Pompe Disease
Conditions
Keywords
Gene Therapy, Pompe Disease, Glycogen Storage Disease
Brief summary
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.
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.
Interventions
DRUGrAAV1-CMV-GAA (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 = 6 subjects.
OTHERRMST
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. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Florida
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label study
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | Change from baseline to 365 post study agent administration. | Change in Adeno-associated virus (AAV) antibody level; Change in Alglucosidase alpha (GAA) Antibody level |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Inspiratory Pressure | Baseline and 365 post study agent administration | Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O |
| Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Screening, Baseline, and 365 post study agent administration. | Median (range) maximal inspiratory pressure, in cm H2O. Timeframe for RMST training was 90 days prior to rAAV1-CMV-GAA gene transfer. Timeframe for following subjects after rAAV1-CMV-GAA gene transfer was 365 days. |
| Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Screening, Baseline, and Day 365 post study agent administration | Best effort tidal volume, referenced to body mass, without use of ventilator assistance. Timeframe for respiratory muscle strength training alone was 90 days prior to dosing, timeframe post adminstration of rAAV1-CMV-GAA was 365 days. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Pediatric Neuromuscular Disorders Clinic at the University of Florida. Subjects were also self-referred from the ClinicalTrials.gov listing.
Pre-assignment details
All subjects underwent a screening process for eligibility determination as well as for safety evaluations.
Participants by arm
| Arm | Count |
|---|---|
| rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.
rAAV1-CMV-GAA (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 = 6 subjects.
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. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. | 3 |
| rAAV1-CMV-GAA Administration-cohort 2 rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.
rAAV1-CMV-GAA (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 = 6 subjects.
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. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. | 6 |
| Total | 9 |
Baseline characteristics
| Characteristic | rAAV1-CMV-GAA Administration-cohort 2 | rAAV1-CMV-GAA Administration-cohort 1 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 3 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 67.3 months | 90 months | 74.8 months |
| Region of Enrollment United States | 6 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 9 |
| other Total, other adverse events | 3 / 3 | 9 / 9 |
| serious Total, serious adverse events | 1 / 3 | 3 / 9 |
Outcome results
Primary
Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration.
Change in Adeno-associated virus (AAV) antibody level; Change in Alglucosidase alpha (GAA) Antibody level
Time frame: Change from baseline to 365 post study agent administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rAAV1-CMV-GAA Administration-cohort 1 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | AAV1antibody Level -Screening | 40,031 mU/mL | Standard Deviation 65324.18978 |
| rAAV1-CMV-GAA Administration-cohort 1 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | AAV1antibody Level - Day 365 | 5,509,882 mU/mL | Standard Deviation 3051265.999 |
| rAAV1-CMV-GAA Administration-cohort 1 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | GAA Antibody level - Screening | 415.6666667 mU/mL | Standard Deviation 61.71169527 |
| rAAV1-CMV-GAA Administration-cohort 1 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | GAA Antibody level - Day 365 | 504.3333333 mU/mL | Standard Deviation 63.88531391 |
| rAAV1-CMV-GAA Administration-cohort 2 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | GAA Antibody level - Day 365 | 494.3333333 mU/mL | Standard Deviation 371.6481311 |
| rAAV1-CMV-GAA Administration-cohort 2 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | AAV1antibody Level -Screening | 29,638 mU/mL | Standard Deviation 12395.02473 |
| rAAV1-CMV-GAA Administration-cohort 2 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | GAA Antibody level - Screening | 330.4 mU/mL | Standard Deviation 271.1112318 |
| rAAV1-CMV-GAA Administration-cohort 2 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | AAV1antibody Level - Day 365 | 1,907,161 mU/mL | — |
Secondary
Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone.
Best effort tidal volume, referenced to body mass, without use of ventilator assistance. Timeframe for respiratory muscle strength training alone was 90 days prior to dosing, timeframe post adminstration of rAAV1-CMV-GAA was 365 days.
Time frame: Screening, Baseline, and Day 365 post study agent administration
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| rAAV1-CMV-GAA Administration-cohort 1 | Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Screening | 2.8 mL/kg |
| rAAV1-CMV-GAA Administration-cohort 1 | Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Baseline | 2.0 mL/kg |
| rAAV1-CMV-GAA Administration-cohort 1 | Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Day 365 | 3.4 mL/kg |
| rAAV1-CMV-GAA Administration-cohort 2 | Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Screening | 7.9 mL/kg |
| rAAV1-CMV-GAA Administration-cohort 2 | Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Baseline | 7.3 mL/kg |
| rAAV1-CMV-GAA Administration-cohort 2 | Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Day 365 | 9.1 mL/kg |
Secondary
Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone.
Median (range) maximal inspiratory pressure, in cm H2O. Timeframe for RMST training was 90 days prior to rAAV1-CMV-GAA gene transfer. Timeframe for following subjects after rAAV1-CMV-GAA gene transfer was 365 days.
Time frame: Screening, Baseline, and 365 post study agent administration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| rAAV1-CMV-GAA Administration-cohort 1 | Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Screening | 6.85 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 1 | Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Baseline | 5.85 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 1 | Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Day 365 | 5.7 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 2 | Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Screening | 60.8 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 2 | Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Baseline | 60.8 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 2 | Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Day 365 | 55.6 cm H2O |
Secondary
Maximal Inspiratory Pressure
Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O
Time frame: Baseline and 365 post study agent administration
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| rAAV1-CMV-GAA Administration-cohort 1 | Maximal Inspiratory Pressure | Baseline | 6 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 1 | Maximal Inspiratory Pressure | Day 365 | 6 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 2 | Maximal Inspiratory Pressure | Baseline | 61 cm H2O |
| rAAV1-CMV-GAA Administration-cohort 2 | Maximal Inspiratory Pressure | Day 365 | 56 cm H2O |