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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

Sponsor
Arrowhead Pharmaceuticals (Industry)
Overall Status
Terminated
CT.gov ID
NCT02065336
Collaborator
ICON Clinical Research (Industry)
58
Enrollment
2
Locations
13
Arms
34.1
Actual Duration (Months)
29
Patients Per Site
0.9
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
58 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Mar 1, 2014
Actual Primary Completion Date :
Jan 1, 2017
Actual Study Completion Date :
Jan 1, 2017

Arms and Interventions

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.

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline Over Time in Quantitative Hepatitis B Surface Antigen (HBsAG) [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

    1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [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.

    2. Number of Participants With Negative Bee Venom Allergy Test Results at Baseline, Day 29, and Day 85 [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.

    3. Change From Baseline in Entecavir Plasma Trough Concentration, Cohorts 1-7 [Baseline, Days 1, 2, 3, 8, 15, 22, 29]

    4. 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 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    5. 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 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    6. 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 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    7. Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Maximum Observed Plasma Concentration (Cmax), Cohorts 1-5 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    8. Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Clearance (CL), Cohorts 1-5 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    9. Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Apparent Volume of Distribution During the Terminal Phase (Vz), Cohorts 1-5 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    10. Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Volume in Steady State (Vss), Cohorts 1-5 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    11. Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Rate Constant (Kel), Cohorts 1-5 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    12. Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Half-Life (t1/2), Cohorts 1-5 [Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Queen Mary Hospital Pokfulam Hong Kong
    2 Prince of Wales Hospital Shatin Hong Kong

    Sponsors and Collaborators

    • Arrowhead Pharmaceuticals
    • ICON Clinical Research

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Arrowhead Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02065336
    Other Study ID Numbers:
    • Heparc-2001
    First Posted:
    Feb 19, 2014
    Last Update Posted:
    Jul 5, 2019
    Last Verified:
    Apr 1, 2019
    Keywords provided by Arrowhead Pharmaceuticals
    HBV
    Hepatitis
    Additional relevant MeSH terms:
    Hepatitis A
    Hepatitis B
    Hepatitis B, Chronic
    Hepatitis
    Chlorpheniramine
    Entecavir

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail No patients were enrolled in Cohorts 8, 11, or 12. Cohort 9 (n=2) and Cohort 10 (n=8) enrolled participants who previously completed treatment in other cohorts.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 Placebo Normal Saline Cohorts 1-5 ARC-520 Cohort 9 ARC-520 Cohort 10
    Arm/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 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 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 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 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 two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune active chronic HBV 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) 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 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 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
    Period Title: Main Study
    STARTED 6 6 6 6 6 6 12 10 0 0
    COMPLETED 6 6 6 6 6 6 12 10 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0
    Period Title: Main Study
    STARTED 0 0 0 0 0 0 0 0 2 8
    COMPLETED 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 2 8

    Baseline Characteristics

    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 Placebo Normal Saline Cohorts 1-5 Total
    Arm/Group Description a single 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 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 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 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 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 two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune active chronic HBV 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) 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 Total of all reporting groups
    Overall Participants 6 6 6 6 6 6 12 10 58
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    49.0
    (8.22)
    43.0
    (4.15)
    42.0
    (1.79)
    39.8
    (2.04)
    39.5
    (7.23)
    33.3
    (4.23)
    39.8
    (10.12)
    44.4
    (9.09)
    41.4
    (7.94)
    Sex: Female, Male (Count of Participants)
    Female
    2
    33.3%
    2
    33.3%
    3
    50%
    1
    16.7%
    2
    33.3%
    3
    50%
    5
    41.7%
    2
    20%
    20
    34.5%
    Male
    4
    66.7%
    4
    66.7%
    3
    50%
    5
    83.3%
    4
    66.7%
    3
    50%
    7
    58.3%
    8
    80%
    38
    65.5%

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline Over Time in Quantitative Hepatitis B Surface Antigen (HBsAG)
    Description
    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)

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamic (PD) Population: all participants who received at least 1 dose of study drug and had evaluable data from at least one postdose PD assessment according to the treatment the participants were assigned.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 Placebo Normal Saline Cohorts 1-5 ARC-520 Cohort 9 ARC-520 Cohort 10
    Arm/Group Description a single 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 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 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 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 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 two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune active chronic HBV 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) 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 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 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
    Measure Participants 6 6 6 6 6 6 12 10 0 8
    Day 1
    -19222
    (27217)
    Day 3
    -554.8
    (861.86)
    -1194.0
    (2083.72)
    -1003.6
    (949.36)
    -1501.0
    (1930.12)
    -1664.7
    (2375.62)
    -948.0
    (1016.31)
    -12401.1
    (17661.02)
    43.3
    (267.60)
    Day 8
    -928.1
    (1285.26)
    -2179.2
    (3170.68)
    -884.3
    (1296.49)
    -2591.2
    (3304.72)
    -1789.8
    (2101.23)
    -1344.0
    (1319.66)
    -20123.8
    (29795.99)
    42.2
    (568.32)
    Day 15
    -1055.1
    (1900.89)
    -2260.8
    (4022.82)
    -470.8
    (2025.31)
    -3069.0
    (3923.45)
    -1672.8
    (1892.73)
    -22915.6
    (34381.59)
    236.6
    (321.17)
    Day 22
    -1225.4
    (1967.15)
    -2266.2
    (3868.90)
    -204.3
    (2077.12)
    -2978.8
    (3536.73)
    -1951.7
    (2819.85)
    -1553.7
    (1596.05)
    -23872.7
    (35753.39)
    115.1
    (594.38)
    Day 29
    -579.1
    (352.71)
    -1826.3
    (2618.78)
    93.3
    (2425.68)
    -2972.8
    (3506.01)
    -1964.3
    (2501.62)
    -1532.3
    (1500.40)
    -24148.3
    (36256.02)
    168.8
    (460.59)
    -22617
    (32653)
    Day 43
    -1020.1
    (1252.98)
    -1288.8
    (1498.60)
    -1471.8
    (1625.30)
    -3219.8
    (3601.70)
    -1939.7
    (2277.79)
    -1566.8
    (1290.46)
    -23932.0
    (35929.80)
    58.3
    (411.60)
    Day 57
    -1056.7
    (773.69)
    -2330.1
    (1676.50)
    -2813.0
    (2665.97)
    -1536.0
    (1373.46)
    -1370.7
    (872.64)
    -22658.4
    (34292.84)
    156.1
    (527.40)
    -22840
    (32239)
    Day 85
    -670.1
    (1825.99)
    -542.8
    (1815.34)
    -2119.3
    (1717.17)
    -926.3
    (1406.29)
    -537.5
    (1901.16)
    -791.0
    (457.04)
    -20827.2
    (31753.76)
    225.4
    (393.81)
    -23305
    (32455)
    Day 113
    -23205
    (32362)
    Day 141
    -23182
    (32379)
    Day 169
    -26481
    (33649)
    Day 197
    -30234
    (34097)
    Day 225
    -1249
    (1273)
    Day 253
    -643
    (905)
    2. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    Description 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.
    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)

    Outcome Measure Data

    Analysis Population Description
    Safety Population: all participants who received any amount of study drug or placebo, and had at least 1 postdose safety assessment. Data for Cohort 9 was not analyzed or summarized due to limited enrollment.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 ARC-520 Cohort 9 ARC-520 Cohort 10 Placebo Normal Saline Cohorts 1-5
    Arm/Group Description a single 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 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 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 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 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 two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune active chronic HBV a single IV dose of open-label ARC-520 4.0 mg/kg administered to treatment-naïve, HBeAg-negative or -positive participants with CHB 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 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 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
    Measure Participants 6 6 6 6 6 6 12 2 8 10
    Any TEAE
    1
    16.7%
    4
    66.7%
    1
    16.7%
    0
    0%
    1
    16.7%
    1
    16.7%
    1
    8.3%
    1
    10%
    7
    12.1%
    0
    NaN
    Any mild TEAE
    1
    16.7%
    3
    50%
    1
    16.7%
    0
    0%
    1
    16.7%
    1
    16.7%
    1
    8.3%
    1
    10%
    7
    12.1%
    0
    NaN
    Any moderate TEAE
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    Any severe TEAE
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    Any TEAE related to study drug
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4
    6.9%
    0
    NaN
    Any TEAE leading to discontinuation of treatment
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    Any SAE
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    Any SAE related to study drug
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    Any life-threatening SAE
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    Any SAE leading to death
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    3. Secondary Outcome
    Title Number of Participants With Negative Bee Venom Allergy Test Results at Baseline, Day 29, and Day 85
    Description 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.
    Time Frame Baseline, Day 29, Day 85

    Outcome Measure Data

    Analysis Population Description
    Safety Population: all participants who received any amount of study drug or placebo, and had at least 1 postdose safety assessment.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 Placebo Normal Saline Cohorts 1-5
    Arm/Group Description a single 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 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 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 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 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 two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune-active chronic HBV a single IV dose of open-label ARC-520 4.0 mg/kg administered to treatment-naïve, HBeAg-negative or -positive participants with CHB 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
    Measure Participants 6 6 6 6 6 6 12 10
    Baseline
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    12
    100%
    10
    100%
    Day 29
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    11
    91.7%
    10
    100%
    Day 85
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    6
    100%
    11
    91.7%
    10
    100%
    4. Secondary Outcome
    Title Change From Baseline in Entecavir Plasma Trough Concentration, Cohorts 1-7
    Description
    Time Frame Baseline, Days 1, 2, 3, 8, 15, 22, 29

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohorts 4 and 5 ARC-520 Cohort 6 ARC-520 Cohort 7 Placebo Normal Saline Cohorts 1-5
    Arm/Group Description a single 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 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 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 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 or participants with HBeAg-positive immune active chronic HBV infection two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune-active chronic HBV a single IV dose of open-label ARC-520 4.0 mg/kg administered to treatment-naïve, HBeAg-negative or -positive participants with CHB 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
    Measure Participants 6 6 6 12 6 12 10
    Day 1
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    Day 2
    0.06
    (0.05)
    0.06
    (0.08)
    0.13
    (0.08)
    0.12
    (0.10)
    -0.91
    (1.59)
    0.16
    (0.04)
    -0.31
    (0.89)
    Day 3
    -0.02
    (0.02)
    -0.06
    (0.09)
    -0.06
    (0.06)
    0.12
    (0.63)
    -1.04
    (1.58)
    0.15
    (0.03)
    -0.29
    (0.88)
    Day 8
    -0.01
    (0.07)
    -0.09
    (0.08)
    -0.09
    (0.13)
    -0.03
    (0.18)
    -1.01
    (1.60)
    0.45
    (0.76)
    -0.30
    (0.90)
    Day 15
    0.01
    (0.05)
    -0.03
    (0.12)
    -0.03
    (0.06)
    0.00
    (0.18)
    -1.01
    (1.63)
    0.32
    (0.11)
    -0.10
    (1.14)
    Day 22
    0.04
    (0.06)
    -0.02
    (0.14)
    -0.03
    (0.09)
    0.00
    (0.13)
    -1.00
    (1.58)
    0.33
    (0.11)
    -0.30
    (0.89)
    Day 29
    0.00
    (0.06)
    -0.01
    (0.11)
    0.01
    (0.07)
    0.00
    (0.15)
    -1.00
    (1.61)
    0.36
    (0.11)
    -0.30
    (0.89)
    5. Secondary Outcome
    Title 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
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    79.1
    (8.28)
    185
    (61.2)
    212
    (34.7)
    318
    (82.3)
    349
    (45.2)
    AD0010
    93.0
    (9.11)
    190
    (43.2)
    301
    (43.9)
    370
    (80.5)
    412
    (47.5)
    6. Secondary Outcome
    Title 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
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    81.4
    (9.25)
    196
    (66.3)
    218
    (37.1)
    326
    (87.3)
    356
    (47.4)
    AD0010
    97.6
    (9.77)
    205
    (50.2)
    317
    (50.7)
    385
    (88.0)
    434
    (53.3)
    7. Secondary Outcome
    Title 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
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    81.4
    (9.26)
    196
    (66.3)
    218
    (37.2)
    326
    (87.4)
    356
    (47.4)
    AD0010
    97.8
    (9.80)
    207
    (51.1)
    318
    (51.2)
    386
    (88.6)
    435
    (53.8)
    8. Secondary Outcome
    Title Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Maximum Observed Plasma Concentration (Cmax), Cohorts 1-5
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    13.7
    (2.42)
    26.4
    (6.84)
    33.5
    (1.78)
    54.8
    (9.59)
    58.2
    (5.88)
    AD0010
    12.7
    (2.07)
    22.5
    (2.74)
    39.7
    (2.60)
    50.5
    (10.6)
    52.4
    (6.44)
    9. Secondary Outcome
    Title Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Clearance (CL), Cohorts 1-5
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    6.21
    (0.724)
    5.58
    (1.84)
    7.11
    (1.56)
    6.47
    (1.51)
    5.70
    (0.781)
    AD0010
    5.16
    (0.522)
    5.08
    (1.19)
    4.84
    (0.952)
    5.41
    (1.19)
    4.65
    (0.586)
    10. Secondary Outcome
    Title Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Apparent Volume of Distribution During the Terminal Phase (Vz), Cohorts 1-5
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    39.5
    (4.13)
    43.2
    (15.8)
    45.7
    (5.72)
    39.0
    (7.27)
    35.4
    (4.06)
    AD0010
    39.4
    (5.01)
    46.1
    (9.99)
    37.1
    (2.52)
    37.9
    (5.83)
    36.9
    (3.18)
    11. Secondary Outcome
    Title Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Volume in Steady State (Vss), Cohorts 1-5
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    39.6
    (6.05)
    45.8
    (11.6)
    45.3
    (3.60)
    39.6
    (6.31)
    35.3
    (3.57)
    AD0010
    40.7
    (6.01)
    46.7
    (8.22)
    38.1
    (2.08)
    39.8
    (6.36)
    38.5
    (4.21)
    12. Secondary Outcome
    Title Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Rate Constant (Kel), Cohorts 1-5
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    0.157
    (0.0115)
    0.132
    (0.0242)
    0.154
    (0.0135)
    0.165
    (0.0120)
    0.161
    (0.00614)
    AD0010
    0.132
    (0.0131)
    0.111
    (0.0188)
    0.130
    (0.0180)
    0.142
    (0.0164)
    0.126
    (0.00793)
    13. Secondary Outcome
    Title Pharmacokinetics of ARC-520 Product Constituents AD0009 and AD0010: Terminal Elimination Half-Life (t1/2), Cohorts 1-5
    Description
    Time Frame Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose

    Outcome Measure Data

    Analysis Population Description
    PK Population: all participants who received at least 1 dose of study drug and had evaluable PK data.
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5
    Arm/Group Description a single 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 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 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 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 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
    Measure Participants 6 6 6 6 6
    AD0009
    4.38
    5.36
    4.64
    4.18
    4.32
    AD0010
    5.29
    6.32
    5.48
    4.79
    5.36

    Adverse Events

    Time Frame From first dose of study drug through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 225 Cohort 10)
    Adverse Event Reporting Description
    Arm/Group Title ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 ARC-520 Cohort 9 ARC-520 Cohort 10 Placebo Normal Saline Cohorts 1-5
    Arm/Group Description a single 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 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 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 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 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 two IV doses of open-label ARC-520 2.0 mg/kg administered to participants with HBeAg-positive immune-active chronic HBV a single IV dose of open-label ARC-520 4.0 mg/kg administered to treatment-naïve, HBeAg-negative or -positive participants with CHB 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 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 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
    All Cause Mortality
    ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 ARC-520 Cohort 9 ARC-520 Cohort 10 Placebo Normal Saline Cohorts 1-5
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 ARC-520 Cohort 9 ARC-520 Cohort 10 Placebo Normal Saline Cohorts 1-5
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 0/8 (0%) 0/10 (0%)
    Other (Not Including Serious) Adverse Events
    ARC-520 Cohort 1 ARC-520 Cohort 2 ARC-520 Cohort 3 ARC-520 Cohort 4 ARC-520 Cohort 5 ARC-520 Cohort 6 ARC-520 Cohort 7 ARC-520 Cohort 9 ARC-520 Cohort 10 Placebo Normal Saline Cohorts 1-5
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/6 (16.7%) 4/6 (66.7%) 1/6 (16.7%) 0/6 (0%) 1/6 (16.7%) 1/6 (16.7%) 1/12 (8.3%) 1/2 (50%) 7/8 (87.5%) 0/10 (0%)
    Gastrointestinal disorders
    Diarrhoea 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 1/2 (50%) 0/8 (0%) 0/10 (0%)
    Epigastric discomfort 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    General disorders
    Pyrexia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/12 (0%) 0/2 (0%) 5/8 (62.5%) 0/10 (0%)
    Influenza like illness 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 5/8 (62.5%) 0/10 (0%)
    Malaise 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Chest discomfort 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Infusion site extravasation 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 0/8 (0%) 0/10 (0%)
    Infections and infestations
    Influenza 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/12 (8.3%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Injury, poisoning and procedural complications
    Procedural pain 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Investigations
    Blood creatine phosphokinase increased 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 0/8 (0%) 0/10 (0%)
    Metabolism and nutrition disorders
    Diabetes mellitus 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 0/8 (0%) 0/10 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Pain in extremity 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 0/8 (0%) 0/10 (0%)
    Temporomandibular joint syndrome 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Nervous system disorders
    Headache 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Dizziness 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 0/8 (0%) 0/10 (0%)
    Presyncope 0/6 (0%) 1/6 (16.7%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 0/8 (0%) 0/10 (0%)
    Renal and urinary disorders
    Haematuria 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 1/8 (12.5%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    Rash 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/6 (0%) 0/12 (0%) 0/2 (0%) 2/8 (25%) 0/10 (0%)

    Limitations/Caveats

    The ARC-520 Injection development program was terminated early for regulatory and business reasons secondary to findings occurring in a non-clinical toxicology study. Program termination was not due to safety findings in humans.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Chief Operating Officer
    Organization Arrowhead Pharmaceuticals, Inc.
    Phone 626-304-3400
    Email
    Responsible Party:
    Arrowhead Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02065336
    Other Study ID Numbers:
    • Heparc-2001
    First Posted:
    Feb 19, 2014
    Last Update Posted:
    Jul 5, 2019
    Last Verified:
    Apr 1, 2019