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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00976352
Recruitment Status : Completed
First Posted : September 14, 2009
Results First Posted : November 17, 2017
Last Update Posted : September 14, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of Florida

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Pompe Disease
Interventions Drug: rAAV1-CMV-GAA (study agent) Administration
Other: RMST
Enrollment 9
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.
Arm/Group Title rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Hide Arm/Group Description

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.

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.

Period Title: Overall Study
Started 3 10
Completed 3 6 [1]
Not Completed 0 4
[1]
Last evaluation of last subject in cohort.
Arm/Group Title rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2 Total
Hide Arm/Group Description

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.

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.

Total of all reporting groups
Overall Number of Baseline Participants 3 6 9
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 6 participants 9 participants
<=18 years
3
 100.0%
6
 100.0%
9
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Full Range)
Unit of measure:  Months
Number Analyzed 3 participants 6 participants 9 participants
90
(66 to 108)
67.3
(30 to 180)
74.8
(30 to 180)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 6 participants 9 participants
Female
0
   0.0%
3
  50.0%
3
  33.3%
Male
3
 100.0%
3
  50.0%
6
  66.7%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 3 participants 6 participants 9 participants
3
 100.0%
6
 100.0%
9
 100.0%
1.Primary Outcome
Title Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration.
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 3 6
Mean (Standard Deviation)
Unit of Measure: mU/mL
AAV1antibody Level -Screening 40,031  (65324.18978) 29,638  (12395.02473)
AAV1antibody Level - Day 365 5,509,882  (3051265.999) 1,907,161  (3,189,557)
GAA Antibody level - Screening 415.6666667  (61.71169527) 330.4  (271.1112318)
GAA Antibody level - Day 365 504.3333333  (63.88531391) 494.3333333  (371.6481311)
2.Secondary Outcome
Title Maximal Inspiratory Pressure
Hide Description Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O
Time Frame Baseline and 365 post study agent administration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 3 6
Median (Full Range)
Unit of Measure: cm H2O
Baseline
6
(2 to 22)
61
(3 to 85)
Day 365
6
(2 to 19)
56
(3 to 75)
3.Secondary Outcome
Title Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone.
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Hide Arm/Group Description:

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 after dosing.

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 after dosing.

Overall Number of Participants Analyzed 3 6
Median (Full Range)
Unit of Measure: cm H2O
Screening
6.85
(1.6 to 26.1)
60.8
(1.9 to 82.6)
Baseline
5.85
(1.55 to 22.85)
60.8
(2.65 to 84.85)
Day 365
5.7
(1.65 to 19.1)
55.6
(2.9 to 75.1)
4.Secondary Outcome
Title Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone.
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Hide Arm/Group Description:
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 after dosing.
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 after dosing.
Overall Number of Participants Analyzed 3 6
Median (Full Range)
Unit of Measure: mL/kg
Screening
2.8
(0.7 to 4.0)
7.9
(.14 to 8.7)
Baseline
2.0
(0.4 to 4.1)
7.3
(.16 to 11.7)
Day 365
3.4
(.71 to 4.3)
9.1
(.18 to 13.3)
Time Frame Data on adverse events were collected on all subjects for 1 year after dosing.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Hide Arm/Group Description

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.

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.

All-Cause Mortality
rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   1/3 (33.33%)      0/9 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/3 (33.33%)      3/9 (33.33%)    
Blood and lymphatic system disorders     
Bacteremia accompanied by fever * [1]  0/3 (0.00%)  0 1/9 (11.11%)  1
Cardiac disorders     
Bilateral pericardial effusion *  0/3 (0.00%)  0 1/9 (11.11%)  1
Supraventricular tachycardia *  1/3 (33.33%)  1 0/9 (0.00%)  0
General disorders     
Hospitalization *  0/3 (0.00%)  0 3/9 (33.33%)  3
Respiratory, thoracic and mediastinal disorders     
Right-sided spontaneous pneumothorax *  1/3 (33.33%)  1 0/9 (0.00%)  0
Bilateral pleural effusion *  0/3 (0.00%)  0 1/9 (11.11%)  1
Right upper lobe collapse with respiratory distress and Clostridium difficile gastritis * [2]  0/3 (0.00%)  0 1/9 (11.11%)  2
Desaturation Episode *  0/3 (0.00%)  0 1/9 (11.11%)  1
Hospitalization: dehydration, increased work of breathing * [3]  0/3 (0.00%)  0 1/9 (11.11%)  1
hospitalization, worsening CHF, pulmonary edema * [4]  0/3 (0.00%)  0 1/9 (11.11%)  1
*
Indicates events were collected by non-systematic assessment
[1]
Occurred 3 months post dosing. This unexpected event was determined to be unrelated to the test article and study procedures.
[2]
The subject was hospitalized 10 months post-dosing during the first occurrence of this SAE. The same subject was hospitalized 11 months post-dosing for an acute episode of desaturation, right upper lobe collapse, recurrent gastritis.
[3]
Hospitalization: dehydration, increased work of breathing
[4]
hospitalization, worsening CHF, pulmonary edema
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
rAAV1-CMV-GAA Administration-cohort 1 rAAV1-CMV-GAA Administration-cohort 2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      9/9 (100.00%)    
Blood and lymphatic system disorders     
Nosebleed *  0/3 (0.00%)  0 1/9 (11.11%)  1
Cardiac disorders     
Tachycardia *  1/3 (33.33%)  2 0/9 (0.00%)  0
Ear and labyrinth disorders     
ear infection and fluids *  1/3 (33.33%)  2 2/9 (22.22%)  2
Eye disorders     
eye infection * [1]  0/3 (0.00%)  0 1/9 (11.11%)  2
Gastrointestinal disorders     
Reflux and Diarrhea, G-tube problems * [2]  3/3 (100.00%)  3 4/9 (44.44%)  8
General disorders     
fever, bacteremia, Dehydration * [3]  3/3 (100.00%)  4 5/9 (55.56%)  7
Pain * [4]  2/3 (66.67%)  3 4/9 (44.44%)  9
Hypokalemia and Hypoglycemia *  1/3 (33.33%)  1 1/9 (11.11%)  2
Musculoskeletal and connective tissue disorders     
Contracturs and scoliosis *  1/3 (33.33%)  2 1/9 (11.11%)  3
Renal and urinary disorders     
urinary issues * [5]  1/3 (33.33%)  1 2/9 (22.22%)  2
Respiratory, thoracic and mediastinal disorders     
Respiratory Tract Infection *  2/3 (66.67%)  2 2/9 (22.22%)  3
Pneumothorax/Capnothorax *  3/3 (100.00%)  5 3/9 (33.33%)  3
respiratory symthomps * [6]  3/3 (100.00%)  10 7/9 (77.78%)  18
Pneumonia *  0/3 (0.00%)  0 1/9 (11.11%)  1
Pulmonary and chest problems * [7]  1/3 (33.33%)  2 2/9 (22.22%)  2
Trachestomy *  0/3 (0.00%)  0 1/9 (11.11%)  1
Skin and subcutaneous tissue disorders     
Skin issue * [8]  2/3 (66.67%)  5 3/9 (33.33%)  6
*
Indicates events were collected by non-systematic assessment
[1]
chalazion
[2]
change to bowel and bladder regimen, Reflux and Diarrhea, stomach virus, G-tube problems, Abdominal abscess
[3]
fever, bacteremia, Dehydration
[4]
pain, cramps
[5]
Increased difficulty urinating, positional; infections
[6]
Cough, Increased secretions, cold symptoms, desaturation, oxygen requirement,Increased work of breathing, wheezing and Diminished breath sounds
[7]
lung contusion, chest problems,
[8]
Swelling, rash,
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Barry Byrne, Professor and Associate Chair
Organization: University of Florida
Phone: 352-273-6563
EMail: bbyrne@ufl.edu
Other Publications:
Layout table for additonal information
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00976352     History of Changes
Other Study ID Numbers: PGTC PD-AAV004-N
P01HL059412-06 ( U.S. NIH Grant/Contract )
First Submitted: July 13, 2009
First Posted: September 14, 2009
Results First Submitted: June 1, 2017
Results First Posted: November 17, 2017
Last Update Posted: September 14, 2018