A Study of Treatment With RO6864018 in Virologically Suppressed Participants With Chronic Hepatitis B Virus (HBV) Infection

Hoffmann-La Roche31 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Hepatitis B, Chronic

Interventions

EntecavirDRUG

Entecavir will be administered as per local labeling.

PlaceboDRUG

Participants will be administered PO placebo capsules matched to RO6864018, either QOD or QWk for 12 weeks of treatment.

RO6864018DRUG

Participants will be administered RO6864018 as 200-mg PO capsules at a dose of 800 mg or 1200 mg, either QOD or QWk for 12 weeks of treatment.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Locations (14)

Queen Mary Hospital

Hong Kong, Hong Kong

Prince of Wales Hospital; Special Medical Clinic

N.T., Hong Kong

Hospital Ampang

Ampang, Malaysia

Outcomes

Primary Outcomes

Safety: Percentage of Participants with Adverse Events

Time frame: Baseline up to approximately 36 weeks

Secondary Outcomes

Pharmacodynamics: Peripheral Blood Levels of Interferon (IFN)-Alpha in QOD Dosing Cohorts

Time frame: 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 IFN-Alpha in QWk Dosing Cohorts

Time frame: 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 IFN-Gamma-Induced Protein (IP)-10 in QOD Dosing Cohorts

Time frame: 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 IP-10 in QWk Dosing Cohorts

Time frame: 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

Time frame: 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

Time frame: 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)

Data from ClinicalTrials.gov

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Tenofovir will be administered as per local labeling.

Hospital Selayang; Medicine

Batu Caves, Malaysia

University Malaya Medical Center

Kuala Lumpur, Malaysia

Auckland Clinical Studies Limited

Grafton, New Zealand

Waikato Hospital

Hamilton, New Zealand

Changi General Hospital

Singapore, Singapore

Seoul National University Hospital

Seoul, South Korea

Severance Hospital, Yonsei University Health System

Seoul, South Korea

...and 4 more locations

Efficacy: Quantitative Hepatitis B Surface Antigen (HBsAg) Level in QOD Dosing Cohorts

Time frame: 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: Quantitative HBsAg Level in QWk Dosing Cohorts

Time frame: 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 Loss of HBsAg in QOD Dosing Cohorts

Time frame: Baseline; on Day 7 of Week 12; then at Week 36 during follow-up

Efficacy: Percentage of Participants with Loss of HBsAg in QWk Dosing Cohorts

Time frame: 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

Time frame: 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 HBeAg in QWk Dosing Cohorts

Time frame: 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

HBsAg Seroconversion = antibody to HBsAg (Anti-HBs) Positive Status and Loss of HBsAg

Time frame: 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

Efficacy: Percentage of Participants with HBsAg Seroconversion in QWk Dosing Cohorts

HBsAg Seroconversion = anti-HBs Positive Status and Loss of HBsAg

Time frame: 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

Efficacy: Percentage of Participants with HBeAg Seroconversion in QOD Dosing Cohorts

HBeAg Seroconversion = antibody to HBeAg (anti-HBe) Positive Status and Loss of HBeAg

Time frame: 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

Efficacy: Percentage of Participants with HBeAg Seroconversion in QWk Dosing Cohorts

HBeAg Seroconversion = anti-HBe Positive Status and Loss of HBeAg

Time frame: 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

Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of RO6864018 Metabolite in QOD Dosing Cohorts

Time frame: 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

Time frame: 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: Time to Maximum Observed Plasma Concentration (Tmax) of RO6864018 Metabolite in QOD Dosing Cohorts

Pharmacokinetics: Tmax of RO6864018 Metabolite in QWk Dosing Cohorts

Time frame: 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: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUCinf) of RO6864018 Metabolite in QOD Dosing Cohorts

Pharmacokinetics: AUCinf of RO6864018 Metabolite in QWk Dosing Cohorts

Time frame: 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: Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast) of RO6864018 Metabolite in QOD Dosing Cohorts

Pharmacokinetics: AUClast of RO6864018 Metabolite in QWk Dosing Cohorts

Time frame: 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

Pharmacokinetics: T1/2 of RO6864018 Metabolite in QWk Dosing Cohorts

Time frame: 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 Neopterin in QOD Dosing Cohorts

Time frame: 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 Neopterin in QWk Dosing Cohorts

Time frame: 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

Time frame: 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

Time frame: 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 Interleukin (IL)-6 in QOD Dosing Cohorts

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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 QOD Dosing Cohorts

Time frame: 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-12p40 in QWk Dosing Cohorts

Time frame: 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

Time frame: 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 Development of Anti-HBe in QWk Dosing Cohorts

Time frame: 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 QOD Dosing Cohorts

Time frame: 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 Development of Anti-HBs in QWk Dosing Cohorts

Time frame: 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: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QWk Cohorts

Time frame: 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

Pharmacodynamics: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QOD Cohorts

Time frame: 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 T Cells, B Cells, and NK Cells (TBNK)

Time frame: 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 Myeloid Cells

Time frame: 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

Time frame: 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

Time frame: 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 Entecavir in QWk Dosing Cohorts

Time frame: 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