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

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	Measure Description	Time Frame
Part 1: Percentage of Participants With Adverse Events		Up to Day 29 (Part 1a), Day 44 (Part 1b), Day 42 (Part 1c)
Parts 1a and 1b: SAD Cohort: Time to Reach Maximum Concentration (Tmax) of RO7049389		Up to 28 days
Parts 1a and 1b: SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO7049389		Up to 28 days
Parts 1a and 1b: SAD Cohort: AUC From Time Zero to Infinity (AUC0-inf) of RO7049389		Up to 28 days
Parts 1a and 1b: SAD Cohort: Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of RO7049389		Up to 28 days
Parts 1a and 1b: SAD Cohort: Half-life (T1/2) of RO7049389		Up to Day 28
Parts 1a and 1b: SAD Cohort: Apparent Oral Clearance (CL/F) of RO7049389		Up to Day 28
Parts 1a and 1b: SAD Cohort: Cumulative Amount Excreted Unchanged in Urine (Ae) of RO7049389		Up to Day 28
Parts 1a and 1b: SAD Cohort: Renal Clearance (CLr) of RO7049389		Up to Day 28
Part 2: Percentage of Participants With Adverse Events		Up to Day 112
Part 2: Quantitative Plasma HBV DNA Level		Baseline - Day 112
Part 3: Proportion of Patients Achieving Functional Cure	Functional cure is defined as HBV DNA < lower limit of quantification (LLOQ, 20 IU/mL) with HBsAg loss (< 0.05 IU/mL) at 24 weeks post-treatment.	Every 2-4 weeks from Baseline through Week 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1b: Food Effect on Cmax of RO7049389	This outcome measure evaluated the effect of food on the pharmacokinetics (PK) of RO7049389 after the administration of a single dose. Participants were fed a high-fat, high-calorie breakfast (per FDA food effect bioavailability and bioequivalence study recommendations) 30 minutes prior to dosing after fasting overnight for at least 8 hours. ANOVA (factors fasted/fed state and subject) was performed for measurements available in subjects in both fasted and fed states.	Day 16
Part 1b: Food Effect on AUCinf of RO7049389	This outcome measure evaluated the effect of food on the pharmacokinetics (PK) of RO7049389 after the administration of a single dose. Participants were fed a high-fat, high-calorie breakfast (per FDA food effect bioavailability and bioequivalence study recommendations) 30 minutes prior to dosing after fasting overnight for at least 8 hours. ANOVA (factors fasted/fed state and subject) was performed for measurements available in subjects in both fasted and fed states.	Day 16
Part 1c: Cmax of Midazolam	This endpoint presents the geometric mean ratio (after RO7049389/before RO7049389).	Up to Day 14
Part 1c: AUCinf of Midazolam	This endpoint presents the geometric mean ratio (after RO7049389/before RO7049389).	Up to Day 14
Part 1c: Tmax of RO7049389		Up to Day 14
Part 1c: Cmax of RO7049389		Up to Day 14
Part 1c: AUC0-12hr of RO7049389		Up to Day 14
Part 1c: CLr of RO7049389		Up to Day 14
Part 1c: Accumulation Ratio of RO7049389	This endpoint presents the geometric mean ratio of AUC after a single dose (Day 1) and AUC after having received multiple doses (Day 14) within each arm.	Day 1, Day 14
Part 1c: T1/2 of RO7049389		Up to Day 14
Part 1c: Ae of RO7049389		Up to Day 14
Part 1c: Ctrough of RO7049389		Up to Day 14
Part 2: HBV DNA < Lower Limit of Quantification (LLOQ)		Baseline - Day 112/Follow-up Day 84
Part 2: Tmax of RO7049389		Up to Day 28
Part 2: Cmax of RO7049389		Up to Day 28
Part 2: AUCtau of RO7049389		Up to Day 28
Part 2: Accumulation Ratio of RO7049389	This endpoint presents the geometric mean ratio of AUC after a single dose (Day 1) and AUC after having received multiple doses (Day 28) within each arm.	Day 1, Day 28
Part 2: T1/2 of RO7049389		Up to Day 28
Part 2: Ctrough of RO7049389		Up to Day 28
Part 3: Percentage of Participants With AEs		72 weeks
Part 3: Hepatitis B Surface Antigen (HBsAg) Level		Baseline - Week 72
Part 3: Hepatitis B e-Antigen (HBeAg) Levels		Baseline - Week 72
Part 3: HBV RNA Level		Baseline - Week 72
Part 3: HBV Core-Related Antigen (HBcrAg) Levels		Baseline - Week 72
Part 3: Alanine Transaminase (ALT) Normalization in Participants With Baseline ALT Elevation		Week 12 - Week 72
Part 3: Percentage of Participants With Anti-Hepatitis B Core Antigen (HBc) Antibodies		Up to Week 72
Part 3: HBV DNA Level		Baseline - Week 72
Part 3: HBV DNA < Lower Limit of Quantification (LLOQ)		Baseline - Week 72
Part 3: Tmax of RO7049389		Day 1 - Week 48
Part 3: Cmax of RO7049389		Day 1 - Week 48
Part 3: AUCtau of RO7049389		Day 1 - Week 48
Part 3: T1/2 of RO7049389		Day 1 - Week 48

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, 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 (Estimated): November 2, 2016

Study Record Updates

• Last Update Posted (Actual): October 31, 2024
• Last Update Submitted That Met QC Criteria: August 20, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

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