A Multicenter Study to Determine the Depth and Duration of Hepatitis B Surface Antigen (HBsAg) Reduction After Single or Multiple Doses of ARC-520, in Combination With Entecavir in Patients With Chronic Hepatitis B Virus (HBV) Infection

April 15, 2019 updated by: Arrowhead Pharmaceuticals

A Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-escalation Study to Determine the Depth and Duration of Hepatitis B Surface Antigen (HBsAg) Reduction After a Single Intravenous Dose of ARC-520 in Combination With Entecavir in Patients With Chronic Hepatitis B Virus (HBV) Infection, Followed by a Two-dose Open-label Cohort and Three Open-label Single-dose Cohorts in Treatment Naïve Patients, Including a Multi-dose Open-label Extension at a Single Center

The purpose of this study is to determine whether ARC-520 in combination with entecavir is effective in the treatment of patients with chronic HBV Infection.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Treatment with ARC-520 for injection is expected to reduce all HBV proteins and replicative intermediates via ribonucleic acid (RNA) interference. The magnitude of the reduction and duration of effect will depend on the dose. Since to date ARC-520 has not been administered to patients with chronic HBV infection, the effective therapeutic dose in patients with chronic HBV infection is unknown. This study is designed to assess the antiviral activity of ARC-520, especially its effect on HBsAg, in patients with chronic HBV infection at different dose levels.

This is a multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study of ARC 520 in combination with entecavir administered to participants with hepatitis B virus e antigen (HBeAg)-negative (Cohorts 1 through 4) or HBeAg-positive (Cohort 5) immune active, chronic HBV infection, followed by a two-dose open-label cohort (Cohort 6), three open-label single-dose cohorts in treatment-naïve participants (Cohorts 7, 11 and 12) and an open-label multi-dose extension study (Cohorts 8, 9, 10). Cohort 6 will investigate ARC-520 in combination with entecavir administered in two doses to participants with HBeAg-positive immune-active chronic HBV infection. Cohorts 7, 11 and 12 will enroll treatment-naïve participants. Cohort 8 will only enroll participants previously completing Cohorts 1-4. Cohort 9 will only enroll participants previously completing Cohort 5 or 6. Cohort 10 will only enroll participants previously completing Cohort 7.

Participants will undergo the following evaluations at regular intervals during the study: medical history, physical examinations, vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature), weight, adverse events (AEs), 12-lead electrocardiograms (ECGs), concomitant medication, blood sample collection for hematology, coagulation, chemistry, pharmacokinetic (PK) and exploratory pharmacodynamic (PD) measures, urinalysis, HBV serology, HBV genotyping and sequencing, follicle stimulating hormone (FSH) testing and pregnancy testing for females of childbearing potential. Clinically significant changes including AEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the participant is lost to follow-up.

Study Type

Interventional

Enrollment (Actual)

58

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
      • Pokfulam, Hong Kong
        • Queen Mary Hospital
      • Shatin, Hong Kong
        • Prince of Wales Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Key Inclusion Criteria:

  • Diagnosis of HBeAg negative and immune active chronic HBV infection (Cohorts 1-4, 8)
  • Diagnosis of HBeAg positive and immune active chronic HBV infection (Cohorts 5-6, 9)
  • Diagnosis of HBeAg negative or HBeAg positive and immune active or tolerant chronic HBV infection (Cohorts 7, 10, 11 & 12)
  • Patients with > 6 months of continuous, 0.5 mg/day oral entecavir, and a willingness to continue taking entecavir throughout the study (Cohorts 1-6, 8-9).
  • Patients naive to entecavir (never on entecavir or on entecavir <30 days prior to screening) and a willingness to take entecavir and willingness to continue taking entecavir throughout the study (Cohorts 7, 11 & 12).

Key Exclusion Criteria:

  • Female patients that have a positive pregnancy test or are lactating.
  • Acute signs of hepatitis/other infection (eg, moderate fever, jaundice, nausea, vomiting, and abdominal pain) evident within 4 weeks of screening and/or at the screening examination.
  • Patients with antiviral therapy other than entecavir within 3 months of screening or prior treatment with interferon or a toll receptor agonist in the last 5 years.
  • Use within the last 6 months or an anticipated requirement for anticoagulants, corticosteroids, immunomodulators, or immunosuppressants.
  • Has any history of autoimmune disease especially autoimmune hepatitis.
  • Has human immunodeficiency virus (HIV) infection, as shown by the presence of anti-HIV antibody (sero-positive).
  • Is sero-positive for hepatitis C virus (HCV), and/or a history of delta virus hepatitis.
  • Has a history of allergy to bee venom or history of hypersensitivity reaction requiring an emergency visit to a physician or hospital and/or requirement for treatment with steroids and/or epinephrine.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ARC-520 Cohort 1
a single intravenous (IV) dose of double-blind ARC-520 Injection 1.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection
Drug: ARC-520
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Placebo Comparator: ARC-520 Cohort 2
a single IV dose of double-blind ARC-520 Injection 2.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection
Drug: ARC-520
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 3
a single IV dose of double-blind ARC-520 Injection 3.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection
Drug: ARC-520
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 4
a single IV dose of double-blind ARC-520 Injection 4.0 mg/kg in combination with entecavir administered to participants with HBeAg-negative immune active chronic HBV infection
Drug: ARC-520
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 5
a single IV dose of double-blind ARC-520 Injection 4.0 mg/kg in combination with entecavir administered to participants with HBeAg-positive immune active chronic HBV infection
Drug: ARC-520
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: Placebo Normal Saline Cohorts 1-5
a single IV dose of double-blind normal saline in combination with entecavir administered to participants with HBeAg-negative or -positive immune active chronic HBV infection
Drug: Placebo
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 6
two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune active chronic HBV
Drug: ARC-520
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 7
a single IV dose of open-label ARC-520 4.0 mg/kg administered to treatment-naïve, HBeAg-negative or -positive participants with chronic hepatitis B (CHB)
Drug: ARC-520
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 8
open-label multi-dose extension cohort: multiple IV doses of open-label ARC-520 (4.0 mg/kg every [Q]4 weeks) administered to HBeAg-negative participants with CHB receiving chronic entecavir therapy who completed Cohorts 1 through 4
Drug: ARC-520
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 9
open-label multi-dose extension cohort: multiple IV doses of open-label ARC-520 (4.0 mg/kg Q6 weeks or Q8 weeks) administered to HBeAg-positive participants with CHB receiving chronic entecavir therapy who completed Cohorts 5 or 6
Drug: ARC-520
Drug: entecavir
Other Names:
  • Baraclude
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 10
open-label multi-dose extension cohort: multiple IV doses of open-label ARC-520 (4.0 mg/kg Q4 weeks) administered to a mixed cohort (HBeAg-negative and -positive participants) who were naïve (within the last 6 months) to entecavir treatment and completed Cohort 7
Drug: ARC-520
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 11
a single IV dose of open-label ARC-520 5.0 mg/kg administered to treatment-naïve, HBeAg-positive participants with CHB
Drug: ARC-520
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.
Experimental: ARC-520 Cohort 12
a single IV dose of open-label ARC-520 6.0 mg/kg administered to treatment-naïve, HBeAg-positive participants with CHB
Drug: ARC-520
Drug: chlorpheniramine
In all cohorts, each participant received an 8 mg dose of oral chlorpheniramine 2 hours prior to each administration of ARC-520 Injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change From Baseline Over Time in Quantitative Hepatitis B Surface Antigen (HBsAG)
Time Frame: Baseline, through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 253 Cohort 10)
Baseline, through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 253 Cohort 10)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame: through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 225 Cohort 10)
An adverse event (AE) is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. An SAE is any 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; or is a medically important event or reaction.Events were categorized as mild, moderate or severe. TEAEs were defined as all AEs starting or worsening after commencement of treatment with investigational product. A treatment-related TEAE was one whose relationship to treatment was noted as unlikely, possibly, or probably related.
through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 225 Cohort 10)
Number of Participants With Negative Bee Venom Allergy Test Results at Baseline, Day 29, and Day 85
Time Frame: Baseline, Day 29, Day 85
Bee venom allergy tests were used to assess immunoglobulin E (IgE) in Cohorts 1-7. Analysis values less than 0.35 kU/L were taken as negative.
Baseline, Day 29, Day 85
Change From Baseline in Entecavir Plasma Trough Concentration, Cohorts 1-7
Time Frame: Baseline, Days 1, 2, 3, 8, 15, 22, 29
Baseline, Days 1, 2, 3, 8, 15, 22, 29
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 of ARC-520 Product Constituents AD0009 and AD0010: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf), Cohorts 1-5 Only
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Maximum Observed Plasma Concentration (Cmax), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Clearance (CL), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Apparent Volume of Distribution During the Terminal Phase (Vz), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Volume in Steady State (Vss), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Rate Constant (Kel), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Half-Life (t1/2), Cohorts 1-5
Time Frame: Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose
Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Arrowhead Pharmaceuticals

Collaborators

ICON Clinical Research

Investigators

  • Study Chair: Bruce Given, MD, Arrowhead Pharmaceuticals, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2014

Primary Completion (Actual)

January 1, 2017

Study Completion (Actual)

January 1, 2017

Study Registration Dates

First Submitted

February 13, 2014

First Submitted That Met QC Criteria

February 18, 2014

First Posted (Estimate)

February 19, 2014

Study Record Updates

Last Update Posted (Actual)

July 5, 2019

Last Update Submitted That Met QC Criteria

April 15, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Heparc-2001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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