Brief Title
Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin (AAT) Deficiency
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
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 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.
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, Recombinant Adeno-Associated Virus Alpha
1-Antitrypsin (rAAV1-CB-hAAT) Gene Vector with a chicken beta actin promoter (CB), 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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Adverse Events Possibly, Probably or Definitely Related to Study Drug
Secondary Outcome
hAAT Expression in Blood Measured Using M-specific Allele ELISA
Condition
Alpha 1-Antitrypsin Deficiency
Intervention
rAAV1-CB-hAAT
Study Arms / Comparison Groups
Group 1 Low Dose
Description: rAAV1-CB-hAAT 6.9 x10e12 vector genomes (vg) administered in a 9.9 ml volume of study agent in nine separate 1.1 mL injections in the deltoid muscle of the "non-dominant" side under ultrasound guidance
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Biological
Estimated Enrollment
9
Start Date
February 2006
Completion Date
January 2015
Primary Completion Date
January 2015
Eligibility 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 (Group 1) and 8 weeks (Groups 2
and 3) 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
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Terence R. Flotte, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00430768
Organization ID
438
Secondary IDs
5R01HL069877
Responsible Party
Principal Investigator
Study Sponsor
University of Massachusetts, Worcester
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Study Sponsor
Terence R. Flotte, MD, Principal Investigator, UMass Medical School
Verification Date
December 2016