A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7049389 in Healthy Volunteers and Chronic Hepatitis B Virus (HBV) Infected Participants

A Safety, Tolerability, Pharmacokinetics and Efficacy Study of ro7049389 in: (1) Single- (With or Without Food) and Multiple- (With Midazolam) Ascending Doses in Healthy Volunteers; (2) Patients Chronically Infected With Hepatitis b Virus (3) Patients With Chronic Hepatitis B.

This study is a multicenter, three-part study. Parts 1 and 2 are randomized, investigator- and participant-blinded, placebo-control, single-ascending dose (SAD) and multiple-ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RO7049389 following oral administration in healthy volunteers and chronic HBV infected participants. Part 3 is a non-randomized, non-controlled, open-label part to assess the efficacy and safety of RO7049389 when administered in combination with standard-of-care therapies for up to 48 weeks in nucleos(t)ide (NUC)-suppressed and treatment-naive chronic hepatitis B (CHB) participants.

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Other: Placebo; Drug: RO7049389; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 192
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Bulgaria
  • Sofia, Bulgaria, 1407
    • Acibadem City Clinic Tokuda Hospital Ead
• China
  • Guangzhou, China, 510515
    • Nanfang Hospital, Southern Medical University
  • Shanghai, China, 200025
    • Shanghai Jiao Tong University School of Medicine (SJTUSM) - Ruijin Hospital (GuangCi Hospital)
  • Shanghai City, China, 200040
    • Huashan Hospital affiliated to Fudan University
• Hong Kong
  • Hong Kong, Hong Kong
    • The University of Hong Kong; Queen Mary Hospital
  • Shatin, New Territories, Hong Kong
    • Prince of Wales Hospital
• New Zealand
  • Auckland, New Zealand
    • Middlemore Hospital
  • Grafton, New Zealand, 1010
    • Auckland Clinical Studies Limited
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
  • Singapore, Singapore, 119228
    • National University Health System
• Taiwan
  • Kaohsiung, Taiwan
    • Chang Gung Memorial Hospital - Kaohsiung Branch
  • Kaohsiung City, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans Gen Hosp
  • Tainan, Taiwan, 70457
    • National Cheng Kung University Hospital
  • Taipei, Taiwan
    • Chang Gung Memorial Hospital - Linkou Branch
  • Taipei City, Taiwan, 112
    • Taipei Veterans General Hospital
• Thailand
  • Bangkok, Thailand, 10330
    • King Chulalongkorn Memorial Hospital
  • Bangkok, Thailand, 10700
    • Siriraj Hospital
  • Chiang Mai, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Part 1- Healthy Volunteers only:

• Absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead Electrocardiogram (ECG), hematology, blood chemistry, serology and urinalysis
• A Body Mass Index (BMI) between 18 to 30 kilograms per square meter (kg/m^2) inclusive
• Female participants must be either surgically sterile or post-menopausal for at least one year
• For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Part 2- Chronic HBV-infected participants only:

• A BMI between 18 to 30 kg/m^2 inclusive
• Chronic Hepatitis B infection, defined as positive test for Hepatitis B surface antigen (HBsAg) for more than 6 months prior to randomization
• HBV DNA at screening greater than or equal to (>/=) 2 × 10^4 international units per milliliter (IU/mL) for Hepatitis B e antigen (HBeAg) positive participants, or >/=2 × 10^3 IU/mL for HBeAg-negative participants
• Liver biopsy, fibroscan or equivalent test obtained within the past 6 months demonstrating liver disease consistent with chronic HBV infection with absence of extensive bridging fibrosis and absence of cirrhosis
• For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
• For women of childbearing potential: agreement to remain abstinent or use non-hormonal contraceptive methods that result in a failure rate of less than (<)1 percent (%) per year during the treatment period and for at least 3 months after the last dose of study drug

Part 3- Chronic HBV Participants Only:

• A BMI between 18 to 32 kg/m^2 inclusive
• Chronic hepatitis B infection, defined as positive test for HBsAg or HBV DNA, or positive HBeAg, for more than 6 months prior to screening
• For Cohorts only enrolling NUC-suppressed CHB participants (e.g. POM Cohort A), participants must have been treated with a single NUC (entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate) for at least 12 months. Participants must be on the same NUC therapy for at least 3 months prior to screening
• For Cohorts only enrolling anti-HBV treatment-naive and immune-active participants (e.g. POM Cohort B and Cohort C), previous anti-HBV treatments <30 days in total, and did not receive any anti-HBV treatments within 3 months prior to the first study dose
• Liver biopsy, fibroscan, or equivalent test obtained within the past 6 months demonstrating liver disease consistent with chronic HBV infection with absence of extensive bridging fibrosis and absence of cirrhosis
• For men: agreement to remain abstinent or use contraceptive measures, and agree to refrain from donating sperm
• For women of childbearing potential: agreement to remain abstinent or to use two approved contraceptive methods during the study and for at least 6 months after the last dose of study drug

Exclusion Criteria:

Part 1- Healthy Volunteers only:

• History or symptoms of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, hematological or allergic disease, metabolic disorder, cancer or cirrhosis
• History of Gilbert's syndrome
• Participants who have had significant acute infection, e.g., influenza, local infection, acute gastrointestinal symptoms or any other clinically significant illness within two weeks of dose administration
• Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies
• Any clinically significant concomitant diseases or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study
• Positive test at screening of any of the following: Hepatitis A (HAV IgM Ab), Hepatitis B (HBsAg), Hepatitis C (HCV RNA or HCV Ab) or human immunodeficiency virus (HIV Ab)
• Acute narrow-angle glaucoma (for MAD-midazolam cohorts)

Part 2- Chronic HBV-infected participants only:

• History or other evidence of bleeding from esophageal varices
• Evidence of liver cirrhosis or decompensated liver disease such as ascites, esophageal or gastric varices, splenomegaly, nodular liver, jaundice, hepatic encephalopathy
• History or other evidence of a medical condition associated with chronic liver disease other than HBV infection (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposure, thalassemia, nonalcoholic steatohepatitis, etc.)
• Documented history or other evidence of metabolic liver disease within one year of randomization
• Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, or human immunodeficiency virus
• History of or suspicion of hepatocellular carcinoma or alphafetoprotein >/= Upper limit of normal (ULN) at screening
• History of clinically significant gastrointestinal, cardiovascular, endocrine, renal, ocular, pulmonary, psychiatric or neurological disease
• History of organ transplantation
• Previous or concurrent HBV treatments in the past 6 months
• Significant acute infection (e.g., influenza, local infection) or any other clinically significant illness within 2 weeks of randomization

Part 3- Chronic Hepatitis B Participants Only:

• History or other evidence of bleeding from esophageal varices
• Evidence of liver cirrhosis or decompensated liver disease such as ascites, esophageal or gastric varices, splenomegaly, nodular liver, jaundice, or hepatic encephalopathy
• History or other evidence of a medical condition associated with chronic liver disease other than HBV infection (e.g. hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposure, thalassemia, nonalcoholic statohepatitis, etc.)
• History of thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests
• Documented history or other evidence of metabolic liver disease within one year of screening
• Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, HEV, or HIV
• Diagnosed or suspected hepatocellular carcinoma
• History of clinically significant gastrointestinal, cardiovascular, endocrine, renal, ocular, pulmonary, psychiatric, or neurological disease
• History of organ transplantation
• Significant acute infection (e.g. influenza, local infection) or any other clinically significant illness within 2 weeks of screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Parts 1a and 1b: SAD in Healthy Volunteers (Placebo); In Part 1a, participants will receive a single oral dose of placebo matching to RO7049389 film coated tablet on Day 1. In Part 1b, minimum 8 participants from Part 1a will be selected and 2 of whom will receive another single dose of placebo matching to RO7049389 on Day 16 after eating the standard United States - Food and Drug Administration (US FDA)-recommended high-fat and high-calorie breakfast.	Other: Placebo; Placebo matching to RO7049389 will be administered as per schedule described in individual arm.
Experimental: Parts 1a and 1b: SAD in Healthy Volunteers (RO7049389); In Part 1a, participants will receive a single oral dose of RO7049389 film coated tablet on Day 1 in dose-escalation cohorts with a starting dose of 150 milligrams (mg). The doses for subsequent cohorts will be defined by an adaptive approach based on the safety and PK data in previously-dosed healthy volunteers. In Part 1b, minimum 8 participants from Part 1a will be selected and 6 of whom will receive another single dose of RO7049389 on Day 16 after eating the standard US FDA-recommended high-fat and high-calorie breakfast.	Drug: RO7049389; RO7049389 will be administered as per schedule described in individual arm.
Placebo Comparator: Part 1c: MAD in Healthy Volunteers (Placebo); Participants will receive placebo matching to RO7049389 film coated tablet from Days 1 to 13 (either once a day [QD] or twice a day [BID]) and a single dose of placebo matching to RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 micrograms [mcg]) on Day -1 and Day 14.	Other: Placebo; Placebo matching to RO7049389 will be administered as per schedule described in individual arm.; Drug: Midazolam; Single dose of 100 mcg midazolam solution will be administered orally, before (Day -1) and after (Day 14) the treatment with RO7049389 or matching placebo
Experimental: Part 1c: MAD in Healthy Volunteers (RO7049389); Participants will receive RO7049389 film coated tablet from Days 1 to 13 (either QD or BID; dose and regimen will be decided based on the available PK and safety data) and a single dose of RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 mcg) on Day -1 and Day 14.	Drug: RO7049389; RO7049389 will be administered as per schedule described in individual arm.; Drug: Midazolam; Single dose of 100 mcg midazolam solution will be administered orally, before (Day -1) and after (Day 14) the treatment with RO7049389 or matching placebo
Placebo Comparator: Part 2: POM in Chronic HBV Participants (Placebo); Participants will receive placebo matching to RO7049389 film coated tablet from Days 1 to 27 (either QD or BID) and a single dose of placebo matching to RO7049389 film coated tablet in the morning of Day 28.	Other: Placebo; Placebo matching to RO7049389 will be administered as per schedule described in individual arm.
Experimental: Part 2: POM in Chronic HBV Participants (RO7049389); Participants will receive RO7049389 film coated tablet from Days 1 to 27 (either QD or BID; dose and regimen will be decided based on the available PK and safety data) and a single dose of RO7049389 film coated tablet in the morning of Day 28.	Drug: RO7049389; RO7049389 will be administered as per schedule described in individual arm.
Experimental: Part 3: POM in NUC-Suppressed CHB Participants (Cohort A); Participants will receive RO7049389 on top of a NUC for 48 weeks at a dose determined from Part 2. NUC therapy will be administered per local label or guidelines.	Drug: RO7049389; RO7049389 will be administered as per schedule described in individual arm.
Experimental: Part 3: POM in Treatment-Naive CHB Participants (Cohort B); Participants will receive RO7049389 for 4 weeks, followed by RO7049389 with an added NUC for 44 weeks. RO7049389 will be administered at a dose determined from Part 2. NUC therapy will be administered per local label or guidelines.	Drug: RO7049389; RO7049389 will be administered as per schedule described in individual arm.
Experimental: Part 3: POM in Treatment-Naive CHB Participants (Cohort C); Participants will receive RO7049389 + NUC + Pegylated-Interferon (Peg-IFN) for 48 weeks. RO7049389 will be administered at a dose determined from Part 2. NUC and Peg-IFN therapy will be administered per local label or guidelines.	Drug: RO7049389; RO7049389 will be administered as per schedule described in individual arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part 1: Percentage of Participants With Adverse Events	From randomization up to Day 44
Part 2: Percentage of Participants With Adverse Events	From randomization up to Day 56
Part 2: HBV DNA Level	Baseline; Days 8, 15, 22, 28, 35, 56, 84, and 112
Part 1c- MAD Cohort: Area Under the Plasma Concentration Versus Time Curve for a Dosing Interval (AUC0-tau) of RO7049389 and Metabolites	Pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hrs post Day 1 morning dose; pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post Day 14 morning dose
Part 1c- MAD Cohort: Plasma Trough Concentration (Ctrough) of RO7049389 and Metabolites	Pre-dose (0 hr before morning dose) on Days 2, 3, 4, 5, 7
Part 1c- MAD Cohort: Apparent Terminal t1/2 of RO7049389 and Metabolites	Pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hrs post Day 1 morning dose; pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post Day 14 morning dose
Part 1c- MAD Cohort: Accumulation Index of RO7049389 and Metabolites	Pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hrs post Day 1 morning dose; pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post Day 14 morning dose
Part 1c- MAD Cohort: Ae of RO7049389 and Metabolites	Pre-dose (0 hr), 0-4, 4-8, 8-12, 12-24 hours post morning dose on Days 1 and 14
Part 1c- MAD Cohort: CLR of RO7049389 and Metabolites	Pre-dose (0 hr), 0-4, 4-8, 8-12, 12-24 hours post morning dose on Days 1 and 14
Part 1a- SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO7049389 and Metabolites	Pre-dose (0 hour [hr]) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 1 dose
Part 1a- SAD Cohort: Time to Reach Cmax (Tmax) of RO7049389 and Metabolites	Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 1 dose
Part 1a- SAD Cohort: Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUC0-last) of RO7049389 and Metabolites	Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 1 dose
Part 1a- SAD Cohort: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO7049389 and Metabolites	Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 1 dose
Part 1a- SAD Cohort: Apparent Terminal Half-life (t1/2) of RO7049389 and Metabolites	Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 1 dose
Part 1a- SAD Cohort: Apparent Oral Clearance (CL/F) of RO7049389 and Metabolites	Pre-dose (0 hr) on Day 1; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 1 dose
Part 1a-SAD Cohort- Cumulative Amount Excreted Unchanged in Urine (Ae) of RO7049389 and Metabolites	Pre-dose (0 hr) on Day 1; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 1 dose
Part 1a- SAD Cohort: Renal Clearance (CLR) of RO7049389 and Metabolites	Pre-dose (0 hr) on Day 1; 0-4, 4-8, 8-12, 12-24, 24-48 hours post Day 1 dose
Part 1c- MAD Cohort: Cmax of RO7049389 and Metabolites	Pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hrs post Day 1 morning dose; pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post Day 14 morning dose
Part 1c- MAD Cohort: Tmax of RO7049389 and Metabolites	Pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hrs post Day 1 morning dose; pre-dose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post Day 14 morning dose
Part 3 HBV DNA Level	Every 2-4 weeks from Baseline through Week 72
Part 3: HBsAg Level	Every 2-4 weeks from baseline through week 72

Secondary Outcome Measures

Outcome Measure	Time Frame
Part 1b- Food-Effect SAD Cohort: Cmax of RO7049389	Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 16 dose
Part 1b- Food-Effect SAD Cohort: Tmax of RO7049389	Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 16 dose
Part 1b- Food-Effect SAD Cohort: AUC0-last of RO7049389	Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 16 dose
Part 1b- Food-Effect SAD Cohort: AUC0-inf of RO7049389	Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 16 dose
Part 1b- Food-Effect SAD Cohort: Apparent Terminal t1/2 of RO7049389	Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 16 dose
Part 1b- Food-Effect SAD Cohort: Apparent CL/F of RO7049389	Pre-dose (0 hr) on Day 16; 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72 and 96 hrs post Day 16 dose
Part 1c- MAD Cohort: Cmax of Midazolam	Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, and 12 hrs post-midazolam dose on Day -1; pre-RO7049389 dose (0 hr) on Day 1; pre-dose (0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hrs post-midazolam dose on Day 14
Part 1c- MAD Cohort: Tmax of Midazolam	Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, and 12 hrs post-midazolam dose on Day -1; pre-RO7049389 dose (0 hr) on Day 1; pre-dose (0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hrs post-midazolam dose on Day 14
Part 1c- MAD Cohort: AUC0-last of Midazolam	Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, and 12 hrs post-midazolam dose on Day -1; pre-RO7049389 dose (0 hr) on Day 1; pre-dose (0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hrs post-midazolam dose on Day 14
Part 1c- MAD Cohort: AUC0-inf of Midazolam	Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, and 12 hrs post-midazolam dose on Day -1; pre-RO7049389 dose (0 hr) on Day 1; pre-dose (0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hrs post-midazolam dose on Day 14
Part 1c- MAD Cohort: Area Under the Plasma Concentration Versus Time Curve up to 6 h Post-dose (AUC0-6h) of Midazolam	Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, and 12 hrs post-midazolam dose on Day -1; pre-RO7049389 dose (0 hr) on Day 1; pre-dose (0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hrs post-midazolam dose on Day 14
Part 1c- MAD Cohort: Apparent Terminal t1/2 of Midazolam	Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, and 12 hrs post-midazolam dose on Day -1; pre-RO7049389 dose (0 hr) on Day 1; pre-dose (0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hrs post-midazolam dose on Day 14
Part 1c- MAD Cohort: CL/F of Midazolam	Pre-dose (0 hr), 0.25, 0.5,1, 2, 4, 6, 8, 10, and 12 hrs post-midazolam dose on Day -1; pre-RO7049389 dose (0 hr) on Day 1; pre-dose (0 hr), 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hrs post-midazolam dose on Day 14
Part 2: Cmax of RO7049389	Pre-dose (0 hr) and 1, 2, 3, 4, 6, and 8 hrs post Day 1 morning dose; pre-dose (0 hr) and 1, 2, 3, 4, 6, 8, and 24 hrs post Day 28 morning dose
Part 2: Tmax of RO7049389	Pre-dose (0 hr) and 1, 2, 3, 4, 6, and 8 hrs post Day 1 morning dose; pre-dose (0 hr) and 1, 2, 3, 4, 6, 8, and 24 hrs post Day 28 morning dose
Part 2: AUC0-tau of RO7049389	Pre-dose (0 hr) and 1, 2, 3, 4, 6, and 8 hrs post Day 1 morning dose; pre-dose (0 hr) and 1, 2, 3, 4, 6, 8, and 24 hrs post Day 28 morning dose
Part 2: Ctrough of RO7049389	Pre-morning dose (0 hr) on Days 2, 3, 4, 8, 15, 22
Part 2: Apparent t1/2 of RO7049389	Pre-dose (0 hr) and 1, 2, 3, 4, 6, and 8 hrs post Day 1 morning dose; pre-dose (0 hr) and 1, 2, 3, 4, 6, 8, and 24 hrs post Day 28 morning dose
Part 2: Accumulation Index of RO7049389	Pre-dose (0 hr) and 1, 2, 3, 4, 6, and 8 hrs post Day 1 morning dose; pre-dose (0 hr) and 1, 2, 3, 4, 6, 8, and 24 hrs post Day 28 morning dose
Part 2: Anti-HBe Antibodies	Baseline; Days 8,15,22,28,35,56,84, and 112
Part 3: Cmax of RO7049389 and its Metabolites	Pre-dose and 1,2,3,4,6, and 8 hours post-dose (Day 1, Week 4 (Cohort B only) and Week 24); pre-dose and 1,2,3,4,6,8, and 24 hours after the last dose (Week 48)
Part 3: Tmax of RO7049389 and its metabolites	Pre-dose and 1,2,3,4,6, and 8 hours post-dose (Day 1, Week 4 (Cohort B only) and Week 24); pre-dose and 1,2,3,4,6,8, and 24 hours after the last dose (Week 48)
Part 3: AUC0-tau of RO7049389 and its metabolites	Pre-dose and 1,2,3,4,6, and 8 hours post-dose (Day 1, Week 4 (Cohort B only) and Week 24); pre-dose and 1,2,3,4,6,8, and 24 hours after the last dose (Week 48)
Part 3: Ctrough of RO7049389 and its metabolites	Pre-dose Days 14 and 28; thereafter predose every 28 days up to Week 48
Part 3: T1/2 of RO7049389 and its metabolites	Pre-dose and 1,2,3,4,6, and 8 hours post-dose (Day 1, Week 4 (Cohort B only) and Week 24); pre-dose and 1,2,3,4,6,8, and 24 hours after the last dose (Week 48)
Part 3: Accumulation Index of RO7049389 and its Metabolites	Pre-dose and 1,2,3,4,6, and 8 hours post-dose (Day 1, Week 4 (Cohort B only) and Week 24); pre-dose and 1,2,3,4,6,8, and 24 hours after the last dose (Week 48)
Part 3: Ctrough of Nucleos(t)ide Analogs (NUCs)	Pre-dose Days 14 (Cohort A and C only) and 28; thereafter predose every 28 days up to Week 48
Part 3: Hepatitis B e-Antigen (HBeAg) Levels	Every 2-4 weeks from Baseline through Week 72
Part 3: Anti-HBs Antibodies	Every 2-4 weeks from Baseline through Week 72
Part 3: Anti-HBe Antibodies	Every 2-4 weeks from Baseline through Week 72
Part 3: Anti-HBc antibodies	Every 2-4 weeks from Baseline through Week 72
Part 3: HBV RNA Level	Every 2-4 weeks from Baseline through Week 72
Part 3: HBV Core-Related Antigen Levels (HBcrAg)	Every 2-4 weeks from baseline through week 72
Part 3: Viral Resistance Monitoring	Every 2-4 weeks from baseline through week 72
Part 3 Percentage of Participants With Adverse Events	From randomization up to 72 Weeks

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Yuen MF, Zhou X, Gane E, Schwabe C, Tanwandee T, Feng S, Jin Y, Triyatni M, Lemenuel-Diot A, Cosson V, Xue Z, Kazma R, Bo Q. Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial. Lancet Gastroenterol Hepatol. 2021 Sep;6(9):723-732. doi: 10.1016/S2468-1253(21)00176-X. Epub 2021 Jul 6.
• Feng S, Gane E, Schwabe C, Zhu M, Triyatni M, Zhou J, Bo Q, Jin Y. A Five-in-One First-in-Human Study To Assess Safety, Tolerability, and Pharmacokinetics of RO7049389, an Inhibitor of Hepatitis B Virus Capsid Assembly, after Single and Multiple Ascending Doses in Healthy Participants. Antimicrob Agents Chemother. 2020 Oct 20;64(11):e01323-20. doi: 10.1128/AAC.01323-20. Print 2020 Oct 20.

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2016
• Primary Completion (Actual): March 16, 2022
• Study Completion (Actual): March 16, 2022

Study Registration Dates

• First Submitted: November 1, 2016
• First Submitted That Met QC Criteria: November 1, 2016
• First Posted (Estimate): November 2, 2016

Study Record Updates

• Last Update Posted (Actual): July 8, 2022
• Last Update Submitted That Met QC Criteria: July 7, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: YP39364