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

Hepatitis B, Chronic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02391805
• Other study ID #: NP28938
• Status: Completed
• Phase: Phase 2
• Start date: May 17, 2015
• Est. completion date: October 16, 2017

Study information

• Verified date: June 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: October 16, 2017
• Est. primary completion date: October 16, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Entecavir
Entecavir will be administered as per local labeling.
• Placebo
Participants will be administered PO placebo capsules matched to RO6864018, either QOD or QWk for 12 weeks of treatment.
• RO6864018
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.
• Tenofovir
Tenofovir will be administered as per local labeling.

Locations

Country	Name	City	State
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Prince of Wales Hospital; Special Medical Clinic	N.t.
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Malaysia	Hospital Ampang	Ampang
Malaysia	Hospital Selayang; Medicine	Batu Caves
Malaysia	University Malaya Medical Center	Kuala Lumpur
New Zealand	Auckland Clinical Studies Limited	Grafton
New Zealand	Waikato Hospital	Hamilton
Singapore	Changi General Hospital	Singapore
Taiwan	Kaohsiung Medical Uni Chung-Ho Memorial Hospital; Dept of Internal Medicine	Kaohsiung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei City

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Hong Kong,  Korea, Republic of,  Malaysia,  New Zealand,  Singapore,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety: Percentage of Participants with Adverse Events		Baseline up to approximately 36 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Efficacy: Percentage of Participants with HBsAg Seroconversion in QOD Dosing Cohorts	HBsAg Seroconversion = antibody to HBsAg (Anti-HBs) Positive Status and Loss of HBsAg	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
Secondary	Efficacy: Percentage of Participants with HBsAg Seroconversion in QWk Dosing Cohorts	HBsAg Seroconversion = anti-HBs Positive Status and Loss of HBsAg	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
Secondary	Efficacy: Percentage of Participants with HBeAg Seroconversion in QOD Dosing Cohorts	HBeAg Seroconversion = antibody to HBeAg (anti-HBe) Positive Status and Loss of HBeAg	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
Secondary	Efficacy: Percentage of Participants with HBeAg Seroconversion in QWk Dosing Cohorts	HBeAg Seroconversion = anti-HBe Positive Status and Loss of HBeAg	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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