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

Overview

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.

Full Title of Study: “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 Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: November 2016

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.

Interventions

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

Arms, Groups and Cohorts

  • Experimental: Part A: 0.38 mg/kg
    • Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers
  • Experimental: Part A: 1.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers
  • Experimental: Part A: 2.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers
  • Experimental: Part A: 3.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers
  • Experimental: Part A: 4.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers
  • Experimental: Part A: 5.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers
  • Experimental: Part A: 6.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers
  • Experimental: Part A: 7.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers
  • Experimental: Part A: 8.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers
  • Placebo Comparator: Part A: Placebo
    • Single dose administration of 0.9% normal saline IV injection in healthy volunteers
  • Experimental: Part B: 2.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD
  • Experimental: Part B: 4.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD
  • Experimental: Part B: 6.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in participants with AATD
  • Experimental: Part B: 7.0 mg/kg
    • Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in participants with AATD
  • Placebo Comparator: Part B: Placebo
    • Single dose administration of 0.9% normal saline IV injection in participants with AATD

Clinical Trial Outcome Measures

Primary Measures

  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs
    • Time Frame: From the first dose of study treatment through Day 29 ± 1 day
    • An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as defined as AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. SAEs are defined as is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction.
  • Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Laboratory Values
    • Time Frame: Day 1 through Day 29 ± 1 day
    • Laboratory values collected include: hematology (haemoglobin, lymphocytes, neutrophils, platelets, white cell count, monocytes); biochemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, creatine kinase, creatinine, gamma-glutamyltransferase, fasting glucose, troponin I); coagulation parameters (fibrinogen, international normalized ratio); and C-reactive protein.
  • Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Vital Signs, Electrocardiograms (ECGs), Pulmonary Function, Physical Findings, and Other Observations
    • Time Frame: Day 1 through Day 29 ± 1 day
    • Values collected include: vital signs (clinically concerning or symptomatic treatment emergent changes in heart rate, systolic blood pressure, diastolic blood pressure, respiratory rate, or temperature); ECGs (clinically significant changes from baseline were observed for ventricular rate, RR interval, QRS duration, QT interval or QT interval corrected for heart rate using Fridericia’s formula [QTcF]; treatment emergent clinically significant changes in ST segments, P wave or T wave morphology; cardiac telemetry monitoring); clinically significant abnormal physical examination findings; treatment emergent sensitivity to bee venom; pulmonary function (clinically significant worsening in spirometry parameters and carbon monoxide diffusing capacity of the lung for carbon monoxide [DLCO]).
  • Pharmacokinetics of ARC-AAT: Maximum Observed Plasma Concentration (Cmax) for the Analytes AD00370 and ARC-Melittin-Like Peptide (MLP; Part A)
    • Time Frame: Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
  • Pharmacokinetics of ARC-AAT: Time to Maximum Observed Concentration (Tmax) for the Analytes AD00370 and ARC-MLP (Part A)
    • Time Frame: Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
  • Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Time 24 Hours (AUC0-24) for the Analytes AD00370 and ARC-MLP (Part A)
    • Time Frame: Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
  • Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From From Zero to Infinity (AUCinf) for the Analytes AD00370 and ARC-MLP (Part A)
    • Time Frame: Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
  • Pharmacokinetics of ARC-AAT: Terminal Elimination Rate Constant Obtained From the Slope of the Line (Kel) for the Analytes AD00370 and ARC-MLP (Part A)
    • Time Frame: Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
  • Pharmacokinetics of ARC-AAT: Half-Life (t1/2) for the Analytes AD00370 and ARC-MLP (Part A)
    • Time Frame: Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
  • Percentage Reduction From Baseline of AAT Up to Day 29
    • Time Frame: Baseline, Days 3, 8, 15, 22 and 29
    • Clinical assay for total serum AAT level was used for Part A. A quantitative measurement of AAT was used for Part B. A negative percent reduction indicates a percentage increase. Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.

Secondary Measures

  • Number of Participants With AAT Reduction > 30% From Baseline (First Occurrence)
    • Time Frame: Baseline, Days 3, 8, 15, 22 and 29
    • Data presents the study visit day upon which a participant had the first occurrence of AAT reduction of > 30% from Baseline, and the number of participants who had a > 30% reduction at any visit (overall). Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.
  • Maximum Percentage Reduction in Mean AAT (Nadir of Mean AAT)
    • Time Frame: Study Day for Nadir of Mean AAT: Day 8 (for Part B 2 mg/kg arm), Day 15 (for Part A 0.38 mg/kg, 2 mg/kg, 4 mg/ kg, Placebo arms; Part B 4 mg/kg, Placebo arms), Day 22 (Part A 3 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg arms), Day 29 (1 mg/kg, 8 mg/kg arms)
  • Number of Participants With a Return From Nadir AAT Blood Levels to Above Normal or Within 15% of Baseline in > 100 Days
    • Time Frame: Baseline, up to Day 29, and through 100 days of follow-up
    • Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.
  • Mean Percentage Change in Circulating Blood Levels of Cytokines 2 Hours Post-Dose
    • Time Frame: Pre-dose, 2 hours post-dose
  • Mean Percentage Change in Circulating Blood Levels of Complement Factors 2 Hours Post-Dose
    • Time Frame: Pre-dose, 2 hours post-dose

Participating in This Clinical Trial

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 Eligibility: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Arrowhead Pharmaceuticals
  • Provider of Information About this Clinical Study
    • Sponsor

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