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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02363946
Recruitment Status : Terminated (Company decision to terminate the trial)
First Posted : February 16, 2015
Last Update Posted : January 6, 2017
Information provided by (Responsible Party):
Arrowhead Pharmaceuticals

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.

Condition or disease Intervention/treatment Phase
Alpha-1 Antitrypsin Deficiency Drug: ARC-AAT Injection Other: Placebo Phase 1

Detailed Description:

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Study Start Date : February 2015
Estimated Primary Completion Date : February 2017
Estimated Study Completion Date : February 2017

Arm Intervention/treatment
Experimental: Active Treatment
ARC-AAT Injection
Drug: ARC-AAT Injection
RNA interference (RNAi)-based, liver-targeted therapeutic
Other Name: ARC-AAT

Experimental: Placebo Comparator
0.9% normal saline
Other: Placebo
0.9 % normal saline

Primary Outcome Measures :
  1. Change from Baseline in physical exams, vital signs, ECGs, pulmonary function tests and clinical laboratory tests [ Time Frame: Through Day 29 ]
  2. Number of participants with adverse events or discontinuing due to toxicity as a measure of Safety and Tolerability [ Time Frame: Through Day 29 ]
  3. Pharmacokinetics - Cmax: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Maximum plasma concentration

  4. Pharmacokinetics - Tmax: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Time to maximum plasma concentration

  5. 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

  6. Pharmacokinetics - AUCinf: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Area under the plasma concentration versus time curve from zero to infinity

  7. Pharmacokinetics - Kel: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Terminal elimination rate constant

  8. Pharmacokinetics - t1/2: Change over time [ Time Frame: Through 48 hours post-dosing ]
    Half life; t1/2=ln(2)/kel

  9. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. Change in circulating blood levels of cytokines [ Time Frame: Through 48 hours post-dosing ]
  5. Change in circulating blood levels of complement [ Time Frame: Through 48 hours post-dosing ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02363946

Australia, Victoria
Nucleus Network Ltd
Melbourne, Victoria, Australia, 3004
Universitatsklinikum des Saarlandes
Homburg/Saar, Germany
Leiden University Medical Center
Leiden, Netherlands, 2333ZA
United Kingdom
Queen Elizabeth Hospital
Edgbaston, Birmingham, United Kingdom, B15 2WB
Sponsors and Collaborators
Arrowhead Pharmaceuticals

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Arrowhead Pharmaceuticals Identifier: NCT02363946     History of Changes
Other Study ID Numbers: ARCAAT-1001
U1111-1171-0247 ( Other Identifier: WHO )
2015-001147-36 ( EudraCT Number )
First Posted: February 16, 2015    Key Record Dates
Last Update Posted: January 6, 2017
Last Verified: September 2016

Keywords provided by Arrowhead Pharmaceuticals:
alpha-1 antitrypsin

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Pathologic Processes
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action