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

NCT ID: NCT02952924

Last Updated: 2024-10-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 192 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-14
• Study Completion Date: 2022-03-16

Brief Summary

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.

Conditions

Hepatitis B, Chronic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo matching to RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

RO7049389

Intervention Type: DRUG

RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: PLACEBO_COMPARATOR

Midazolam

Intervention Type: DRUG

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

Intervention Type: OTHER

Placebo matching to RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

Midazolam

Intervention Type: DRUG

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

RO7049389

Intervention Type: DRUG

RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo matching to RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

RO7049389

Intervention Type: DRUG

RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

RO7049389

Intervention Type: DRUG

RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

RO7049389

Intervention Type: DRUG

RO7049389 will be administered as per schedule described in individual arm.

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.

Group Type: EXPERIMENTAL

RO7049389

Intervention Type: DRUG

RO7049389 will be administered as per schedule described in individual arm.

Interventions

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

Intervention Type: DRUG

Placebo

Placebo matching to RO7049389 will be administered as per schedule described in individual arm.

Intervention Type: OTHER

RO7049389

RO7049389 will be administered as per schedule described in individual arm.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Royal Brisbane and Women's Hospital

Herston, Queensland, Australia

Royal Melbourne Hospital

Parkville, Victoria, Australia

Acibadem City Clinic Tokuda Hospital Ead

Sofia, , Bulgaria

Nanfang Hospital, Southern Medical University

Guangzhou, , China

Shanghai Jiao Tong University School of Medicine (SJTUSM) - Ruijin Hospital (GuangCi Hospital)

Shanghai, , China

Huashan Hospital Affiliated to Fudan University

Shanghai, , China

The University of Hong Kong; Queen Mary Hospital

Hong Kong, , Hong Kong

Prince of Wales Hospital

Shatin, New Territories, , Hong Kong

Middlemore Hospital

Auckland, , New Zealand

Auckland Clinical Studies Limited

Grafton, , New Zealand

National University Health System

Singapore, , Singapore

Singapore General Hospital

Singapore, , Singapore

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, , Taiwan

Chang Gung Memorial Hospital - Kaohsiung Branch

Kaohsiung City, , Taiwan

Taichung Veterans Gen Hosp

Taichung, , Taiwan

National Cheng Kung University Hospital

Tainan City, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

Chang Gung Memorial Hospital - Linkou Branch

Taipei, , Taiwan

King Chulalongkorn Memorial Hospital

Bangkok, , Thailand

Siriraj Hospital

Bangkok, , Thailand

Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, , Thailand

Countries

Australia; Bulgaria; China; Hong Kong; New Zealand; Singapore; Taiwan; Thailand

References

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.

Reference Type: DERIVED

PMID: 34237271 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32839221 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

YP39364

Identifier Type: -

Identifier Source: org_study_id