Brief Title
A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD)
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 Volunteer Subjects and in Patients With Alpha-1 Antitrypsin Deficiency (AATD)
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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs
Secondary Outcome
Number of Participants With AAT Reduction > 30% From Baseline (First Occurrence)
Condition
Alpha-1 Antitrypsin Deficiency
Intervention
ARC-AAT Injection
Study Arms / Comparison Groups
Part A: 0.38 mg/kg
Description: Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers
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
Drug
Estimated Enrollment
65
Start Date
February 2015
Completion Date
November 2016
Primary Completion Date
November 2016
Eligibility Criteria
Inclusion Criteria:
(Part A - Healthy Volunteers)
- Male or female healthy volunteers 18-50 years of age
- Written informed consent
- Body mass index between 18.0 and 28.0 kg/m2
- 12-lead electrocardiogram (ECG) at Screening and pre-dose assessment with no
clinically significant abnormalities
- Non-pregnant/non-nursing females
- Non-smoker for at least one year with current non-smoking status confirmed by urine
cotinine
- Normal lung function (or not clinically significant per investigator assessment) based
on spirometry and diffusion capacity of lung for carbon monoxide (DLCO) according to
American Thoracic Society (ATS) - European Respiratory Society (ERS) criteria
- Highly effective, double barrier contraception (both male and female partners) during
the study and for 3 months following the dose of ARC-AAT
- Willing and able to comply with all study assessments and adhere to protocol schedule
- Suitable venous access for blood sampling
- No abnormal finding of clinical relevance at screening
- Normal AAT level
(Part B-Patients) - As for Part A with the following exceptions:
- Male or female patients 18-70 years of age
- Confirmed diagnosis of homozygous alpha 1-protease inhibitor deficiency (PiZZ
genotype) not receiving alpha-1 antitrypsin augmentation therapy for more than 4 weeks
- BMI between 18.0 and 35.0 kg/m2
- Non-smoker for at least three years with current non-smoking status confirmed by urine
cotinine
Exclusion Criteria:
(Part A-Healthy Volunteers)
- Current regular smoker of cigarettes or cigars or was a regular smoker over the past 1
year
- Recent (within last 6 weeks) transfusion of fresh frozen plasma, platelets, or packed
red blood cells, or anticipated need for transfusion during study
- Acute signs of hepatitis/other infection within 4 weeks of screening and/or baseline
- Concurrent anticoagulants
- Use of dietary and/or herbal supplements that can interfere with liver metabolism
within 7 days of screening
- Use of any drugs known to induce or inhibit hepatic drug metabolism within 14 days
prior to study treatment
- Depot injection/implant of any drug other than birth control within 3 months prior to
study treatment
- Diagnosis of diabetes mellitus or history of glucose intolerance
- History of poorly controlled autoimmune disease or any history of autoimmune hepatitis
- Human immunodeficiency virus (HIV) infection
- Seropositive for hepatitis B virus (HBV) or hepatitis C virus (HCV), and/or history of
delta virus hepatitis
- Uncontrolled hypertension (blood pressure > 150/100 mmHg)
- History of cardiac rhythm disturbances
- Family history of congenital long QT syndrome or unexplained sudden cardiac death
- Symptomatic heart failure (per New York Heart Association [NYHA] guidelines)
- Unstable angina, myocardial infarction, severe cardiovascular disease, transient
ischemic attack (TIA) or cerebrovascular accident (CVA) within past 6 months
- History of malignancy within last 5 years except adequately treated basal cell
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical
cancer.
- History of major surgery within 3 months of screening
- Regular use of alcohol within 1 month prior to screening (i.e., more than fourteen
units of alcohol per week)
- Evidence of acute inflammation, sepsis or hemolysis or clinical evidence of lower
respiratory tract infection
- Diagnosis of significant psychiatric disorder
- Use of illicit drugs (such as cocaine, phencyclidine [PCP] and crack) within 1 year
prior to screening or positive urine drug screen
- History of allergy or hypersensitivity reaction to bee venom
- Use of an investigational agent or device within 30 days prior to dosing or current
participation in an investigational study
- Clinically significant history/presence of any gastrointestinal pathology, unresolved
gastrointestinal symptoms, liver or kidney disease
- Other conditions known to interfere with the absorption, distribution, metabolism, or
excretion of drugs
- Any clinically significant history/presence of poorly controlled neurological,
endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric,
metabolic or other uncontrolled systemic disease
- Blood donation (500 mL) within 7 days prior to study treatment
- History of fever within 2 weeks of screening
- Concomitant medical/psychiatric condition or social situation that would affect
compliance or result in additional safety risk
- Excessive exercise/physical activity within 3 days of screening or enrollment or
planned during the study
- History of thromboembolic disease, stroke within 6 months of baseline, and/or
concurrent anticoagulant medication(s)
(Part B-Patients) - As for Part A with the following exceptions:
- History of major surgery within 2 months of Screening
- Forced expiratory volume at one second (FEV1) at baseline < 60%
- AATD patients with liver elastography score > 11 at Screening
Gender
All
Ages
18 Years - 70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Contacts
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Location Countries
Australia
Location Countries
Australia
Administrative Informations
NCT ID
NCT02363946
Organization ID
ARCAAT-1001
Secondary IDs
U1111-1171-0247
Responsible Party
Sponsor
Study Sponsor
Arrowhead Pharmaceuticals
Study Sponsor
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Verification Date
October 2017