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

NCT00430768 | Completed Phase 1 Results DMC

• 9 other identifiers: 4385R01HL069877NIH-OBA 0404-638NCRR-supported GCRC# 611UF IBC RD 2630AGTC-AAV1-001WIRB # 20052374BB-IND 12728RR00032, RR00082
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

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.

Conditions

Alpha 1-Antitrypsin Deficiency

Keywords

Gene Transfer Techniques; Gene Therapy; AAV; AAT; Phase I; Intramuscular transfer

Outcome Measures

Primary Outcomes (1)

• 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 1. Mild toxicity, usually transient, requiring no special treatment and generally not interfering with usual daily activities 2. Moderate toxicity which may be ameliorated by simple therapeutic maneuvers, and impairs usual activities 3. Severe toxicity which requires therapeutic intervention and interrupts usual activities. Hospitalization may or may not be required 4. Life-threatening toxicity which requires hospitalization

  During 1 year after study agent administration

Secondary Outcomes (1)

• hAAT Expression in Blood Measured Using M-specific Allele ELISA

  Baseline, Days 14, 30, 45, 60, 90, (180, 270, and 365 if not on protein replacement therapy)

Study Arms (3)

Group 1 Low Dose

EXPERIMENTAL

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

Group 2 Middle Dose

EXPERIMENTAL

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

Group 3 High Dose

EXPERIMENTAL

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

Interventions

rAAV1-CB-hAAT BIOLOGICAL

Group 1 Low Dose; Group 2 Middle Dose; Group 3 High Dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Massachusetts, Worcester: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Beacon Therapeutics: collaborator
• Alpha-1 Foundation: collaborator
• University of Florida: collaborator
• National Center for Research Resources (NCRR): collaborator

Study Sites (2)

University of Florida, College of Medicine, Department of Pediatrics

Gainesville, Florida, 32610, United States

Location

University of Massachusetts School of Medicine

Worcester, Massachusetts, 01655, United States

Location

Related Publications (3)

• 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.

  PMID: 9826709 BACKGROUND

• 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.

  PMID: 16518879 BACKGROUND

• 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.

  PMID: 17115945 BACKGROUND

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Study results based on small number of subjects No statistical analysis.

Results Point of Contact

• Title: Dr. Terry Flotte
• Organization: UMASS Medical School

Terry.Flotte@umassmed.edu

(508) 856-2107

Study Officials

• Terence R. Flotte, MD

  UMass Medical School

  PRINCIPAL INVESTIGATOR

• Mark L Brantly, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Study Principle Investigator

Study Record Dates

• First Submitted: January 31, 2007
• First Posted: February 2, 2007
• Study Start: February 1, 2006
• Primary Completion: January 1, 2015
• Study Completion: January 1, 2015
• Last Updated: December 15, 2016
• Results First Posted: December 15, 2016

Record last verified: 2016-12

Data Sharing

• IPD Sharing: Will share

Locations

US (2)