A Study in Healthy Volunteers and in Participants With Chronic Hepatitis B to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of RO7020531

Hoffmann-La Roche160 enrolled

Overview

This sponsor-open, investigator- and participant-blinded, multi-center study will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7020531 in healthy participants and in participants with chronic hepatitis B. Part I will be conducted in two portions: Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) which will include only healthy volunteers. Part II will commence after completion of the MAD portion of Part I and will include only Chronic Hepatitis B (CHB) participants.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

160

Conditions

Hepatitis B, Chronic

Interventions

Placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: Part 1: SAD and MAD in Healthy Volunteers * Non-smokers, or use of less than (\<) 10 cigarettes (or equivalent nicotine-containing product) per day * Negative Anti-Nuclear Antibody (ANA) test; or positive with dilutions not greater than 1:40 and with no associated history or symptoms of potential connective tissue disease or other immune-mediated diseases Part 2: CHB Participants * CHB infection (positive test for Hepatitis B surface antigen \[HBsAg\] for more than 6 months prior to randomization) * For Cohort 1, 2, 3 and 4: HBsAg detectable at screening * For Cohort 1, 2 and 3: Hepatitis B virus deoxyribose nuclic acid (HBV DNA) \< 90 international unit per milliliter (IU/mL) for at least 6 months prior to randomization; HBV DNA \< 90 IU/mL at screening by Roche Cobas assay * For Cohort 4: HBV DNA at screening \>= 2 × 10\*4 IU/mL for HBeAg positive and \>= 2 x 10\*3 IU/mL for hepatitis B e antigen (HBeAg) negative participants * For Cohort 1, 2 and 3: Alanine amino transferase (ALT) =\<1.5 × upper limit of normal (ULN) during the 6 months prior to randomization confirmed by two measurements separated by at least 14 days; ALT at screening =\< 1.5 × ULN. * For Cohort 4: ALT and aspartate aminotransferase (AST) at screening and Day -1 visit: =\< 5 × ULN. * Negative ANA test; or positive with dilutions not greater than 1:40 and with no associated history or symptoms of potential connective tissue disease or other immune-mediated diseases * Liver biopsy, Fibroscan® or equivalent elastography test obtained within 6 months prior to randomization demonstrating liver disease consistent with chronic HBV infection with absence of cirrhosis and absence of extensive bridging fibrosis (cirrhosis or extensive bridging fibrosis are defined as greater than or equal to (\>/=) Metavir 3, recommended cut-off for Fibroscan 8.5 kilopascals \[kPa\]) * For Cohort 1, 2 and 3: On treatment with tenofovir, entecavir, adefovir, or telbivudine, either as single agents or in combination, for at least 6 months * For Cohort 4: Hepatitis B virus (HBV) treatment naïve or not on any anti-HBV treatment for the past 6 months Exclusion Criteria: Part 1: SAD and MAD in Healthy Volunteers * History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune haemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or any other autoimmune disease); clinically significant psychiatric disease, acute infection (e.g., influenza), gastrointestinal (GI) disease (including inflammatory bowel disease, peptic ulcer disease, GI hemorrhage) * History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral or inhaled corticosteroids, IFN or pegylated interferon \[PEG-IFN\]) within the 8 weeks prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study * Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment of 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 Hepatitis A virus antibody (HAV Ab IgM), HBsAg, Hepatitis C antibody (HCV Ab), or positive for human immunodeficiency virus (HIV) at screening * History of clinically significant thyroid disease; also, participants with clinically significant elevated thyroid-stimulating hormone (TSH) concentrations at screening * Positive results for anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA) or thyroid peroxidase antibody Part 2: CHB Participants * History of liver cirrhosis * History or other evidence of bleeding from esophageal varices * Decompensated liver disease (e.g., Child-Pugh Class B or C clinical classification or clinical evidence such as ascites or varices) * 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 steato-hepatitis, etc.). A clinical diagnosis of fatty liver is allowed provided that non alcoholic steatohepatitis (NASH) has been excluded by liver biopsy. * Documented history or other evidence of metabolic liver disease within one year of randomization * Positive test for Hepatitis A virus (IgM anti-HAV), Hepatitis C virus (HCV), Hepatitis D virus, Hepatitis E virus (HEV), or human immunodeficiency virus (HIV). * History of or suspicion of hepatocellular carcinoma or alpha fetoprotein \>/=13 nanograms per milliliter (ng/mL) at screening * History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune haemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis, multiple sclerosis, or any other autoimmune disease); clinically significant psychiatric disease; acute infection (e.g., influenza); GI disease (including inflammatory bowel disease, peptic ulcer disease, GI hemorrhage, or history of pancreatitis); clinically significant cardiovascular (including postural hypotension), endocrine, renal, ocular, pulmonary or neurological disease. * History of having received or currently receiving any systemic anti-neoplastic (including radiation) or immune-modulatory treatment (including systemic oral or inhaled corticosteroids,IFN or PEG-IFN) within the 8 weeks prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study * Cohort 4: Concurrent HBV treatments * History of organ transplantation * Clinically significant thyroid disease; also, participants with clinically significant elevated TSH concentrations at screening * Positive results for AMA, ASMA or thyroid peroxidase antibody

Locations (18)

Gastroenterology department, Second clinic of internal diseases

Sofia, Bulgaria

COMAC Medical; Clinical Research Unit for Phase I

Sofia, Bulgaria

Queen Mary Hospital

Hong Kong, Hong Kong

The Chinese University of Hong Kong

Shatin, Hong Kong

Azienda Ospedaliero Universitaria Di Modena Policlinico; U.O. Farmacia

Modena, Emilia-Romagna, Italy

ASST PAPA GIOVANNI XXIII; Epatologia e gastroenterologia pediatrica e dei trapianti

Bergamo, Lombardy, Italy

Medicina Generale ed Epatologia (Humanitas-Rozzano)

Rozzano, Lombardy, Italy

Academisch Medisch Centrum Universiteit Amsterdam; Dermatology and VU University Medical Center

Amsterdam, Netherlands

Auckland Clinical Studies

Auckland, New Zealand

National Cheng Kung University Hospital

Tainan, Taiwan

...and 8 more locations

Outcomes

Primary Outcomes

Part 1: Percentage of SAD Participants With Adverse Events (AEs)

An AE is any untoward medical occurrence in a clinical investigation healthy volunteer (HV)/participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity of a known condition and recurrence of an intermittent medical condition (e.g., headache) not present at baseline.

Time frame: From randomization up to Day 29

Part 1: Percentage of MAD Participants With AEs

Time frame: From randomization up to Day 41

Part 2: Percentage of Chronic Hepatitis B Participants With AEs

An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity of a known condition and recurrence of an intermittent medical condition (e.g., headache) not present at baseline.

Time frame: From randomization up to Week 12

Part 1: Percentage of SAD Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results

For all laboratory parameters included, there exists a Roche predefined standard reference range. Laboratory values falling outside this standard reference range were labeled "H" for high or "L" for low in HV/participant listings of laboratory data.

Time frame: From randomization up to Day 8

Part 1: Percentage of MAD Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results

Time frame: From randomization up to Day 20

Part 2: Percentage of Chronic Hepatitis B Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results

Time frame: From randomization up to Week 12

Part 1: Percentage of SAD Participants With Abnormalities in Electrocardiograph (ECG) Parameters

Triplicate 12-lead ECGs were obtained after the participant has been in a supine position for at least 10 minutes. Clinically significant RO7020531-related changes included confirmation of mean QTc 500 milliseconds (msec) or 60 msec longer than the pre-dose baseline.

Time frame: From randomization up to Day 8

Part 1: Percentage of MAD Participants With Abnormalities in ECG Parameters

Triplicate 12-lead ECGs were obtained after the participants has been in a supine position for at least 10 minutes. Clinically significant RO7020531-related changes included confirmation of mean QTc 500 msec or 60 msec longer than the pre-dose baseline.

Time frame: From randomization up to Day 20

Part 2: Percentage of Chronic Hepatitis B Participants With Abnormalities in ECG Parameters

Time frame: From randomization up to Week 12

Part 1: Percentage of SAD Participants With Abnormalities in Vital Signs

Vital signs include blood pressure, pulse rate, respiratory rate and body temperature. Blood pressure, respiratory rate and pulse rate were obtained after the participant had been in a supine or sitting position for at least 5 minutes. Blood pressure measurement were performed in triplicate (can be as short as 20 second to 1 minute interval between measurements).

Time frame: From randomization up to Day 8

Part 1: Percentage of MAD Participants With Abnormalities in Vital Signs

Time frame: From randomization up to Day 20

Part 2: Percentage of Chronic Hepatitis B Participants With Abnormalities in Vital Signs

Time frame: From randomization up to Week 12

Secondary Outcomes

Part 1: Maximum Observed Plasma Concentration (Cmax) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD

Time frame: SAD: Predose and 0.5, 1, 1.5 , 2, 3, 4, 6,8, 12,18, and 24hours post dose on Day 1; MAD: Predose and 0.25, 0.5, 1, 1.5, 2 , 3, 4, 6, 8, 12,18, and 24 hours post dose on Days 1 and 13

Part 2: Cmax of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805

Time frame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41

Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD

Time frame: SAD: Predose and 0.5, 1, 1.5 , 2, 3, 4, 6,8, 12,18, and 24hours post dose on Day 1; MAD: Predose and 0.25, 0.5, 1, 1.5, 2 , 3, 4, 6, 8, 12,18, and 24 hours post dose on Days 1 and 13

Part 2: Tmax of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805

Time frame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41

Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD

Time frame: SAD: Predose and 0.5, 1, 1.5 , 2, 3, 4, 6,8, 12,18, and 24hours post dose on Day 1; MAD: Predose and 0.25, 0.5, 1, 1.5, 2 , 3, 4, 6, 8, 12,18, and 24 hours post dose on Days 1 and 13

Part 2: AUCinf of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805

Time frame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41

Part 1: Area Under the Plasma Concentration Versus Time Curve up to the Last Measurable Concentration (AUClast) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD

Time frame: SAD: Predose and 0.5, 1, 1.5 , 2, 3, 4, 6,8, 12,18, and 24hours post dose on Day 1; MAD: Predose and 0.25, 0.5, 1, 1.5, 2 , 3, 4, 6, 8, 12,18, and 24 hours post dose on Days 1 and 13