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Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency

This study is ongoing, but not recruiting participants.
National Heart, Lung, and Blood Institute (NHLBI)
Alpha-1 Foundation
University of Florida
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
Terence Flotte, University of Massachusetts, Worcester Identifier:
First received: September 14, 2006
Last updated: February 8, 2017
Last verified: February 2017
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
Alpha 1-Antitrypsin Deficiency
Genetic: rAAV2-CB-hAAT Gene Vector

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
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

Resource links provided by NLM:

Further study details as provided by University of Massachusetts, Worcester:

Primary Outcome Measures:
  • Arm circumference [ Time Frame: Measured at Day 3 ]
  • Presence of rAAV2-CB-hAAT vector in blood and semen [ Time Frame: Measured at Day 14 ]
  • Serum chemistries, hematology, urinalysis, immune response, and pulmonary function [ Time Frame: Measured at Day 90 ]
  • Human AAT levels and phenotype in the blood [ Time Frame: Measured at Day 180 ]
  • Adverse events [ Time Frame: 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 2021
Estimated Primary Completion Date: October 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
rAAV2-CB-hAAT Gene Vector
Genetic: rAAV2-CB-hAAT Gene Vector
Participants will 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.

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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
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Please refer to this study by its identifier: NCT00377416

United States, Florida
University of Florida, College of Medicine, Department of Pediatrics
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Massachusetts, Worcester
National Heart, Lung, and Blood Institute (NHLBI)
Alpha-1 Foundation
University of Florida
National Center for Research Resources (NCRR)
Principal Investigator: Terence R. Flotte, MD Departments of Pediatrics, Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida
  More Information

Responsible Party: Terence Flotte, Study Principle Investigator, University of Massachusetts, Worcester Identifier: NCT00377416     History of Changes
Other Study ID Numbers: 366
R01HL069877 ( US NIH Grant/Contract Award Number )
Grant 1 R01 HL069877
NIH Protocol # 30104-465
UF GCRC # 567
UF IBC RD 2101
IRB # 306-03
Study First Received: September 14, 2006
Last Updated: February 8, 2017

Keywords provided by University of Massachusetts, Worcester:
Gene Transfer Techniques
Gene Therapy

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Pathologic Processes
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action processed this record on May 25, 2017