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

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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