pompe Disease

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Assessment of the safety of intramuscular administration of a recombinant adeno-associated virus, rAAV1-CMV-GAA, in children with ventilator dependent Pompe disease. [ Time Frame: Days 1, 3, 14, 30, 60, 90, 180, 270 and 365 post study agent administration. ] [ Designated as safety issue: Yes ]
    Ventilatory assistance is defined as any use of ventilation-support (including, but not limited to BiPAP, CPAP, Mechanical Ventilation, Diaphragmatic Pacemaker).


Secondary Outcome Measures:
  • Determination of the dose of rAAV1-CMV-GAA vector required to achieve diaphragm transduction and restoration of GAA activity in the diaphragm. [ Time Frame: Day 14, 90, 180, 270, and 365 post study agent administration ] [ Designated as safety issue: No ]
    Efficacy measure. AAV antibodies, GAA antibodies and Western Blot.

  • Evaluation of Ventilatory performance benefit of rAAV1-CMV-GAA gene transfer and RMST compared to RMST alone. [ Time Frame: Screening, Baseline, (pre-study agent administration) and Day 14, 90, 180, 270, and 365 post study agent administration. ] [ Designated as safety issue: No ]
    Pulmonary Function Testing to include: MIP, Best Unassisted Tidal Volume (TV), Maximal Voluntary Ventilation (MVV), Unassisted Ventilatory Endurance.


Estimated Enrollment: 10
Study Start Date: September 2010
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Study Agent Administration: cohort 1
rAAV1-CMV-GAA: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.
Drug: Study Agent Administration
rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 3 subjects. Cohort 3 = 4 subjects.
Other Names:
  • Gene transfer
  • Gene therapy
  • Pompe disease
  • Diaphragm
  • GAA
Other: Safety Labs
Adeno-associated virus(AAV) antibody level; Alglucosidase alpha (GAA) antibody level; Western Blot
Other: Pulmonary Function Testing
Pulmonary Function Testing to include: MIP, Best Unassisted Tidal Volume (TV), Maximal Voluntary Ventilation (MVV), Unassisted Ventilatory Endurance. Completed at Screening, Baseline, Day 14, Day 90, Day 180, Day 270, and Day 365.
Other: RMST
After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration.
Experimental: Study Agent Administration: Cohort 2
rAAV1-CMV-GAA: 5.0 x 10e12 vector genomes Cohort 2 = 3 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.
Drug: Study Agent Administration
rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 3 subjects. Cohort 3 = 4 subjects.
Other Names:
  • Gene transfer
  • Gene therapy
  • Pompe disease
  • Diaphragm
  • GAA
Other: Safety Labs
Adeno-associated virus(AAV) antibody level; Alglucosidase alpha (GAA) antibody level; Western Blot
Other: Pulmonary Function Testing
Pulmonary Function Testing to include: MIP, Best Unassisted Tidal Volume (TV), Maximal Voluntary Ventilation (MVV), Unassisted Ventilatory Endurance. Completed at Screening, Baseline, Day 14, Day 90, Day 180, Day 270, and Day 365.
Other: RMST
After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration.
Experimental: Study Agent Administration: Cohort 3
rAAV1-CMV-GAA: 1.0 x 10e12 vector genomes Cohort 3 = 4 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.
Drug: Study Agent Administration
rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 3 subjects. Cohort 3 = 4 subjects.
Other Names:
  • Gene transfer
  • Gene therapy
  • Pompe disease
  • Diaphragm
  • GAA
Other: Safety Labs
Adeno-associated virus(AAV) antibody level; Alglucosidase alpha (GAA) antibody level; Western Blot
Other: Pulmonary Function Testing
Pulmonary Function Testing to include: MIP, Best Unassisted Tidal Volume (TV), Maximal Voluntary Ventilation (MVV), Unassisted Ventilatory Endurance. Completed at Screening, Baseline, Day 14, Day 90, Day 180, Day 270, and Day 365.
Other: RMST
After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration.

Detailed Description:

The goal of the current study is to evaluate an experimental gene transfer procedure in which normal copies of the GAA gene are inserted into cells. In this study, a modified virus, adeno-associated virus (AAV), has been engineered to carry a normal copy of the GAA gene, known as rAAV1-CMV-hGAA, which is used to place normal copies of the GAA gene into diaphragm muscle cells. The purpose of this study is to evaluate the safety of rAAV1-CMV-hGAA delivery into individuals with GAA deficiency (Pompe Disease).

Participants currently using enzyme replacement therapy will continue to receive their regular medical regimen during the 12 month duration of the study. Participants will first attend a screening study visit to confirm study eligibility. Participants will then attend a 3-5 day inpatient visit, during which they will receive a series of intradiaphragmatic injections consisting of the study agent (rAAV1-CMV-hGAA). Follow-up study visits will occur on Days 14, 90, 180, 270 and 365. Participants will have yearly follow-up evaluations by either telephone or mail for a total of 15 years, or as required by the FDA and other regulatory agencies.

  Eligibility

Ages Eligible for Study:   2 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female subjects 2-18 years of age.
  • Have a diagnosis of Pompe, as defined by protein assay, DNA sequence of the acid alpha-glucosidase gene and clinical symptoms of the disease.
  • Using assisted ventilation at baseline. Mechanical Ventilation is defined as any use of ventilation support, (including but not limited to BiPAP, CPAP), a minimum of 1 hours per day.
  • Willing to discontinue aspirin, aspirin-containing products and other drugs that may alter platelet function, 7 days prior to dosing, resuming 24 hours after the dose has been administered.

Exclusion Criteria:

The subject must not:

  • Have required acute, as distinguished from long-term, maintenance or chronic suppressive, oral or intravenous antibiotic therapy for a respiratory infection within 15 days prior to baseline screening.
  • Have required oral or systemic corticosteroids within the last 15 days prior to baseline screening.
  • Have a platelet count less than 75,000/ cu mm.
  • Have an INR greater than 1.3.
  • Serological evidence of hepatitis B, hepatitis C, or HIV positive.
  • Be currently or within the past 30 days participating in any other research protocol involving investigational agents or therapies.
  • Have received gene transfer agents within the past 6 months.
  • Have history of platelet dysfunction, evidence of abnormal platelet function at screening or history of recent use of drugs that may alter platelet function which the subject is unable/unwilling to discontinue for study agent administration.
  • Have any other concurrent condition which, in the opinion of the investigator, would make the subject unsuitable for the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00976352

Locations
United States, Florida
Shands at the University of Florida
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Investigators
Principal Investigator: Barry J Byrne, MD, PhD University of Florida
Principal Investigator: Shelley Collins, MD University of Florida
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00976352     History of Changes
Other Study ID Numbers: PGTC PD-AAV004
Study First Received: July 13, 2009
Last Updated: June 24, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Florida:
Gene Therapy
Pompe Disease
Glycogen Storage Disease

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
Genetic Diseases, Inborn
Glycogen Storage Disease
Lysosomal Storage Diseases
Metabolic Diseases
Metabolism, Inborn Errors
Carbohydrate Metabolism, Inborn Errors

ClinicalTrials.gov processed this record on October 19, 2014