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

Arrowhead Pharmaceuticals

Status and phase

Terminated

Phase 2

Conditions

Hepatitis B, Chronic

Treatments

Drug: chlorpheniramine

Drug: Placebo

Drug: ARC-520

Drug: entecavir

Study type

Interventional

Funder types

Industry

Identifiers

NCT02065336

Heparc-2001

Details and patient eligibility

About

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.

Full 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.

Enrollment

58 patients

Sex

All

Ages

18 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Triple Blind

58 participants in 13 patient groups, including a placebo group

ARC-520 Cohort 1

Experimental group

Description:

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

Treatment:

Drug: entecavir

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 2

Placebo Comparator group

Description:

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

Treatment:

Drug: entecavir

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 3

Experimental group

Description:

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

Treatment:

Drug: entecavir

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 4

Experimental group

Description:

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

Treatment:

Drug: entecavir

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 5

Experimental group

Description:

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

Treatment:

Drug: entecavir

Drug: ARC-520

Drug: chlorpheniramine

Placebo Normal Saline Cohorts 1-5

Experimental group

Description:

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

Treatment:

Drug: entecavir

Drug: Placebo

Drug: chlorpheniramine

ARC-520 Cohort 6

Experimental group

Description:

two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune active chronic HBV

Treatment:

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 7

Experimental group

Description:

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)

Treatment:

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 8

Experimental group

Description:

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

Treatment:

Drug: entecavir

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 9

Experimental group

Description:

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

Treatment:

Drug: entecavir

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 10

Experimental group

Description:

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

Treatment:

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 11

Experimental group

Description:

a single IV dose of open-label ARC-520 5.0 mg/kg administered to treatment-naïve, HBeAg-positive participants with CHB

Treatment:

Drug: ARC-520

Drug: chlorpheniramine

ARC-520 Cohort 12

Experimental group