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

Related Clinical Trial
A Single Ascending and Repeated Dose Study of Oral ZF874 in Healthy Volunteers and PiMZ Subjects ARALAST NP Alpha-1 Lung Density Chronic Obstructive Pulmonary Disease-Emphysema (COPD-E) Study Early Access Program Using Alpha 1 Antitrypsin Infusion for Patients With Steroid Refractory Acute GvHD After Hematopoietic Stem Cell Transplantation (HSCT) Characterization of the Pathobiology of Early Lung Destruction in Alpha 1-Antitrypsin Deficient Individuals COPD Exacerbation Blood and Urine Biomarkers Study Alpha-1 Carrier Genomics Study Evaluation of the Efficacy and Safety of VX-814 in Subjects With the PiZZ Genotype Study of ARO-AAT in Normal Adult Volunteers Safety Study of Alfalastin (Human Alpha-1 Antitrypsin) Administered at Home AL1TER™: Alpha-1 Therapy, Evaluation, and Research Patient Registry Respreeza® Self-administration and Learning Program (AmAREtTI Study) Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin (AAT) Deficiency Lung Disease and Its Affect on the Work of White Blood Cells in the Lungs A 12-week Study Treating Participants Who Have alpha1-antitrypsin-related COPD With Alvelestat (MPH966) or Placebo. Environment Effect on Six-Minute Walk Test Performance Alpha-1 Foundation DNA and Tissue Bank Alpha1-antitrypsin Deficiency Registry Alpha-1 Research Registry Stage 1 Study of ARALAST NP and GLASSIA in A1PI Deficiency Alpha-1 Coded Testing(ACT) Study Long-Term Follow-up Study of ADVM-043 Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency 4-PBA: Will it Increase the Level of Alpha 1-Antitrypsin(AAT) in Persons With AAT Deficiency? Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin Deficiency Management of Patients With Alpha-1 Antitrypsin Deficiency Associated Emphysema Phase II, Safety and Efficacy Study of Kamada-alpha-1-antitrypsin (AAT) for Inhalation” EARCO REGISTRY. History Of Patients With Alpha-1 Antitrypsin GLASSIA Safety, Immunogenicity, and Bronchoalveolar Lavage Study Safety, Tolerability and Effect of ARC-AAT Injection on Circulating and Intrahepatic Alpha-1 Antitrypsin Levels Efficacy/Safety of HA Inhalation Solution for Hereditary Emphysema in Patients With Alpha-1 Antitrypsin Deficiency Safety and Pharmacokinetics of Alpha-1 MP in Patients With Alpha1-Antitrypsin Deficiency Phase II/III Study of an Alpha-1 Proteinase Inhibitor (Kamada-API) in Individuals With Alpha-1 Antitrypsin Deficiency Study of the Effect of Aerosolized, Recombinant Alpha 1-Antitrypsin on Epithelial Lining Fluid Analytes in Subjects With Alpha 1-Antitrypsin Deficiency Alvelestat (MPH966) for the Treatment of ALpha-1 ANTitrypsin Deficiency The Safety and Tolerability of Alpha-1 Modified Process (MP) In Subjects With Alpha-1-antitrypsin (AAT) Deficiency Lung Volume Reduction Coils for Emphysema in Alpha-1 Antitrypsin Deficiency Study of Genotype and Phenotype in Patients With Alpha 1-Antitrypsin Deficiency Alpha-1 Foundation Research Registry Targeting Pulmonary Perfusion in Alpha-1 Antitrypsin Deficiency Effects of Exercise Training in Chronic Obstructive Pulmonary Disease Versus Alpha-1-Antitrypsin-deficiency-patients Evaluate Efficacy and Safety of “Kamada-AAT for Inhalation” in Patients With AATD A Study of DCR-A1AT in Healthy Adult Volunteers and Patients With A1ATD-Associated Liver Disease Safety & Efficacy Study of rAAV1-CB-hAAT for Alpha-1 Antitrypsin Deficiency Effects of Different Exercise Training Modalities in Alpha-1 Antitrypsin Deficiency Patients Safety Study of an Aerosolized, Recombinant Alpha 1-Antitrypsin in Subjects With Alpha 1-Antitrypsin Deficiency Study Comparing Weekly Intravenous Administration of OctaAlpha1 With a Marketed Preparation Glassia® in Subjects With Alpha-1-antitrypsin Deficiency Long-term Safety of Alpha1-Proteinase Inhibitor (Human) in Japanese Subjects With Alpha1 Antitrypsin Deficiency (GTI1401-OLE) Efficacy and Safety Study of Augmentation Therapy With ARALAST Fraction IV-1 (Human Alpha 1 – Proteinase Inhibitor) Aralast alpha1-proteinase Inhibitor Surveillance Study Pharmacokinetic Study of ARALAST (Human Alpha1- PI) The Use of High Resolution Chest Computed Tomography in Alpha-1 Antitrypsin Deficiency Prevalence of Alpha-1 Antitrypsin Deficiency in Chronic Obstructive Pulmonary Disease (COPD) Comparison of Pharmacokinetic, Safety, Tolerability of Alpha-1 MP and Prolastin In Alpha1-antitrypsin Deficient Adults Phase 1 Study to Assess the Safety, PK and PD of INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency Safety and Pharmacokinetics of Alpha-1 Proteinase Inhibitor in Subjects With Alpha1-Antitrypsin Deficiency The Impact of Delayed Diagnosis of Alpha-1 Antitrypsin Deficiency Epigenetic Regulation of Immunity in Alpha-1 Anti-trypsin Deficiency Microbioma in Sputa From COPD With Alpha-1 Antitrypsin Deficiency A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD) A Study to Assess Safety and PK of Liquid Alpha₁-Proteinase Inhibitor (Human) in Treating Alpha₁-Antitrypsin Deficiency

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


Primary Outcome

Adverse Events Possibly, Probably or Definitely Related to Study Drug

Secondary Outcome

 hAAT Expression in Blood Measured Using M-specific Allele ELISA


Alpha 1-Antitrypsin Deficiency



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


* 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


Estimated Enrollment


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

          -  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

          -  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

          -  Pregnant or breastfeeding




18 Years - N/A

Accepts Healthy Volunteers



Terence R. Flotte, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party

Principal Investigator

Study Sponsor

University of Massachusetts, Worcester


 National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Terence R. Flotte, MD, Principal Investigator, UMass Medical School

Verification Date

December 2016