Clinical Trials/NCT02391805

NCT02391805

Completed

Phase 2

A Multiple-Center, Randomized, Partially Double-Blind, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antiviral Effects of 12-Week Treatment With RO6864018 in Virologically Suppressed Patients With Chronic Hepatitis B Virus Infection

Hoffmann-La Roche14 sites in 6 countries31 target enrollmentMay 17, 2015

ConditionsHepatitis B, Chronic

InterventionsEntecavir Placebo Tenofovir RO6864018

DrugsEntecavir Placebo RO6864018 Tenofovir

Overview

Phase: Phase 2
Intervention: Entecavir
Conditions: Hepatitis B, Chronic
Sponsor: Hoffmann-La Roche
Enrollment: 31
Locations: 14
Primary Endpoint: Safety: Percentage of Participants with Adverse Events
Status: Completed
Last Updated: 7 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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.

Registry

clinicaltrials.gov

Start Date

May 17, 2015

End Date

October 16, 2017

Last Updated

7 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Hoffmann-La Roche

Responsible Party

Sponsor

Eligibility Criteria

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

Arms & Interventions

Placebo, Every Other Day (QOD)

Placebo orally (PO) QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Entecavir

Placebo, Every Other Day (QOD)

Placebo orally (PO) QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Placebo

Placebo, Every Other Day (QOD)

Placebo orally (PO) QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Tenofovir

Placebo, Once a Week (QWk)

Placebo PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Entecavir

Placebo, Once a Week (QWk)

Placebo PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Placebo

Placebo, Once a Week (QWk)

Placebo PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Tenofovir

RO6864018, 1200 milligrams (mg) QOD

RO6864018 1200 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Entecavir

RO6864018, 1200 milligrams (mg) QOD

RO6864018 1200 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: RO6864018

RO6864018, 1200 milligrams (mg) QOD

RO6864018 1200 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Tenofovir

RO6864018, 1200 mg QWk

RO6864018 1200 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Entecavir

RO6864018, 1200 mg QWk

RO6864018 1200 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: RO6864018

RO6864018, 1200 mg QWk

RO6864018 1200 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Tenofovir

RO6864018, 800 mg QOD

RO6864018 800 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Entecavir

RO6864018, 800 mg QOD

RO6864018 800 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: RO6864018

RO6864018, 800 mg QOD

RO6864018 800 mg PO QOD for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Tenofovir

RO6864018, 800 mg QWk

RO6864018 800 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Entecavir

RO6864018, 800 mg QWk

RO6864018 800 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: RO6864018

RO6864018, 800 mg QWk

RO6864018 800 mg PO QWk for 12 weeks + noninvestigational entecavir or tenofovir as prescribed by participant's physician

Intervention: Tenofovir

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 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)
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)
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)
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)
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)