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

Primary Purpose

Pompe Disease

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

rAAV1-CMV-GAA (study agent) Administration

RMST

About this trial

This is an interventional treatment trial for Pompe Disease focused on measuring Gene Therapy, Pompe Disease, Glycogen Storage Disease

Eligibility Criteria

2 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Shands at the University of Florida

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

rAAV1-CMV-GAA administration-cohort 1

rAAV1-CMV-GAA administration-cohort 2

Arm 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: 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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Maximal Inspiratory Pressure

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.

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.

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.

Full Information

NCT ID

NCT00976352

First Posted

July 13, 2009

Last Updated

September 12, 2018

Sponsor

University of Florida

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT00976352

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2018

Overall Recruitment Status

Completed

Study Start Date

September 2010 (Actual)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Florida

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pompe Disease

Keywords

Gene Therapy, Pompe Disease, Glycogen Storage Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Masking Description

Open label study

Allocation

Non-Randomized

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

rAAV1-CMV-GAA administration-cohort 1

Arm Type

Experimental

Arm Description

Arm Title

rAAV1-CMV-GAA administration-cohort 2

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

rAAV1-CMV-GAA (study agent) Administration

Other Intervention Name(s)

Gene transfer, study agent (rAAV1-CMV-GAA)

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

RMST

Other Intervention Name(s)

Respiratory Muscle Strength Training

Intervention Description

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.

Primary Outcome Measure Information:

Title

Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration.

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.

Secondary Outcome Measure Information:

Title

Maximal Inspiratory Pressure

Description

Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O

Time Frame

Baseline and 365 post study agent administration

Title

Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone.

Description

Time Frame

Screening, Baseline, and 365 post study agent administration.

Title

Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone.

Description

Time Frame

Screening, Baseline, and Day 365 post study agent administration

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Barry J Byrne, MD, PhD

Organizational Affiliation

University of Florida

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Shelley Collins, MD

Organizational Affiliation

University of Florida

Official's Role

Principal Investigator

Facility Information:

Facility Name

Shands at the University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

11991748

Citation

Fraites TJ Jr, Schleissing MR, Shanely RA, Walter GA, Cloutier DA, Zolotukhin I, Pauly DF, Raben N, Plotz PH, Powers SK, Kessler PD, Byrne BJ. Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol Ther. 2002 May;5(5 Pt 1):571-8. doi: 10.1006/mthe.2002.0580.

Results Reference

background

PubMed Identifier

15920463

Citation

Mah C, Cresawn KO, Fraites TJ Jr, Pacak CA, Lewis MA, Zolotukhin I, Byrne BJ. Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Ther. 2005 Sep;12(18):1405-9. doi: 10.1038/sj.gt.3302550.

Results Reference

background

PubMed Identifier

17245350

Citation

Mah C, Pacak CA, Cresawn KO, Deruisseau LR, Germain S, Lewis MA, Cloutier DA, Fuller DD, Byrne BJ. Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther. 2007 Mar;15(3):501-7. doi: 10.1038/sj.mt.6300100. Epub 2007 Jan 23.

Results Reference

background

PubMed Identifier

11268285

Citation

Pauly DF, Fraites TJ, Toma C, Bayes HS, Huie ML, Hirschhorn R, Plotz PH, Raben N, Kessler PD, Byrne BJ. Intercellular transfer of the virally derived precursor form of acid alpha-glucosidase corrects the enzyme deficiency in inherited cardioskeletal myopathy Pompe disease. Hum Gene Ther. 2001 Mar 20;12(5):527-38. doi: 10.1089/104303401300042447.

Results Reference

background

PubMed Identifier

24021025

Citation

Conlon TJ, Erger K, Porvasnik S, Cossette T, Roberts C, Combee L, Islam S, Kelley J, Cloutier D, Clement N, Abernathy CR, Byrne BJ. Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid alpha-glucosidase. Hum Gene Ther Clin Dev. 2013 Sep;24(3):127-33. doi: 10.1089/humc.2013.147.

Results Reference

background

PubMed Identifier

23903569

Citation

Byrne BJ. Pathway for approval of a gene therapy orphan product: treading new ground. Mol Ther. 2013 Aug;21(8):1465-6. doi: 10.1038/mt.2013.157. No abstract available.

Results Reference

background

PubMed Identifier

25541616

Citation

Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clement N, Erger K, Lavassani E, Green M, Doerfler P, Herzog R, Byrne B. B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study. Mol Ther Methods Clin Dev. 2014;1:14033-. doi: 10.1038/mtm.2014.33.

Results Reference

background

PubMed Identifier

23570273

Citation

Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, Fuller DD, Cleaver BD, Clement N, Phillips D, Islam S, Dobjia N, Byrne BJ. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013 Jun;24(6):630-40. doi: 10.1089/hum.2012.250.

Results Reference

result

PubMed Identifier

22794786

Citation

Byrne BJ, Falk DJ, Clement N, Mah CS. Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther. 2012 Aug;23(8):808-15. doi: 10.1089/hum.2012.140.

Results Reference

derived

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

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