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

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

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.

Study Overview

• Status: Completed
• Conditions: Alpha 1-Antitrypsin Deficiency
• Intervention / Treatment: Biological: rAAV1-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, 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 Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida, College of Medicine, Department of Pediatrics
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Biological: rAAV1-CB-hAAT
Experimental: 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	Biological: rAAV1-CB-hAAT
Experimental: 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	Biological: rAAV1-CB-hAAT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events Possibly, Probably or Definitely Related to Study Drug	Adverse events considered possibly, probably or definitely related to study drug/study drug procedure Criteria to evaluate severity according to Attachment 2 of the Protocol; Mild toxicity, usually transient, requiring no special treatment and generally not interfering with usual daily activities; Moderate toxicity which may be ameliorated by simple therapeutic maneuvers, and impairs usual activities; Severe toxicity which requires therapeutic intervention and interrupts usual activities. Hospitalization may or may not be required; Life-threatening toxicity which requires hospitalization	During 1 year after study agent administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hAAT Expression in Blood Measured Using M-specific Allele ELISA	4 subjects received prior AAT augmentation therapy; 2 subjects from Group 1 having only washed out for only 28 days complicated the measurement of M-specific levels 2 subjects from group 1 and the other subject did not have an appreciable change in M-specific AAT levels. Thus reporting only Cohorts 2 and 3. After day 90 patients were able to resume AAT protein therapy and thus levels were not collected following commencement of therapy on 201 and 303. 202, Day 365 blood hemolyzed; level not determinable.	Baseline, Days 14, 30, 45, 60, 90, (180, 270, and 365 if not on protein replacement therapy)

Collaborators and Investigators

• Sponsor: University of Massachusetts, Worcester
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Florida; National Center for Research Resources (NCRR); Applied Genetic Technologies Corp; Alpha-1 Foundation
• Investigators: Principal Investigator: Terence R. Flotte, MD, UMass Medical School

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: January 31, 2007
• First Submitted That Met QC Criteria: January 31, 2007
• First Posted (Estimate): February 2, 2007

Study Record Updates

• Last Update Posted (Estimate): December 15, 2016
• Last Update Submitted That Met QC Criteria: December 13, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Gene Therapy; Phase I; AAV; AAT; Gene Transfer Techniques; Intramuscular transfer
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Liver Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency
• Other Study ID Numbers: 438; 5R01HL069877 (U.S. NIH Grant/Contract); NIH-OBA 0404-638 (Registry Identifier: Gene Therapy Protocol Number); NCRR-supported GCRC# 611 (Other Identifier: University of Florida); UF IBC RD 2630 (Other Identifier: University of Florida); AGTC-AAV1-001 (Other Identifier: Applied Genetics Technologies C); WIRB # 20052374 (Other Identifier: Western Institutional Review B); BB-IND 12728 (Other Identifier: FDA); RR00032, RR00082 (Other Grant/Funding Number: NCRR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Laboratory information shared as received; copy of manuscript given to patients; at 5 year follow up Principal investigator explained results to patients