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Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency

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: NCT00377416
Recruitment Status : Completed
First Posted : September 18, 2006
Last Update Posted : April 10, 2020
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Alpha-1 Foundation
University of Florida
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
University of Massachusetts, Worcester

Brief Summary:
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 or disease Intervention/treatment Phase
Alpha 1-Antitrypsin Deficiency Genetic: rAAV2-CB-hAAT Gene Vector Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
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
Study Start Date : March 2004
Actual Primary Completion Date : October 2006
Actual Study Completion Date : January 2020


Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. Arm circumference [ Time Frame: Measured at Day 3 ]
  2. Presence of rAAV2-CB-hAAT vector in blood and semen [ Time Frame: Measured at Day 14 ]
  3. Serum chemistries, hematology, urinalysis, immune response, and pulmonary function [ Time Frame: Measured at Day 90 ]
  4. Human AAT levels and phenotype in the blood [ Time Frame: Measured at Day 180 ]
  5. Adverse events [ Time Frame: Measured at Year 1 and at yearly follow-up evaluations over 15 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00377416


Locations
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United States, Florida
University of Florida, College of Medicine, Department of Pediatrics
Gainesville, Florida, United States, 32610
United States, Massachusetts
UMass Medical School
Worcester, Massachusetts, United States, 01655
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)
Investigators
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Principal Investigator: Terence R. Flotte, MD UMass Medical School
Publications:
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Responsible Party: University of Massachusetts, Worcester
ClinicalTrials.gov Identifier: NCT00377416    
Other Study ID Numbers: 366
R01HL069877 ( U.S. NIH Grant/Contract )
NIH Protocol # 30104-465 ( Other Identifier: NIH )
UF GCRC # 567 ( Other Identifier: University of Florida )
UF IBC RD 2101 ( University of Florida )
UF GTC TRF AAV001
IRB # 306-03
First Posted: September 18, 2006    Key Record Dates
Last Update Posted: April 10, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Massachusetts, Worcester:
Gene Transfer Techniques
Gene Therapy
Additional relevant MeSH terms:
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Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes