Study of ARC-520 in Participants With Hepatitis B Virus e Antigen (HBeAg) Positive Chronic Hepatitis B Virus

A Multicenter, Randomized, Double-blind, Placebo-controlled, Multi-dose Study to Determine the Depth of Hepatitis B Surface Antigen (HBsAg) Reduction Following Intravenous ARC-520 in Combination With Entecavir or Tenofovir in Patients With HBeAg Positive, Chronic Hepatitis B Virus (HBV) Infection

Participants with chronic HBV infection will receive multiple doses of ARC-520 in combination with entecavir or tenofovir and be evaluated for safety and efficacy.

Study Overview

• Status: Terminated
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Placebo; Drug: ARC-520; Drug: Entecavir; Drug: Tenofovir; Drug: diphenhydramine

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94118
      • Kaiser Permanente
  • Florida
    • Miami, Florida, United States, 33136
      • Univ. Of Miami School Of Medicine/Center For Liver Diseases
  • New York
    • New York, New York, United States, 10029
      • Ichan School of Medicine at Mount Sinai
  • Texas
    • San Antonio, Texas, United States, 78215
      • The Texas Liver Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, 18 to 75 years of age
• Written informed consent
• Body mass index (BMI) between 17.5 and 30.0 kg/m2
• No clinically significant abnormalities at screening/pre-dose 12-lead ECG assessment
• No abnormal finding of clinical relevance
• Diagnosis of HBeAg positive, immune active, chronic HBV infection
• > 2 months of continuous treatment with daily oral entecavir or tenofovir
• Must use 2 effective methods of contraception (double barrier contraception or hormonal contraceptive along with a barrier contraceptive)

Exclusion Criteria:

• Pregnant or lactating
• Acute signs of hepatitis/other infection within 4 weeks of screening
• Hepatic transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) > 3 times the upper limits of normal
• Liver Elastography (i.e. FibroScan®) score > 9
• Antiviral therapy other than entecavir or tenofovir within 3 months of screening
• Prior treatment with interferon in the last 3 years
• Use of anticoagulants, corticosteroids, immunomodulators, or immunosuppressants within 6 months of screening
• Use within 7 days prior to screening of dietary and/or herbal supplements that can interfere with liver metabolism
• Use of any drugs known to induce or inhibit hepatic drug metabolism within 30 days of study drug administration
• Use of prescription medication within 14 days prior to study drug administration
• Depot injection/implant of any drug except birth control within 3 months prior to study drug administration
• Known diagnosis of diabetes mellitus
• History of autoimmune disease
• Human immunodeficiency virus (HIV) infection
• Sero-positive for Hepatitis C Virus (HCV), and/or a history of delta virus hepatitis
• Hypertension; blood pressure > 150/100 mmHg
• History of cardiac rhythm disturbances
• Family history of congenital long QT syndrome, Brugada syndrome or unexplained sudden cardiac death
• Symptomatic heart failure, unstable angina, myocardial infarction, severe cardiovascular disease within 6 months prior to study entry
• History of malignancy, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, in situ cervical cancer
• Major surgery within 3 months of screening
• History of alcohol and/or drug abuse < 12 months from screening
• Regular use of alcohol within 6 months (ie, more than 14 units of alcohol per week)
• Evidence of systemic acute inflammation, sepsis, or hemolysis
• Diagnosed with a significant psychiatric disorder
• Use of drugs of abuse
• History of allergy to bee venom
• Positive reaction to the bee venom allergy immunoglobulin E (IgE) test
• Use of investigational agents or devices within 30 days
• Clinically significant inherited or acquired gastrointestinal pathology, unresolved gastrointestinal symptoms, liver or kidney disease
• Presence of cholangitis, cholecystitis, cholestasis, or duct obstruction
• Clinically significant history or presence of uncontrolled systemic disease
• Donated or had a loss of whole blood of 50 milliliters (mL) to 499 mL within 30 days or more than 499 mL between 31 and 56 days prior to study treatment
• History of fever within 2 weeks of screening
• Immunization/planned immunization with live attenuated vaccine except influenza vaccine
• Presence of any medical or psychiatric condition or social situation that impacts compliance or results in additional safety risk
• Excessive exercise/physical activity within 7 days of screening/enrolment or during study
• History of coagulopathy/stroke within past 6 months, and/or concurrent anticoagulant medication(s)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARC-520; Intravenous administration of 1.0 mg/kg ARC-520 once every 4 weeks for 3 total doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day), taken throughout the study. Pretreatment with diphenhydramine 50 mg 2 hours (±30 minutes) prior to administration of study drug.	Drug: ARC-520; Drug: Entecavir; 0.5 or 1.0 mg/day orally; Other Names: Baraclude; Drug: Tenofovir; 300 mg/day orally; Other Names: Viread; Drug: diphenhydramine; 50 mg orally as pretreatment antihistamine
Placebo Comparator: Placebo; Intravenous administration of normal saline (0.9%) once every 4 weeks for 3 total doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day), taken throughout the study. Pretreatment with diphenhydramine 50 mg 2 hours (±30 minutes) prior to administration of placebo.	Drug: Placebo; Drug: Entecavir; 0.5 or 1.0 mg/day orally; Other Names: Baraclude; Drug: Tenofovir; 300 mg/day orally; Other Names: Viread; Drug: diphenhydramine; 50 mg orally as pretreatment antihistamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 85	Baseline, Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to Adverse Events (AEs)	An AE was defined as any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with treatment. An SAE was defined as any untoward medical occurrence that, at any dose: 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; or is a medically important event or reaction. An AE was classified as a TEAE if the AE was not present prior to the first study medication administration and started at or after the time of initiation of administration of study medication, or if the AE presented prior to initiation of administration of study medication, continued and increased in intensity after administration of study medication.	From time of informed consent through Day 147 ± 3 days
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of ARC-520: Apparent Clearance (CL)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2)		Through 48 hours post-dosing on Days 1 and 57
Pharmacokinetics of Entecavir or Tenofovir: AUC0-24		Through 24 hours post-dosing on Days 1 and 57
Pharmacokinetics of Entecavir or Tenofovir: AUClast		Through 24 hours post-dosing on Days 1 and 57
Pharmacokinetics of Entecavir or Tenofovir: Cmax		Through 24 hours post-dosing on Days 1 and 57
Pharmacokinetics of Entecavir or Tenofovir: Time of Cmax (Tmax)		Through 24 hours post-dosing on Days 1 and 57

Collaborators and Investigators

• Sponsor: Arrowhead Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: May 15, 2015
• First Submitted That Met QC Criteria: May 21, 2015
• First Posted (Estimate): May 22, 2015

Study Record Updates

• Last Update Posted (Actual): December 5, 2017
• Last Update Submitted That Met QC Criteria: October 31, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: HBV; Chronic Hepatitis B; Hepatitis B Virus
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Sensory System Agents; Anesthetics; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Hypnotics and Sedatives; Anesthetics, Local; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Tenofovir; Entecavir; Diphenhydramine; Promethazine
• Other Study ID Numbers: Heparc-2004