A Study of Treatment With RO6864018 in Virologically Suppressed Participants With Chronic Hepatitis B Virus (HBV) Infection
Phase 2
Completed
- Conditions
- Hepatitis B, Chronic
- Interventions
- Registration Number
- NCT02391805
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This randomized, multicenter, partially double-blind, placebo-controlled study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antiviral effects of treatment with RO6864018 in virologically suppressed participants with chronic HBV infection.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 31
Inclusion Criteria
- Chronic hepatitis B infection
- Positive test for HBsAg for more than 6 months prior to randomization
- HBsAg titer greater than or equal to (>/=) 250 international units per milliliter (IU/mL) at Screening
- Treatment with any nucleoside/nucleotide analogue for >/= 1 year with ongoing entecavir and/or tenofovir treatment at randomization and for at least 3 months prior to randomization
- HBV DNA less than (<) 90 IU/mL for at least the preceding 6 months
- HBeAg positive at randomization and for at least 6 months prior to randomization
Exclusion Criteria
- Pregnant or lactating women
- Documented history of HBV genotype D
- History or other evidence of bleeding from esophageal varices
- History of decompensated liver disease, chronic liver disease other than HBV infection, or any evidence of metabolic liver disease
- Positive test for hepatitis A, hepatitis C, or human immunodeficiency virus (HIV)
- Documented history of hepatitis D infection
- History of or suspicion of hepatocellular carcinoma
- History of immunologically mediated disease
- History of organ transplantation
- History of thyroid disease
- Significant acute infection
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo, Every Other Day (QOD) Tenofovir Placebo orally (PO) QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician Placebo, Once a Week (QWk) Tenofovir Placebo PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 800 mg QOD Tenofovir RO6864018 800 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician Placebo, Every Other Day (QOD) Placebo Placebo orally (PO) QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician Placebo, Once a Week (QWk) Placebo Placebo PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 1200 milligrams (mg) QOD RO6864018 RO6864018 1200 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 800 mg QOD RO6864018 RO6864018 800 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 800 mg QWk RO6864018 RO6864018 800 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 1200 mg QWk RO6864018 RO6864018 1200 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 800 mg QWk Tenofovir RO6864018 800 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician Placebo, Every Other Day (QOD) Entecavir Placebo orally (PO) QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician Placebo, Once a Week (QWk) Entecavir Placebo PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 1200 milligrams (mg) QOD Entecavir RO6864018 1200 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 1200 milligrams (mg) QOD Tenofovir RO6864018 1200 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 1200 mg QWk Entecavir RO6864018 1200 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 1200 mg QWk Tenofovir RO6864018 1200 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 800 mg QOD Entecavir RO6864018 800 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician RO6864018, 800 mg QWk Entecavir RO6864018 800 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician
- Primary Outcome Measures
Name Time Method Safety: Percentage of Participants with Adverse Events Baseline up to approximately 36 weeks
- Secondary Outcome Measures
Name Time Method Pharmacodynamics: Peripheral Blood Levels of IFN-Alpha in QWk Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with Loss of HBsAg in QWk Dosing Cohorts Baseline; on Day 7 of Week 12; then at Week 36 during follow-up Efficacy: Percentage of Participants with Loss of Hepatitis B Envelope Antigen (HBeAg) in QOD Dosing Cohorts Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of Interferon (IFN)-Alpha in QOD Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Quantitative HBsAg Level in QWk Dosing Cohorts Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of IFN-Gamma-Induced Protein (IP)-10 in QOD Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with Loss of HBeAg in QWk Dosing Cohorts Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with HBsAg Seroconversion in QOD Dosing Cohorts Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Week 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up HBsAg Seroconversion = antibody to HBsAg (Anti-HBs) Positive Status and Loss of HBsAg
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of RO6864018 Metabolite in QOD Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 Pharmacokinetics: Cmax of RO6864018 Metabolite in QWk Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 Pharmacokinetics: Tmax of RO6864018 Metabolite in QWk Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 Pharmacokinetics: AUCinf of RO6864018 Metabolite in QWk Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 Pharmacokinetics: Half-life (t1/2) of RO6864018 Metabolite in QOD Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 Pharmacodynamics: Peripheral Blood Levels of Neopterin in QWk Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of Tumor Necrosis Factor (TNF)-Alpha in QOD Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with Development of Anti-HBe in QWk Dosing Cohorts Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with Development of Anti-HBs in QWk Dosing Cohorts Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Percentage of T Cells, B Cells, and NK Cells (TBNK) For QOD and QWk Cohorts: Baseline; pre-dose (0 hours) on Day 1 of Weeks 1, 2, 5; then Weeks 20, 28, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of IP-10 in QWk Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Quantitative HBV Deoxyribonucleic Acid (DNA) Level in QOD Dosing Cohorts Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up; and at any point that breakthrough occurs (up to 36 weeks) Efficacy: Quantitative HBV DNA Level in QWk Dosing Cohorts Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up; and at any point that breakthrough occurs (up to 36 weeks) Efficacy: Quantitative Hepatitis B Surface Antigen (HBsAg) Level in QOD Dosing Cohorts Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with Loss of HBsAg in QOD Dosing Cohorts Baseline; on Day 7 of Week 12; then at Week 36 during follow-up Efficacy: Percentage of Participants with HBeAg Seroconversion in QWk Dosing Cohorts Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up HBeAg Seroconversion = anti-HBe Positive Status and Loss of HBeAg
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUCinf) of RO6864018 Metabolite in QOD Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 Pharmacodynamics: Peripheral Blood Levels of Neopterin in QOD Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of TNF-alpha in QWk Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of IL-10 in QOD Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of IL-10 in QWk Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with Development of Anti-HBe in QOD Dosing Cohorts Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QWk Cohorts QWk: Baseline; pre-dose (0 hours) and post-dose (6 and 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12, and Day 7 of Week 12; then Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with HBsAg Seroconversion in QWk Dosing Cohorts Baseline; pre-dose (0 hours) on Day 1 of Weeks 2, 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up HBsAg Seroconversion = anti-HBs Positive Status and Loss of HBsAg
Efficacy: Percentage of Participants with HBeAg Seroconversion in QOD Dosing Cohorts Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Week 5; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up HBeAg Seroconversion = antibody to HBeAg (anti-HBe) Positive Status and Loss of HBeAg
Pharmacokinetics: Time to Maximum Observed Plasma Concentration (Tmax) of RO6864018 Metabolite in QOD Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 Pharmacokinetics: Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast) of RO6864018 Metabolite in QOD Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Days 1, 7 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 3, 5, 7, 12 and Day 6 of Week 12 Pharmacokinetics: AUClast of RO6864018 Metabolite in QWk Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 Pharmacokinetics: T1/2 of RO6864018 Metabolite in QWk Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 Pharmacodynamics: Peripheral Blood Levels of Interleukin (IL)-6 in QOD Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of IL-6 in QWk Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Peripheral Blood Levels of IL-12p40 in QWk Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Day 1 of Weeks 1, 2, 3, 5, 7, 12; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacokinetics: AUCinf of Entecavir in QWk Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12 Pharmacodynamics: Peripheral Blood Levels of IL-12p40 in QOD Dosing Cohorts Baseline; pre-dose (0 hours) and post-dose (6, 24 hours) on Days 1, 3, 7 of Week 1; on Day 1 of Weeks 3, 5, 7; and Day 6 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Efficacy: Percentage of Participants with Development of Anti-HBs in QOD Dosing Cohorts Baseline; pre-dose (0 hours) on Day 7 of Week 1 and Day 1 of Weeks 3, 5, 7; on Day 7 of Week 12; then at Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QOD Cohorts Baseline; pre-dose; post-dose (6 and 24 hours) on Days 1, 3, and 7 for Week 1, Day 1 of Weeks 3, 5, 7, Day 6 of Week 12; then Weeks 16, 20, 24, 28, 32, 36 during follow-up Pharmacodynamics: Percentage of Myeloid Cells For QOD and QWk Cohorts: Baseline; pre-dose (0 hours) on Day 1 of Weeks 1, 2, 5; then Weeks 20, 28, 36 during follow-up Pharmacodynamics: Percentage of Plasmacytoid Dendritic Cells For QOD and QWk Cohorts: Baseline; pre-dose (0 hours) on Day 1 of Weeks 1, 2, 5; then Weeks 20, 28, 36 during follow-up Pharmacokinetics: Cmax of Entecavir in QWk Dosing Cohorts Pre-dose (0 hours) and post-dose (0.25, 1, 2, 4, 6, 8, 12, 24 hours) on Day 1 of Week 1; pre-dose (0 hours) and post-dose (1, 2-4 hours) on Day 1 of Weeks 2, 3, 5, 7, 12
Trial Locations
- Locations (14)
University Malaya Medical Center
🇲🇾Kuala Lumpur, Malaysia
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Taipei Veterans General Hospital
🇨🇳Taipei City, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Queen Mary Hospital
ðŸ‡ðŸ‡°Hong Kong, Hong Kong
Kaohsiung Medical Uni Chung-Ho Memorial Hospital; Dept of Internal Medicine
🇨🇳Kaohsiung, Taiwan
Hospital Ampang
🇲🇾Ampang, Malaysia
Hospital Selayang; Medicine
🇲🇾Batu Caves, Malaysia
Auckland Clinical Studies Limited
🇳🇿Grafton, New Zealand
Changi General Hospital
🇸🇬Singapore, Singapore
Waikato Hospital
🇳🇿Hamilton, New Zealand
Prince of Wales Hospital; Special Medical Clinic
ðŸ‡ðŸ‡°N.t., Hong Kong