Clinical trial NCT02391805: A Study of Treatment With RO6864018 in Virologically Suppressed Participants With Chronic Hepatitis B Virus (HBV) Infection
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis B, Chronic
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-03-18
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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
* Significant acute infection

Primary outcomes:
measure: Safety: Percentage of Participants with Adverse Events
timeFrame: Baseline up to approximately 36 weeks
Secondary outcomes:
measure: Pharmacodynamics: Peripheral Blood Levels of Interferon (IFN)-Alpha in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IFN-Alpha in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IFN-Gamma-Induced Protein (IP)-10 in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IP-10 in QWk Dosing Cohorts
timeFrame: 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
measure: Efficacy: Quantitative HBV Deoxyribonucleic Acid (DNA) Level in QOD Dosing Cohorts
timeFrame: 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)
measure: Efficacy: Quantitative HBV DNA Level in QWk Dosing Cohorts
timeFrame: 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)
measure: Efficacy: Quantitative Hepatitis B Surface Antigen (HBsAg) Level in QOD Dosing Cohorts
timeFrame: 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
measure: Efficacy: Quantitative HBsAg Level in QWk Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with Loss of HBsAg in QOD Dosing Cohorts
timeFrame: Baseline; on Day 7 of Week 12; then at Week 36 during follow-up
measure: Efficacy: Percentage of Participants with Loss of HBsAg in QWk Dosing Cohorts
timeFrame: Baseline; on Day 7 of Week 12; then at Week 36 during follow-up
measure: Efficacy: Percentage of Participants with Loss of Hepatitis B Envelope Antigen (HBeAg) in QOD Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with Loss of HBeAg in QWk Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with HBsAg Seroconversion in QOD Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with HBsAg Seroconversion in QWk Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with HBeAg Seroconversion in QOD Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with HBeAg Seroconversion in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of RO6864018 Metabolite in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: Cmax of RO6864018 Metabolite in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: Time to Maximum Observed Plasma Concentration (Tmax) of RO6864018 Metabolite in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: Tmax of RO6864018 Metabolite in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUCinf) of RO6864018 Metabolite in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: AUCinf of RO6864018 Metabolite in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast) of RO6864018 Metabolite in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: AUClast of RO6864018 Metabolite in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: Half-life (t1/2) of RO6864018 Metabolite in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: T1/2 of RO6864018 Metabolite in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of Neopterin in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of Neopterin in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of Tumor Necrosis Factor (TNF)-Alpha in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of TNF-alpha in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of Interleukin (IL)-6 in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IL-6 in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IL-10 in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IL-10 in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IL-12p40 in QOD Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Peripheral Blood Levels of IL-12p40 in QWk Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with Development of Anti-HBe in QOD Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with Development of Anti-HBe in QWk Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with Development of Anti-HBs in QOD Dosing Cohorts
timeFrame: 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
measure: Efficacy: Percentage of Participants with Development of Anti-HBs in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacodynamics: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QWk Cohorts
timeFrame: 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
measure: Pharmacodynamics: Transcriptional Responses as Measured by messenger ribonucleic acid (mRNA) Levels for QOD Cohorts
timeFrame: 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
measure: Pharmacodynamics: Percentage of T Cells, B Cells, and NK Cells (TBNK)
timeFrame: 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
measure: Pharmacodynamics: Percentage of Myeloid Cells
timeFrame: 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
measure: Pharmacodynamics: Percentage of Plasmacytoid Dendritic Cells
timeFrame: 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
measure: Pharmacokinetics: Cmax of Entecavir in QWk Dosing Cohorts
timeFrame: 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
measure: Pharmacokinetics: AUCinf of Entecavir in QWk Dosing Cohorts
timeFrame: 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
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: N.t.
country: Hong Kong
facility: Prince of Wales Hospital; Special Medical Clinic
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Ampang
country: Malaysia
facility: Hospital Ampang
city: Batu Caves
country: Malaysia
facility: Hospital Selayang; Medicine
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Center
city: Grafton
country: New Zealand
facility: Auckland Clinical Studies Limited
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Singapore
country: Singapore
facility: Changi General Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical Uni Chung-Ho Memorial Hospital; Dept of Internal Medicine
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: