Conditions: Alpha-1 Antitrypsin Deficiency
Keywords: alpha-1 antitrypsin AATD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: yes

Brief summary:
The purpose of the study is to determine the safety and tolerability of escalating doses of ARC-AAT and to evaluate the pharmacokinetics of ARC-AAT and the effect of ARC-AAT on circulating levels of alpha-1 antitrypsin (AAT). The study will consist of two parts, Part A (conducted in healthy volunteers) and Part B (conducted in AATD patients) at up to 9 escalating dose levels with 6 participants per dose level.

Detailed description:
Healthy volunteers and AATD patients will be randomized to receive a single intravenous injection of either ARC-AAT or Placebo in double-blind fashion. Up to thirteen cohorts (6 participants per cohort) will be enrolled. Participants in all cohorts will be confined to the clinical facility beginning on Day -1 with discharge on Day 2. Escalation to the next dose level will proceed until a participant experiences a dose-limiting toxicity (DLT) or there is achievement of pre-determined threshold reductions in AAT levels. Dosing in participants with AATD will commence based on pre-determined threshold reductions in AAT levels for healthy volunteers. For each participant, the duration of the study clinic visits is up to 11 weeks, from Screening to the End-of-Study examination. However, including a Day 90 Follow-Up telephone call, the maximum study duration is approximately 20 weeks.

Arms:
arm 1: Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers arm 2: Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers arm 3: Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers arm 4: Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers arm 5: Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers arm 6: Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers arm 7: Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers arm 8: Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers arm 9: Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers arm 10: Single dose administration of 0.9% normal saline IV injection in healthy volunteers arm 11: Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD arm 12: Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD arm 13: Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in participants with AATD arm 14: Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in participants with AATD arm 15: Single dose administration of 0.9% normal saline IV injection in participants with AATD

Interventions: intervention 1: ARC-AAT Injection intervention 2: Placebo intervention 3: Diphenhydramine
Intervention descriptions: intervention 1: RNA interference-based, liver-targeted therapeutic intervention 2: 0.9 % normal saline intervention 3: Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.

Protocol document: