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

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT02363946
• Date of registration: 02/02/2015
• Prospective Registration: No
• Primary sponsor: Arrowhead Pharmaceuticals
• Public title: A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD)
• Scientific 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)
• Date of first enrolment: February 2015
• Target sample size: 65
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT02363946
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Investigator, Outcomes Assessor).
• Phase: Phase 1

Countries of recruitment

Australia, Germany, Netherlands, United Kingdom

Key inclusion & exclusion criteria

Inclusion Criteria:

(Part A - Healthy Volunteers)

- Male or female healthy volunteers 18-50 years of age

- Written informed consent

- BMI between 18.0 and 28.0 kg/m2

- 12-lead 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 (BP > 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 six (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

- FEV1 (forced expiratory volume at one second) at baseline < 60%

- AATD Patients with liver Elastography score > 11 at Screening



Age minimum: 18 Years
Age maximum: 70 Years
Gender: All

Health Condition(s) or Problem(s) studied

Alpha-1 Antitrypsin Deficiency

Intervention(s)

Drug: ARC-AAT Injection

Other: Placebo

Primary Outcome(s)

Change from Baseline in physical exams, vital signs, ECGs, pulmonary function tests and clinical laboratory tests [Time Frame: Through Day 29]

Pharmacokinetics - t1/2: Change over time [Time Frame: Through 48 hours post-dosing]

Pharmacokinetics - Cmax: Change over time [Time Frame: Through 48 hours post-dosing]

Pharmacokinetics - AUCinf: Change over time [Time Frame: Through 48 hours post-dosing]

Pharmacokinetics - AUC0-24: Change over time [Time Frame: Through 48 hours post-dosing]

Change in circulating blood levels of alpha-1 antitrypsin as a measure of activity of ARC-AAT [Time Frame: Through Day 29, and follow-up every two weeks up to 90 days]

Number of participants with adverse events or discontinuing due to toxicity as a measure of Safety and Tolerability [Time Frame: Through Day 29]

Pharmacokinetics - Kel: Change over time [Time Frame: Through 48 hours post-dosing]

Pharmacokinetics - Tmax: Change over time [Time Frame: Through 48 hours post-dosing]

Secondary Outcome(s)

Change in circulating blood levels of complement [Time Frame: Through 48 hours post-dosing]

Change in circulating blood levels of cytokines [Time Frame: Through 48 hours 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]

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]

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]

Secondary ID(s)

ARCAAT-1001

2015-001147-36

U1111-1171-0247

Source(s) of Monetary Support

Please refer to primary and secondary sponsors