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Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Applied Genetic Technologies Corp
Alpha-1 Foundation
University of Florida
Information provided by (Responsible Party):
Terence Flotte, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier:
NCT00430768
First received: January 31, 2007
Last updated: December 20, 2013
Last verified: December 2013
  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 with the expectation that the AAT protein may be produced at normal levels. This study will evaluate the safety of the experimental gene transfer procedure in individuals with AAT deficiency. The study will also determine what dose may be required to achieve normal levels of AAT.


Condition Intervention Phase
Alpha 1-Antitrypsin Deficiency
Biological: rAAV1-CB-hAAT
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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 (rAAV1-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: Day 3 ] [ Designated as safety issue: Yes ]
  • Presence of rAAV1-CB-hAAT vector in blood and semen [ Time Frame: Days 3, 14, and 90 ] [ Designated as safety issue: Yes ]
  • Serum chemistries, hematology, urinalysis, immune response, and pulmonary function [ Time Frame: Days 3, 14, and 90 ] [ Designated as safety issue: Yes ]
  • Adverse events (measured through Year 1 and at yearly follow-up evaluations over 5 years) [ Time Frame: Days 1, 2, 3, 14, 30, 45, 60, 75, 90, 180, 270, 365, and annual followup ] [ Designated as safety issue: Yes ]
  • Antigen Specific Reactivity (ASR) [ Time Frame: Days 3, 14, and 90 ] [ Designated as safety issue: Yes ]
  • Presence of anti-AAV antibodies [ Time Frame: Days 3, 14, and 90 ] [ Designated as safety issue: Yes ]
  • Anti-hAAT antibodies [ Time Frame: Days 3, 14, and 90 ] [ Designated as safety issue: Yes ]
  • AAV1 Elispot testing to measure T cell responses to the AAV capsid [ Time Frame: Days 14, 30, 45, 60, 75, and 90 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • AAT Serum level [ Time Frame: Days 3, 14, 30, 45, 60, 75, 90, 180, 270, and 365 ] [ Designated as safety issue: No ]
  • hAAT expression in blood measured using M-specific Allele ELISA [ Time Frame: Days 3, 14, 30, 45, 60, 75, 90, 180, 270, and 365 if not on protein replacement therapy ] [ Designated as safety issue: No ]
  • hAAT expression in blood using isoelectric focusing (IEF) [ Time Frame: Days 3, 14, 30, 45, 60, 75, 90, 180, 270, and 365 ] [ Designated as safety issue: No ]

Enrollment: 9
Study Start Date: February 2006
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1
6.9 x1012 vector genomes
Biological: rAAV1-CB-hAAT
Three groups of 3 subjects in drug escalation. Group 1 receives rAAV1-CB-hAAT 6.9 x1012 vg (vector genomes), Group 2 receives rAAV1-CB-hAAT 2.1 x1013 vg, and Group 3 receives rAAV1-CB-hAAT 6.0 x1013 vg
Experimental: Group 2
2.1 x 1013 vector genomes
Biological: rAAV1-CB-hAAT
Three groups of 3 subjects in drug escalation. Group 1 receives rAAV1-CB-hAAT 6.9 x1012 vg (vector genomes), Group 2 receives rAAV1-CB-hAAT 2.1 x1013 vg, and Group 3 receives rAAV1-CB-hAAT 6.0 x1013 vg
Experimental: Group 3
rAAV1-CB-hAAT 6.0 x1013 vg
Biological: rAAV1-CB-hAAT
Three groups of 3 subjects in drug escalation. Group 1 receives rAAV1-CB-hAAT 6.9 x1012 vg (vector genomes), Group 2 receives rAAV1-CB-hAAT 2.1 x1013 vg, and Group 3 receives rAAV1-CB-hAAT 6.0 x1013 vg

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, rAAV1-CB-hAAT, may be able to carry normal copies of the AAT gene into muscle cells with the expectation that additional AAT would be produced. The purpose of this study is to evaluate the safety of injecting rAAV1-CB-hAAT into individuals with AAT deficiency.

This 14-month study will enroll individuals with AAT deficiency. Participants currently using AAT protein replacement will discontinue its use for 19 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 rAAV1-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 5 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 8 weeks prior to study entry, and to resume 11 weeks after rAAV1-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 rAAV1-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 rAAV1-CB-hAAT administration
  • Required oral or systemic corticosteroids in the 28 days prior to rAAV1-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
  • Abnormal ECG, heart disease, pulmonary edema, or embolism in the 6 months prior to study entry
  • Current or recent facial or chest trauma that makes it medically impossible to perform pulmonary function tests (PFTs)
  • Any other medical condition that the investigator deems unsuitable for study participation
  • Pregnant or breastfeeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00430768

Locations
United States, Florida
University of Florida, College of Medicine, Department of Pediatrics
Gainesville, Florida, United States, 32610
United States, Massachusetts
University of Massachusetts School of Medicine
Worcester, Massachusetts, United States, 01655
Sponsors and Collaborators
University of Massachusetts, Worcester
Applied Genetic Technologies Corp
Alpha-1 Foundation
University of Florida
Investigators
Principal Investigator: Terence R. Flotte, MD UMass Medical School
Principal Investigator: Mark L Brantly, MD University of Florida
  More Information

Publications:
Responsible Party: Terence Flotte, Study Principle Investigator, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier: NCT00430768     History of Changes
Other Study ID Numbers: 438, R01HL069877-03, Grant 1 R01 HL069877-03, NIH 0404-638, GCRC # 611, UF IBC RD 2630, AGTC-AAV1-001, WIRB # 20052374
Study First Received: January 31, 2007
Last Updated: December 20, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Massachusetts, Worcester:
Gene Transfer Techniques
Gene Therapy
AAV
AAT
Phase I
Intramuscular transfer

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Digestive System Diseases
Emphysema
Genetic Diseases, Inborn
Liver Diseases
Lung Diseases
Pathologic Processes
Respiratory Tract Diseases
Subcutaneous Emphysema
Alpha 1-Antitrypsin
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Serine Proteinase Inhibitors
Trypsin Inhibitors

ClinicalTrials.gov processed this record on November 25, 2014