Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency - Full Text View

Sponsors and Collaborators:	National Heart, Lung, and Blood Institute (NHLBI) Alpha-1 Foundation University of Florida National Center for Research Resources (NCRR)
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00377416

Purpose

Individuals with a deficiency of the Alpha 1-antitrypsin (AAT) protein are at risk for developing emphysema and liver damage. Researchers have developed a way to introduce normal AAT genes into muscle cells so that the AAT protein is produced at normal levels. This study will evaluate the safety of the experimental gene transfer procedure in individuals with AAT deficiency.

Condition	Intervention	Phase
Alpha 1-Antitrypsin Deficiency	Gene Transfer: rAAV2-CB-hAAT Gene Vector	Phase I

Genetics Home Reference related topics: alpha-1 antitrypsin deficiency

MedlinePlus related topics: Alpha-1 Antitrypsin Deficiency

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Dose Comparison, Single Group Assignment, Safety/Efficacy Study
Official Title:	Preclinical & Phase I/II Trials of AAV-AAT Vectors: Phase I Trial of Intramuscular Injection of a Recombinant Adeno-Associated Virus Alpha 1-Antitrypsin (rAAV2-CB-hAAT) Gene Vector to AAT-Deficient Adults

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:

Arm circumference (measured at Day 3)
Presence of rAAV2-CB-hAAT vector in blood and semen (measured at Day 14)
Serum chemistries, hematology, urinalysis, immune response, and pulmonary function (measured at Day 90)
Human AAT levels and phenotype in the blood (measured at Day 180)
Adverse events (measured at Year 1 and at yearly follow-up evaluations over 15 years)

Estimated Enrollment:	12
Study Start Date:	March 2004
Estimated Study Completion Date:	October 2006

Detailed Description:

AAT deficiency is a genetic disorder in which individuals have inadequate levels of the AAT protein. AAT protects the lungs from white blood cell enzymes that can damage air sacs within the lungs, potentially leading to emphysema. Experimental gene transfer procedures, in which normal copies of genes are inserted into cells, are being developed to treat many genetic diseases, including AAT deficiency. In this study, a modified virus, adeno-associated virus (AAV), has been genetically engineered to contain a normal copy of the AAT gene. When AAV is combined with the AAT gene, the resulting agent, rAAV2-CB-hAAT, is able to carry normal copies of the AAT gene into muscle cells to produce additional AAT. The purpose of this study is to evaluate the safety of injecting rAAV2-CB-hAAT into individuals with AAT deficiency.

This 13-month study will enroll individuals with AAT deficiency. Participants currently using AAT protein replacement will discontinue its use for 15 weeks during the study. Participants will first attend a baseline study visit, which will include a medical history review; a physical examination; an electrocardiogram (ECG) to record heart activity; blood, urine, and semen collection; pulmonary function tests; and chest and arm scans. Participants will then attend a 5-day inpatient visit, during which they will receive a series of injections consisting of one of four different doses of rAAV2-CB-hAAT. Physical examinations will occur on all 5 inpatient days; pulmonary function testing, arm circumference measurements, and collection of blood, urine, and semen will occur on selected days of the inpatient stay. Follow-up study visits, with possible overnight stays, will occur on Days 14 and 90. On Days 30, 45, 60, 75, 180, 270, and 365, participants will have blood drawn at a local clinic. On these same days, study staff will contact participants by telephone to review their medical history and symptoms. Unused blood and semen samples will be frozen and stored for future research purposes. Participants will have yearly follow-up evaluations by either telephone or mail for a total of 15 years.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diagnosed with AAT deficiency
Forced expiratory volume in one second (FEV1) greater than 24% of predicted value (post bronchodilator)
Willing to discontinue AAT protein replacement 4 weeks prior to study entry, and to resume 11 weeks after rAAV2-CB-hAAT has been administered
Willing to discontinue aspirin, aspirin-containing products, and other drugs that may alter platelet function 7 days prior to study entry, and to resume 24 hours after rAAV2-CB-hAAT has been administered
Willing to use contraception throughout the study

Exclusion Criteria:

Required antibiotic therapy for a respiratory infection in the 28 days prior to rAAV2-CB-hAAT administration
Required oral or systemic corticosteroids in the 28 days prior to rAAV2-CB-hAAT administration
Liver disease
Currently receiving or has received an investigational study agent in the 30 days prior to study entry
Received gene transfer agents in the 6 months prior to study entry
Currently smokes cigarettes or uses illegal drugs
History of immune response to human AAT replacement
History of platelet dysfunction
Any other medical condition that the investigator deems unsuitable for study participation
Pregnant or breastfeeding

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00377416

Locations

United States, Florida
University of Florida, College of Medicine, Department of Pediatrics
Gainesville, Florida, United States, 32610

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Alpha-1 Foundation

University of Florida

National Center for Research Resources (NCRR)

Investigators

Principal Investigator:

Terence R. Flotte, MD

Departments of Pediatrics, Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida

More Information

Publications:

Flotte TR, Brantly ML, Spencer LT, Byrne BJ, Spencer CT, Baker DJ, Humphries M. Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Hum Gene Ther. 2004 Jan;15(1):93-128.

Song S, Morgan M, Ellis T, Poirier A, Chesnut K, Wang J, Brantly M, Muzyczka N, Byrne BJ, Atkinson M, Flotte TR. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14384-8.

Study ID Numbers:	366, Grant 1 R01 HL069877, NIH Protocol # 30104-465, UF GCRC # 567, UF IBC RD 2101, UF GTC TRF AAV001, IRB # 306-03
Study First Received:	September 14, 2006
Last Updated:	September 14, 2006
ClinicalTrials.gov Identifier:	NCT00377416
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):

Gene Transfer Techniques
Gene Therapy

Study placed in the following topic categories:

Virus Diseases
Protein C Inhibitor
Alpha 1-Antitrypsin

Alpha 1-Antitrypsin Deficiency
Alpha 1-antitrypsin deficiency
Connective Tissue Diseases

Additional relevant MeSH terms:

Serine Proteinase Inhibitors
Molecular Mechanisms of Pharmacological Action
Trypsin Inhibitors

Enzyme Inhibitors
Pharmacologic Actions
Protease Inhibitors

ClinicalTrials.gov processed this record on January 15, 2009