Conditions: Alpha-1 Antitrypsin Deficiency
Keywords: Alpha-1 antitrypsin deficiency Adeno-associated virus vector AAV Gene therapy Human gene transfer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 9
Healthy volunteers: no

Brief 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

Detailed description:
The study is a non-randomized, open-label, multi-center, sequential, three-arm, Phase 2 clinical trial evaluating the safety and efficacy of administration of a rAAV1-CB-hAAT vector administered by IM injection. Each participant will receive rAAV1-CB-hAAT on a single occasion. Three groups of three subjects each will receive rAAV1-CB-hAAT at dosage levels of 6 x 10e11 vg/kg, 1.9 x 10e12 vg/kg or 6 x 10e12 vg/kg by IM injection. Subjects in group 1 will receive a total of 10 IM injections distributed across a single muscle site, subjects in group 2 will receive a total of 32 IM injections distributed across three muscle sites, and subjects in group 3 will receive 100 IM injections distributed across 10 muscle sites. Each injection will be given in a volume of 1.35 mL, at the appropriate vector concentration to achieve the desired total vector dose.

The three groups were enrolled sequentially, with review of safety data by a Data and Safety Monitoring Board before enrollment of each higher dosage level group.

Safety was monitored by evaluation of adverse events, hematology and clinical chemistry parameters, histological examination of muscle biopsies, and measurement of serum antibodies to AAT. Efficacy was measured by evaluation of serum concentrations of M-specific AAT and total AAT, and serum AAT phenotype determined on isoelectric focusing gels. Additional information collected included presence of the vector in blood or semen, changes in serum anti-AAV antibody titers, and changes in T cell responses to AAV and AAT.

Arms:
arm 1: rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg arm 2: rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg arm 3: rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg

Interventions: intervention 1: rAAV1-CB-hAAT
Intervention descriptions: intervention 1: Recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin

Protocol document: