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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 58
- 试验地点
- 2
- 主要终点
- Change From Baseline Over Time in Quantitative Hepatitis B Surface Antigen (HBsAG)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
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
干预措施: ARC-520 (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: Placebo (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: chlorpheniramine (Drug)
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)
干预措施: ARC-520 (Drug)
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)
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: entecavir (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: chlorpheniramine (Drug)
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
干预措施: ARC-520 (Drug)
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
干预措施: chlorpheniramine (Drug)
结局指标
主要结局
Change From Baseline Over Time in Quantitative Hepatitis B Surface Antigen (HBsAG)
时间窗: Baseline, through Day 85 (Cohorts 1-7) and through 24 weeks post-last dose (last dose: Day 85 Cohort 9; Day 253 Cohort 10)
次要结局
- 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))
- Number of Participants With Negative Bee Venom Allergy Test Results at Baseline, Day 29, and Day 85(Baseline, Day 29, Day 85)
- Change From Baseline in Entecavir Plasma Trough Concentration, Cohorts 1-7(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(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(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(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(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(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(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(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(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(Day 1 predose, immediately prior to the end of infusion, 0.5, 1, 3, 6, 24, and 48 hours postdose)