Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin (AAT) Deficiency

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

9 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-02-28

Study Completion Date

2015-01-31

Brief Summary

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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

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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.

Conditions

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Alpha 1-Antitrypsin Deficiency

Keywords

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Gene Transfer Techniques Gene Therapy AAV AAT Phase I Intramuscular transfer

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Group 1 Low Dose

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

Group Type EXPERIMENTAL

rAAV1-CB-hAAT

Intervention Type BIOLOGICAL

Group 2 Middle Dose

rAAV1-CB-hAAT 2.2 x 10e13 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

Group Type EXPERIMENTAL

rAAV1-CB-hAAT

Intervention Type BIOLOGICAL

Group 3 High Dose

rAAV1-CB-hAAT 6.0 x10e13 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

Group Type EXPERIMENTAL

rAAV1-CB-hAAT

Intervention Type BIOLOGICAL

Interventions

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rAAV1-CB-hAAT

Intervention Type BIOLOGICAL

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Terence Flotte

Study Principle Investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Terence R. Flotte, MD

Role: PRINCIPAL_INVESTIGATOR

UMass Medical School

Mark L Brantly, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

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University of Florida, College of Medicine, Department of Pediatrics

Gainesville, Florida, United States

Site Status

University of Massachusetts School of Medicine

Worcester, Massachusetts, United States

Site Status

Countries

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United States

References

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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. doi: 10.1073/pnas.95.24.14384.

Reference Type BACKGROUND

PMID: 9826709 (View on PubMed)

Lu Y, Choi YK, Campbell-Thompson M, Li C, Tang Q, Crawford JM, Flotte TR, Song S. Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J Gene Med. 2006 Jun;8(6):730-5. doi: 10.1002/jgm.896.

Reference Type BACKGROUND

PMID: 16518879 (View on PubMed)

Brantly ML, Spencer LT, Humphries M, Conlon TJ, Spencer CT, Poirier A, Garlington W, Baker D, Song S, Berns KI, Muzyczka N, Snyder RO, Byrne BJ, Flotte TR. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther. 2006 Dec;17(12):1177-86. doi: 10.1089/hum.2006.17.1177.

Reference Type BACKGROUND

PMID: 17115945 (View on PubMed)