Clinical trial NCT02952924: 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
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis B, Chronic
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-11-02
Enrollment: 192
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Part 1: Percentage of Participants With Adverse Events
timeFrame: Up to Day 29 (Part 1a), Day 44 (Part 1b), Day 42 (Part 1c)
measure: Parts 1a and 1b: SAD Cohort: Time to Reach Maximum Concentration (Tmax) of RO7049389
timeFrame: Up to 28 days
measure: Parts 1a and 1b: SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO7049389
timeFrame: Up to 28 days
measure: Parts 1a and 1b: SAD Cohort: AUC From Time Zero to Infinity (AUC0-inf) of RO7049389
timeFrame: Up to 28 days
measure: Parts 1a and 1b: SAD Cohort: Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of RO7049389
timeFrame: Up to 28 days
measure: Parts 1a and 1b: SAD Cohort: Half-life (T1/2) of RO7049389
timeFrame: Up to Day 28
measure: Parts 1a and 1b: SAD Cohort: Apparent Oral Clearance (CL/F) of RO7049389
timeFrame: Up to Day 28
measure: Parts 1a and 1b: SAD Cohort: Cumulative Amount Excreted Unchanged in Urine (Ae) of RO7049389
timeFrame: Up to Day 28
measure: Parts 1a and 1b: SAD Cohort: Renal Clearance (CLr) of RO7049389
timeFrame: Up to Day 28
measure: Part 2: Percentage of Participants With Adverse Events
timeFrame: Up to Day 112
measure: Part 2: Quantitative Plasma HBV DNA Level
timeFrame: Baseline - Day 112
measure: Part 3: Proportion of Patients Achieving Functional Cure
timeFrame: Every 2-4 weeks from Baseline through Week 72
Secondary outcomes:
measure: Part 1b: Food Effect on Cmax of RO7049389
timeFrame: Day 16
measure: Part 1b: Food Effect on AUCinf of RO7049389
timeFrame: Day 16
measure: Part 1c: Cmax of Midazolam
timeFrame: Up to Day 14
measure: Part 1c: AUCinf of Midazolam
timeFrame: Up to Day 14
measure: Part 1c: Tmax of RO7049389
timeFrame: Up to Day 14
measure: Part 1c: Cmax of RO7049389
timeFrame: Up to Day 14
measure: Part 1c: AUC0-12hr of RO7049389
timeFrame: Up to Day 14
measure: Part 1c: CLr of RO7049389
timeFrame: Up to Day 14
measure: Part 1c: Accumulation Ratio of RO7049389
timeFrame: Day 1, Day 14
measure: Part 1c: T1/2 of RO7049389
timeFrame: Up to Day 14
measure: Part 1c: Ae of RO7049389
timeFrame: Up to Day 14
measure: Part 1c: Ctrough of RO7049389
timeFrame: Up to Day 14
measure: Part 2: HBV DNA < Lower Limit of Quantification (LLOQ)
timeFrame: Baseline - Day 112/Follow-up Day 84
measure: Part 2: Tmax of RO7049389
timeFrame: Up to Day 28
measure: Part 2: Cmax of RO7049389
timeFrame: Up to Day 28
measure: Part 2: AUCtau of RO7049389
timeFrame: Up to Day 28
measure: Part 2: Accumulation Ratio of RO7049389
timeFrame: Day 1, Day 28
measure: Part 2: T1/2 of RO7049389
timeFrame: Up to Day 28
measure: Part 2: Ctrough of RO7049389
timeFrame: Up to Day 28
measure: Part 3: Percentage of Participants With AEs
timeFrame: 72 weeks
measure: Part 3: Hepatitis B Surface Antigen (HBsAg) Level
timeFrame: Baseline - Week 72
measure: Part 3: Hepatitis B e-Antigen (HBeAg) Levels
timeFrame: Baseline - Week 72
measure: Part 3: HBV RNA Level
timeFrame: Baseline - Week 72
measure: Part 3: HBV Core-Related Antigen (HBcrAg) Levels
timeFrame: Baseline - Week 72
measure: Part 3: Alanine Transaminase (ALT) Normalization in Participants With Baseline ALT Elevation
timeFrame: Week 12 - Week 72
measure: Part 3: Percentage of Participants With Anti-Hepatitis B Core Antigen (HBc) Antibodies
timeFrame: Up to Week 72
measure: Part 3: HBV DNA Level
timeFrame: Baseline - Week 72
measure: Part 3: HBV DNA < Lower Limit of Quantification (LLOQ)
timeFrame: Baseline - Week 72
measure: Part 3: Tmax of RO7049389
timeFrame: Day 1 - Week 48
measure: Part 3: Cmax of RO7049389
timeFrame: Day 1 - Week 48
measure: Part 3: AUCtau of RO7049389
timeFrame: Day 1 - Week 48
measure: Part 3: T1/2 of RO7049389
timeFrame: Day 1 - Week 48
Other outcomes:
Locations:
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic Tokuda Hospital Ead
city: Guangzhou
country: China
facility: Nanfang Hospital, Southern Medical University
city: Shanghai City
country: China
facility: Huashan Hospital Affiliated to Fudan University
city: Shanghai
country: China
facility: Shanghai Jiao Tong University School of Medicine (SJTUSM) - Ruijin Hospital (GuangCi Hospital)
city: Hong Kong
country: Hong Kong
facility: The University of Hong Kong; Queen Mary Hospital
city: Shatin, New Territories
country: Hong Kong
facility: Prince of Wales Hospital
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Grafton
country: New Zealand
facility: Auckland Clinical Studies Limited
city: Singapore
country: Singapore
facility: National University Health System
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Chang Gung Memorial Hospital - Kaohsiung Branch
city: Taichung
country: Taiwan
facility: Taichung Veterans Gen Hosp
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Chang Gung Memorial Hospital - Linkou Branch
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.