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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Phase I, Sponsor-Open, Investigator-Blinded, Subject-Blinded, Multi-Center, Placebo-Controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Oral Administration of RO7020531: (1). Single and Multiple Ascending Doses in Healthy Male and Female Subjects; (2). 6-week Treatment of Patients With Chronic Hepatitis B Virus Infection

Conditions
-----------------
Hepatitis B, Chronic

Intervention / Treatment
-----------------
* Other: Placebo
* Drug: RO7020531


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part 1: SAD and MAD in Healthy Volunteers A Body Mass Index (BMI) between 18 to 32 kilograms per square meter (kg/m^2), inclusive 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 A BMI between 21 to 32 kg/m^2, inclusive. 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: HBV DNA < 90 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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: SAD in Healthy Volunteers<br>Healthy volunteers will receive single dose of RO7020531 or matching placebo orally on Day 1 of each cohort. A planned dose-escalation sequence for SAD is 3 milligrams (mg), 10 mg, 20 mg, 40 mg, 60 mg, 100 mg, 140 mg, and 170 mg. | Other: Placebo<br>* Placebo matching to RO7020531 will be administered as per schedule specified in the respective arm.<br>Drug: RO7020531<br>* RO7020531 will be administered as per schedule specified in the respective arm.<br>|
| Experimental: Part I: MAD in Healthy Volunteers<br>Healthy volunteers will receive RO7020531 (100 mg, 140 mg, and 170 mg as selected based on safety, PK and PD data of SAD cohorts) or matching placebo orally every other day (QOD) from Day 1 through to Day 13. | Other: Placebo<br>* Placebo matching to RO7020531 will be administered as per schedule specified in the respective arm.<br>Drug: RO7020531<br>* RO7020531 will be administered as per schedule specified in the respective arm.<br>|
| Experimental: Part II: CHB Participants<br>CHB participants will receive RO7020531 (150 mg and 170 mg as selected based on safety, PK and PD data of MAD cohorts) or matching placebo orally QOD from Day 1 through to Day 41, unless in Cohort 4 in case of QW dosing as dose modification. | Other: Placebo<br>* Placebo matching to RO7020531 will be administered as per schedule specified in the respective arm.<br>Drug: RO7020531<br>* RO7020531 will be administered as per schedule specified in the respective arm.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Percentage of SAD Participants With Adverse Events |  | From randomization up to Day 29 | 
| Part I: Percentage of MAD Participants With Adverse Events |  | From randomization up to Day 41 | 
| Part II: Percentage of Participants With Adverse Events |  | From randomization up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Maximum Observed Plasma Concentration (Cmax) of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | SAD:Predose(0-2 hours [hrs] before dose),0.25,0.5,1,1.5,2,3,4,6,8,12,18,24,36,48 hrs postdose. MAD:Predose(0-2 hrs before dose),0.25,0.5,1,1.5,2,3,4,6,8,12,18,24 hrs postdose on Day 1,13; Predose(0-2 hrs before dose),2,6,24 hrs postdose on Day 3,5,7,9,11 | 
| Part II: Cmax of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | Predose (0-2 hrs before dose), 0.25, 1, 2, 4, 6, 8, 24 hrs postdose on Days 1, 41; Predose (0-2 hrs before dose), 2-4 hrs postdose on Days 3, 7, 21 | 
| Part I: Time to Reach Cmax (Tmax) of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | SAD: Predose(0-2 hrs before dose),0.25,0.5,1,1.5,2,3,4,6,8,12,18,24,36,48 hrs postdose. MAD: Predose (0-2 hrs before dose), 0.25,0.5,1,1.5,2,3,4,6,8,12,18,24 hrs postdose on Days 1,13; Predose (0-2 hrs before dose), 2,6,24 hrs postdose on Days 3,5,7,9,11 | 
| Part II: Tmax of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | Predose (0-2 hrs before dose), 0.25, 1, 2, 4, 6, 8, 24 hrs postdose on Days 1, 41; Predose (0-2 hrs before dose), 2-4 hrs postdose on Days 3, 7, 21 | 
| Part I: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUCinf) of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | SAD: Predose(0-2 hrs before dose),0.25,0.5,1,1.5,2,3,4,6,8,12,18,24,36,48 hrs postdose. MAD: Predose (0-2 hrs before dose), 0.25,0.5,1,1.5,2,3,4,6,8,12,18,24 hrs postdose on Days 1,13; Predose (0-2 hrs before dose), 2,6,24 hrs postdose on Days 3,5,7,9,11 | 
| Part II: AUCinf of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | Predose (0-2 hrs before dose), 0.25, 1, 2, 4, 6, 8, 24 hrs postdose on Days 1, 41; Predose (0-2 hrs before dose), 2-4 hrs postdose on Days 3, 7, 21 | 
| Part I: 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: Predose(0-2 hrs before dose),0.25,0.5,1,1.5,2,3,4,6,8,12,18,24,36,48 hrs postdose. MAD: Predose (0-2 hrs before dose), 0.25,0.5,1,1.5,2,3,4,6,8,12,18,24 hrs postdose on Days 1,13; Predose (0-2 hrs before dose), 2,6,24 hrs postdose on Days 3,5,7,9,11 | 
| Part II: AUClast of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | Predose (0-2 hrs before dose), 0.25, 1, 2, 4, 6, 8, 24 hrs postdose on Days 1, 41; Predose (0-2 hrs before dose), 2-4 hrs postdose on Days 3, 7, 21 | 
| Part I: Half-Life (t1/2) of RO7020531; and its Metabolites Including RO7011785, RO7018822 and RO7033805 |  | SAD: Predose(0-2 hrs before dose),0.25,0.5,1,1.5,2,3,4,6,8,12,18,24,36,48 hrs postdose. MAD: Predose (0-2 hrs before dose), 0.25,0.5,1,1.5,2,3,4,6,8,12,18,24 hrs postdose on Days 1,13; Predose (0-2 hrs before dose), 2,6,24 hrs postdose on Days 3,5,7,9,11 | 
| Part II: t1/2 of RO7020531; and its Metabolites including RO7011785, RO7018822 and RO7033805 |  | Predose (0-2 hrs before dose), 0.25, 1, 2, 4, 6, 8, 24 hrs postdose on Days 1, 41; Predose (0-2 hrs before dose), 2-4 hrs postdose on Days 3, 7, 21 | 
| Part I: Total Amount of RO7020531, RO7011785, RO7018822 and RO7033805 in Urine |  | 0 to 24 hrs post-dose on Day 1 | 
| Part I and II: Pharmacodynamics: Plasma Neopterin Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 2, 3, 5, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Plasma Interferon (INF)-alpha Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 2, 3, 5, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Plasma Interferon Gamma-Inducible Protein 10 (IP-10) Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Plasma Tumor Necrosis Factor (TNF)-alpha Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Plasma IL-6 Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Plasma IL-10 Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Plasma IL-12p40 Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Peripheral Blood Interferon-Stimulated Gene (ISG) 15 messenger Ribonucleic Acid (mRNA) Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Peripheral Blood Oligoadenylate Synthetase (OAS)-1 mRNA Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Peripheral Blood Myxovirus Resistance 1 gene (MX1) mRNA Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) | 
| Part I and II: Pharmacodynamics: Peripheral blood Toll-Like Receptor (TLR) 7 mRNA Levels | SAD: Predose (0-2 hrs before dose), 2, 6, 12, 24, 48, 96 hrs postdose; Day 8. MAD: Predose (0-2 hrs before dose), 2, 6, 12, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 2, 6, 24 hrs postdose on Days 3, 5, 7, 13; Day 20. Part II: Predose (0-2 hrs before dose), 6, 8, 24 hrs postdose on Day 1; Predose (0-2 hrs before dose), 4-6, 24 hrs postdose on Days 3, 7, 21; Predose (0-2 hrs before dose), 6, 24 hrs postdose on Day 41 | SAD: Days 1, 8. MAD: Days 1, 3, 5, 7, 13, 20. Part II: Days 1, 3, 7, 21, 41 (detailed timeframe is provided in outcome measure description) |