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

Roche

Status and phase: Completed; Phase 1

Conditions: Hepatitis B, Chronic

Treatments: Drug: RO7020531; Other: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02956850

NP39305

2016-003723-38 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 160 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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160 participants in 3 patient groups

Part I: SAD in Healthy Volunteers

Experimental group

Description:

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.

Treatment:

Drug: RO7020531

Other: Placebo

Part I: MAD in Healthy Volunteers

Experimental group

Description:

Healthy volunteers will receive RO7020531 (100 mg, 140 mg, and 170 mg as selected based on safety, pharmacokinetic (PK) and pharmacodynamic (PD) data of SAD cohorts) or matching placebo orally every other day (QOD) from Day 1 through to Day 13.

Treatment:

Drug: RO7020531

Other: Placebo

Part II: CHB Participants

Experimental group

Description:

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 once a week (QW) dosing as dose modification.

Treatment:

Drug: RO7020531

Other: Placebo