Safety & Efficacy Study of rAAV1-CB-hAAT for Alpha-1 Antitrypsin Deficiency
Condition: Alpha-1 Antitrypsin Deficiency
MeSH terms: Alpha 1-Antitrypsin Deficiency
Intervention: rAAV1-CB-hAAT
Intervention description: Recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Alpha-1 antitrypsin deficiency; Adeno-associated virus vector; AAV; Gene therapy; Human gene transfer

Summary:

      Assessment of the safety and efficacy of intramuscular (IM) administration of a recombinant
      adenoassociated virus (rAAV) alpha-1 antitrypsin (AAT) vector (rAAV1-CB-hAAT) in
      AAT-deficient adults at three dosage levels [6.0 × 10e11, 1.9 × 10e12 and 6.0 × 10e12 vector
      genome particles (vg) per kg body weight].

      Funding Sources - The FDA Office of Orphan Products Development and NIH National Heart, Lung,
      and Blood Institute
    

Eligibility criteria:

        Inclusion Criteria:

          1. Have a diagnosis of AAT-deficiency, as defined by a serum AAT level of less than 11 µM
             and a phenotype or genotype either homozygous for PI*Z or compound heterozygous
             consisting of PI*Z and another allele known to be associated with disease

          2. Be at least 18 and not more than 75 years of age

          3. Have a forced expiratory volume at one second (FEV1) >25% of predicted value (post
             bronchodilator)

          4. Weigh ≤ 90 kg

          5. Not receiving AAT augmentation therapy currently or with the past 3 months, and not
             planning to begin such therapy for at least 12 months after administration of
             rAAV1-CB-hAAT

          6. Be willing to discontinue aspirin, aspirin-containing products, and other drugs that
             may alter platelet function, 7 days prior to dosing, resuming no earlier than 24 hours
             after the dose has been administered

          7. Have acceptable laboratory parameters:

               -  Hemoglobin ≥ 11.2 g/dL for females, ≥ 12.8 g/dL for males,

               -  White blood cell count 3,300 - 12,000 cells/mm3,

               -  Platelet count 125,000 - 550,000/mm3,

               -  Serum creatine kinase (CK) ≤ 3 times upper normal range for study laboratory,

               -  Alanine aminotransferase (ALT) ≤ 2 times upper normal range for study laboratory,

               -  Serum bilirubin ≤ 1.5 times upper normal range for study laboratory,

               -  Serum creatinine within normal range for study laboratory,

               -  Prothrombin time (PT) ≤ 14.5 seconds and partial thromboplastin time (PTT)

                  ≤ 36 seconds,

               -  Normal urine dipstick (negative glucose, negative hemoglobin, and negative or
                  trace protein),

          8. For females of childbearing potential:

               -  A negative pregnancy test (urine or serum) at screening and at baseline (within 2
                  days before administration of study agent)

               -  Agreement to consistently use barrier contraception (condoms, diaphragm or
                  cervical cap with spermicide) or another form of contraception (e.g. intrauterine
                  device or hormonal contraception) from the screening visit until 12 months after
                  administration of rAAV1-CB-hAAT, for sexual activity that could lead to pregnancy

          9. For males of reproductive potential, agreement to consistently use barrier
             contraception (condoms with spermicide) for 12 months after administration of
             rAAV1-CB-hAAT, for sexual activity that could lead to pregnancy,

         10. Provide signed informed consent before screening

        Exclusion Criteria:

          1. Prior receipt of any AAV gene therapy product

          2. Use of anticoagulants or anti-platelet agents within 7 days prior to study agent
             administration

          3. History of immune response to human AAT augmentation therapy as indicated by clinical
             history of an adverse immune response to infusion and/or decreased therapeutic effect
             in combination with documentation of serum anti-AAT antibodies

          4. Use of acute oral or intravenous antibiotic therapy for a respiratory infection within
             28 days prior to study agent administration (long-term maintenance or chronic
             suppressive oral antibiotics, and antibiotics for a non-respiratory indication, are
             allowed)

          5. Use of oral or systemic corticosteroids within 28 days prior to study agent
             administration

          6. Use of any investigational agent, or any immunosuppressive drug(s), within 3 months
             prior to enrollment

          7. For females of childbearing potential, a positive pregnancy test at screening or
             baseline (within 2 days before rAAV1-CB-hAAT administration) Note: At the Cincinnati
             Children's Hospital Medical Center site, women of childbearing potential were not
             permitted to enroll in the study.

          8. Females who are breast feeding

          9. Have a significant abnormal EKG finding at screening and/or cardiac disease (e.g.
             recent myocardial infarction or CHF) within past 6 months

         10. Have had pulmonary edema or a pulmonary embolism within the past 6 months

         11. Have a history of immunodeficiency or other medical condition which leads the
             investigator to believe that the participant cannot comply with the protocol
             requirements or that may place the participant at an unacceptable risk for
             participation