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

NCT02952924 | Completed Phase 1 Results

• 1 other identifier: YP39364
• Study Type: interventional
• Target: 192
• Locations: 8 countries
• Sites: 21

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

Outcome Measures

Primary Outcomes (12)

• 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 Outcomes (32)

• Part 1b: Food Effect on Cmax of RO7049389

  Day 16

• Part 1b: Food Effect on AUCinf of RO7049389

  Day 16

• Part 1c: Cmax of Midazolam

  Up to Day 14

• Part 1c: AUCinf of Midazolam

  Up to Day 14

• Part 1c: Tmax of RO7049389

  Up to Day 14

Study Arms (9)

Parts 1a and 1b: SAD in Healthy Volunteers (Placebo)

PLACEBO COMPARATOR

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

Parts 1a and 1b: SAD in Healthy Volunteers (RO7049389)

EXPERIMENTAL

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

Part 1c: MAD in Healthy Volunteers (Placebo)

PLACEBO COMPARATOR

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.

Drug: Midazolam; Other: Placebo

Part 1c: MAD in Healthy Volunteers (RO7049389)

EXPERIMENTAL

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: Midazolam; Drug: RO7049389

Part 2: POM in Chronic HBV Participants (Placebo)

PLACEBO COMPARATOR

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

Part 2: POM in Chronic HBV Participants (RO7049389)

EXPERIMENTAL

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

Part 3: POM in NUC-Suppressed CHB Participants (Cohort A)

EXPERIMENTAL

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

Part 3: POM in Treatment-Naive CHB Participants (Cohort B)

EXPERIMENTAL

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

Part 3: POM in Treatment-Naive CHB Participants (Cohort C)

EXPERIMENTAL

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

Interventions

Midazolam 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

Part 1c: MAD in Healthy Volunteers (Placebo); Part 1c: MAD in Healthy Volunteers (RO7049389)

Placebo OTHER

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

Part 1c: MAD in Healthy Volunteers (Placebo); Part 2: POM in Chronic HBV Participants (Placebo); Parts 1a and 1b: SAD in Healthy Volunteers (Placebo)

RO7049389 DRUG

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

Part 1c: MAD in Healthy Volunteers (RO7049389); Part 2: POM in Chronic HBV Participants (RO7049389); Part 3: POM in NUC-Suppressed CHB Participants (Cohort A); Part 3: POM in Treatment-Naive CHB Participants (Cohort B); Part 3: POM in Treatment-Naive CHB Participants (Cohort C); Parts 1a and 1b: SAD in Healthy Volunteers (RO7049389)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (21)

Royal Brisbane and Women's Hospital

Herston, Queensland, 4029, Australia

Location

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Acibadem City Clinic Tokuda Hospital Ead

Sofia, 1407, Bulgaria

Location

Nanfang Hospital, Southern Medical University

Guangzhou, 510515, China

Location

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

Shanghai, 200025, China

Location

Huashan Hospital Affiliated to Fudan University

Shanghai, 200040, China

Location

The University of Hong Kong; Queen Mary Hospital

Hong Kong, Hong Kong

Location

Prince of Wales Hospital

Shatin, New Territories, Hong Kong

Location

Middlemore Hospital

Auckland, New Zealand

Location

Auckland Clinical Studies Limited

Grafton, 1010, New Zealand

Location

National University Health System

Singapore, 119228, Singapore

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, 807, Taiwan

Location

Chang Gung Memorial Hospital - Kaohsiung Branch

Kaohsiung City, Taiwan

Location

Taichung Veterans Gen Hosp

Taichung, 40705, Taiwan

Location

National Cheng Kung University Hospital

Tainan, 70457, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 112, Taiwan

Location

Chang Gung Memorial Hospital - Linkou Branch

Taipei, Taiwan

Location

King Chulalongkorn Memorial Hospital

Bangkok, 10330, Thailand

Location

Siriraj Hospital

Bangkok, 10700, Thailand

Location

Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, 50200, Thailand

Location

Related Publications (2)

• 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.

  PMID: 34237271 DERIVED

• 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.

  PMID: 32839221 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

Midazolam

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

1-800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2016
• First Posted: November 2, 2016
• Study Start: December 14, 2016
• Primary Completion: March 16, 2022
• Study Completion: March 16, 2022
• Last Updated: October 31, 2024
• Results First Posted: October 31, 2024

Record last verified: 2024-08

Locations

NZ (2); SG (2); TH (3); HK (2); CN (3); BU (1); AU (2); TW (6)