Clinical Trial: A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD)

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Double-Blind, Placebo-Controlled, Dose-Escalating, Phase 1 Study to Determine the Safety, Tolerability, Pharmacokinetics and Effect of Circulating Alpha-1 Antitrypsin Levels of ARC-AAT in Healthy Vo

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. 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 Summary:

This is a multi-center, randomized, placebo-controlled, double-blind, single-dose-escalation first-in-human, Phase 1 study. 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. Subjects 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 AATD patients will commence based on pre-determined threshold reductions in AAT levels for healthy volunteers.

Participants will undergo the following evaluations at regular intervals: medical history, physical examinations, bee venom allergy blood test, vital sign measurements, weight, adverse event monitoring, ECGs, pregnancy test (females), concurrent medication, pulmonary function testing and sample collection for hematology, coagulation, chemistry, pharmacokinetics (PK), complement, cytokines, drug screens, serum alpha-1antitrypsin levels, and urinalysis. 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.


Sponsor: Arrowhead Pharmaceuticals

Current Primary Outcome:

  • Change from Baseline in physical exams, vital signs, ECGs, pulmonary function tests and clinical laboratory tests [ Time Frame: Through Day 29 ]
  • Number of participants with adverse events or discontinuing due to toxicity as a measure of Safety and Tolerability [ Time Frame: Through Day 29 ]
  • Pharmacokinetics - Cmax: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Maximum plasma concentration
  • Pharmacokinetics - Tmax: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Time to maximum plasma concentration
  • Pharmacokinetics - AUC0-24: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Area under the plasma concentration versus time curve from zero to 24 hours
  • Pharmacokinetics - AUCinf: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Area under the plasma concentration versus time curve from zero to infinity
  • Pharmacokinetics - Kel: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Terminal elimination rate constant
  • Pharmacokinetics - t1/2: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Half life; t1/2=ln(2)/kel
  • Change in circulating blood levels of alpha-1 antitrypsin as a measure of activity of ARC-AAT [&n

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Dose level, in healthy volunteers, at which pre-determined threshold level of AAT knockdown is achieved as a measure of activity of ARC-AAT. [ Time Frame: Day 22 post-dosing ]
    • Dose level, AATD patients, at which pre-determined threshold level of AAT knockdown is achieved as a measure of activity of ARC-AAT. [ Time Frame: Day 29 post-dosing ]
    • Time between nadir of alpha-1 antitrypsin blood levels and return to baseline blood levels [ Time Frame: Through Day 29, and follow-up every two weeks up to 90 days ]
    • Change in circulating blood levels of cytokines [ Time Frame: Through 48 hours post-dosing ]
    • Change in circulating blood levels of complement [ Time Frame: Through 48 hours post-dosing ]


    Original Secondary Outcome: Same as current

    Information By: Arrowhead Pharmaceuticals

    Dates:
    Date Received: February 2, 2015
    Date Started: February 2015
    Date Completion: February 2017
    Last Updated: January 4, 2017
    Last Verified: September 2016