Hepatitis B, ChronicPhase 1NCT02952924
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 Phase 1 study testing Midazolam and RO7049389 in people with Hepatitis B, Chronic, run by Hoffmann-La Roche at 21 sites in 8 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Hepatitis B, Chronic
- What is being tested?
- Midazolam and RO7049389
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 192 participants
- Where
- 21 sitesin 8 countries
- Study dates
- 14 Dec 2016to 16 Mar 2022
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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:
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
21 sites in 8 countries.
21 sites in 8 countries
Taiwan6 sites
Kaohsiung Medical University Chung-Ho Memorial Hospital
Kaohsiung City, 807
Chang Gung Memorial Hospital - Kaohsiung Branch
Kaohsiung City
Taichung Veterans Gen Hosp
Taichung, 40705
National Cheng Kung University Hospital
Tainan, 70457
Taipei Veterans General Hospital
Taipei, 112
Chang Gung Memorial Hospital - Linkou Branch
Taipei
China3 sites
Nanfang Hospital, Southern Medical University
Guangzhou, 510515
Shanghai Jiao Tong University School of Medicine (SJTUSM) - Ruijin Hospital (GuangCi Hospital)
Shanghai, 200025
Huashan Hospital Affiliated to Fudan University
Shanghai, 200040
Thailand3 sites
King Chulalongkorn Memorial Hospital
Bangkok, 10330
Siriraj Hospital
Bangkok, 10700
Maharaj Nakorn Chiang Mai Hospital
Chiang Mai, 50200
Australia2 sites
Royal Brisbane and Women's Hospital
Herston, Queensland, 4029
Royal Melbourne Hospital
Parkville, Victoria, 3050
Hong Kong2 sites
The University of Hong Kong; Queen Mary Hospital
Hong Kong
Prince of Wales Hospital
Shatin, New Territories
New Zealand2 sites
Middlemore Hospital
Auckland
Auckland Clinical Studies Limited
Grafton, 1010
Singapore2 sites
National University Health System
Singapore, 119228
Singapore General Hospital
Singapore, 169608
About this study
Official title: 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.
- Conditions
- Hepatitis B, Chronic
- Being tested
- Midazolam, Placebo, RO7049389
- Medical subject headings
- Hepatitis B, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MidazolamDrug
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
PlaceboOther
Placebo matching to RO7049389 will be administered as per schedule described in individual arm.
RO7049389Drug
RO7049389 will be administered as per schedule described in individual arm.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: RO7049389 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part 1: Percentage of Participants With Adverse Events
Measured: 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
Measured: Up to 28 days
Parts 1a and 1b: SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO7049389
Measured: Up to 28 days
Parts 1a and 1b: SAD Cohort: AUC From Time Zero to Infinity (AUC0-inf) of RO7049389
Measured: 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
Measured: Up to 28 days
Parts 1a and 1b: SAD Cohort: Half-life (T1/2) of RO7049389
Measured: Up to Day 28
Parts 1a and 1b: SAD Cohort: Apparent Oral Clearance (CL/F) of RO7049389
Measured: Up to Day 28
Parts 1a and 1b: SAD Cohort: Cumulative Amount Excreted Unchanged in Urine (Ae) of RO7049389
Measured: Up to Day 28
Parts 1a and 1b: SAD Cohort: Renal Clearance (CLr) of RO7049389
Measured: Up to Day 28
Part 2: Percentage of Participants With Adverse Events
Measured: Up to Day 112
Part 2: Quantitative Plasma HBV DNA Level
Measured: 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.
Measured: Every 2-4 weeks from Baseline through Week 72
Secondary outcomes (32)
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.
Measured: 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.
Measured: Day 16
Part 1c: Cmax of Midazolam
This endpoint presents the geometric mean ratio (after RO7049389/before RO7049389).
Measured: Up to Day 14
Part 1c: AUCinf of Midazolam
This endpoint presents the geometric mean ratio (after RO7049389/before RO7049389).
Measured: Up to Day 14
Part 1c: Tmax of RO7049389
Measured: Up to Day 14
Part 1c: Cmax of RO7049389
Measured: Up to Day 14
Part 1c: AUC0-12hr of RO7049389
Measured: Up to Day 14
Part 1c: CLr of RO7049389
Measured: 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.
Measured: Day 1, Day 14
Part 1c: T1/2 of RO7049389
Measured: Up to Day 14
Part 1c: Ae of RO7049389
Measured: Up to Day 14
Part 1c: Ctrough of RO7049389
Measured: Up to Day 14
Part 2: HBV DNA < Lower Limit of Quantification (LLOQ)
Measured: Baseline - Day 112/Follow-up Day 84
Part 2: Tmax of RO7049389
Measured: Up to Day 28
Part 2: Cmax of RO7049389
Measured: Up to Day 28
Part 2: AUCtau of RO7049389
Measured: 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.
Measured: Day 1, Day 28
Part 2: T1/2 of RO7049389
Measured: Up to Day 28
Part 2: Ctrough of RO7049389
Measured: Up to Day 28
Part 3: Percentage of Participants With AEs
Measured: 72 weeks
Part 3: Hepatitis B Surface Antigen (HBsAg) Level
Measured: Baseline - Week 72
Part 3: Hepatitis B e-Antigen (HBeAg) Levels
Measured: Baseline - Week 72
Part 3: HBV RNA Level
Measured: Baseline - Week 72
Part 3: HBV Core-Related Antigen (HBcrAg) Levels
Measured: Baseline - Week 72
Part 3: Alanine Transaminase (ALT) Normalization in Participants With Baseline ALT Elevation
Measured: Week 12 - Week 72
Part 3: Percentage of Participants With Anti-Hepatitis B Core Antigen (HBc) Antibodies
Measured: Up to Week 72
Part 3: HBV DNA Level
Measured: Baseline - Week 72
Part 3: HBV DNA < Lower Limit of Quantification (LLOQ)
Measured: Baseline - Week 72
Part 3: Tmax of RO7049389
Measured: Day 1 - Week 48
Part 3: Cmax of RO7049389
Measured: Day 1 - Week 48
Part 3: AUCtau of RO7049389
Measured: Day 1 - Week 48
Part 3: T1/2 of RO7049389
Measured: Day 1 - Week 48
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Nov 2016 (estimated)
- Study start14 Dec 2016
- Primary completion16 Mar 2022
- Study completion16 Mar 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Hepatitis B, ChronicStudies of the same condition, open and under way.
- More trials run by Hoffmann-La RocheThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 192 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hoffmann-La Roche
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Hoffmann-La Roche
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02952924
- Sponsor's protocol ID
- YP39364
- Status last verified
- Aug 2024
- First submitted
- 1 Nov 2016
- Last updated
- 31 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
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.
PubMed 34237271Feng 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.
PubMed 32839221