Clinical trial NCT02956850: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis B, Chronic
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-11-06
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Part 1: Percentage of SAD Participants With Adverse Events (AEs)
timeFrame: From randomization up to Day 29
measure: Part 1: Percentage of MAD Participants With AEs
timeFrame: From randomization up to Day 41
measure: Part 2: Percentage of Chronic Hepatitis B Participants With AEs
timeFrame: From randomization up to Week 12
measure: Part 1: Percentage of SAD Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results
timeFrame: From randomization up to Day 8
measure: Part 1: Percentage of MAD Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results
timeFrame: From randomization up to Day 20
measure: Part 2: Percentage of Chronic Hepatitis B Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results
timeFrame: From randomization up to Week 12
measure: Part 1: Percentage of SAD Participants With Abnormalities in Electrocardiograph (ECG) Parameters
timeFrame: From randomization up to Day 8
measure: Part 1: Percentage of MAD Participants With Abnormalities in ECG Parameters
timeFrame: From randomization up to Day 20
measure: Part 2: Percentage of Chronic Hepatitis B Participants With Abnormalities in ECG Parameters
timeFrame: From randomization up to Week 12
measure: Part 1: Percentage of SAD Participants With Abnormalities in Vital Signs
timeFrame: From randomization up to Day 8
measure: Part 1: Percentage of MAD Participants With Abnormalities in Vital Signs
timeFrame: From randomization up to Day 20
measure: Part 2: Percentage of Chronic Hepatitis B Participants With Abnormalities in Vital Signs
timeFrame: From randomization up to Week 12
Secondary outcomes:
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD
timeFrame: 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
measure: Part 2: Cmax of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805
timeFrame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41
measure: Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD
timeFrame: 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
measure: Part 2: Tmax of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805
timeFrame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41
measure: 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
timeFrame: 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
measure: Part 2: AUCinf of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805
timeFrame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41
measure: 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
timeFrame: 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
measure: Part 2: AUClast of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805
timeFrame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41
measure: Part 1: Half Life (t1/2) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD
timeFrame: 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
measure: Part 2: t1/2 of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805
timeFrame: Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41
measure: Part 1: Total Amount of RO7020531, RO7011785, RO7018822 and RO7033805 in Urine: SAD
timeFrame: 0 to 24 hrs Postdose on Day 1
measure: Part 1:Mean Concentration of Interferon Alpha (IFN-alpha): SAD and MAD
timeFrame: SAD: Predose, 2, 6, 12 and 24 hrs Postdose; MAD: Predose, 2, 6, 12, and 24 hrs Postdose on Day 1; Predose, 2, 6 and 24 hrs Postdose on Days 3, 5, 7, 13 and 20
measure: Part 2: Mean Concentration of IFN-alpha
timeFrame: Predose, 6, 8 and 24 hrs Postdose on Day 1; Predose, 4-6, 24 hrs Postdose on Days 3, 7 and 21; Predose, 6, 24 hrs Postdose on Day 41
measure: Part 1: Mean Fold Change From Baseline in Cytokine Markers: SAD and MAD
timeFrame: SAD: Predose, 2, 6, 12, 24, 48 (only Neopterin) and 96 hrs (only Neopterin) Postdose; MAD: Predose, 2, 6, 12, and 24 hrs Postdose on Day 1; Predose, 2, 6 and 24 hrs Postdose on Days 3, 5, 7, 13 and 20
measure: Part 2: Mean Fold Change From Baseline in Cytokine Markers
timeFrame: Predose, 6, 8 and 24 hrs Postdose on Day 1; Predose, 4-6, 24 hrs Postdose on Days 3, 7 and 21; Predose, 6, 24 hrs Postdose on Day 41
measure: Part 1:Mean Fold Change From Baseline in Markers of Transcriptional Responses: SAD and MAD
timeFrame: SAD: Predose, 2, 6, 12 and 24 Postdose; MAD: Predose, 2, 6, 12, and 24 hrs Postdose on Day 1; Predose, 2, 6 and 24 hrs Postdose on Days 3, 5, 7, 13 and 20
measure: Part 2: Mean Fold Change From Baseline in Markers of Transcriptional Responses
timeFrame: Predose, 6, 8, 24 hrs postdose on Day 1; Predose, 4-6, 24 hrs postdose on Days 3, 7, 21; Predose, 6, 24 hrs postdose on Day 41
measure: Effect of RO7020531 Dosing on ECG Parameters (PR [PQ], QRS, QT, QTcF in Miliseconds [ms]) Using Exposure-response Analysis: SAD and MAD
timeFrame: SAD: Predose, 0.5, 1, 2, 4, 6, 12, 24 and 48 hrs Post dose on Day 1; MAD: Predose, 0.5, 1,2,4 and 12 hrs Postdose on Day 1 and 13; Predose, 2 and 6 hrs Postdose on Day 3, Predose, 6 and 24 hrs Postdose on Day , 7, 9, and 11
measure: Part 2: Plasma Concentrations of Tenofovir, Tenofovir Alafenamide, Entecavir, Adefovir and Telbivudine
timeFrame: Pre-dose and 2-4 hours post-dose on Day 1, Day 21 and Day 41
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: Gastroenterology department, Second clinic of internal diseases
city: Sofia
country: Bulgaria
facility: COMAC Medical; Clinical Research Unit for Phase I
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: The Chinese University of Hong Kong
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria Di Modena Policlinico; U.O. Farmacia
state: Emilia-Romagna
city: Bergamo
country: Italy
facility: ASST PAPA GIOVANNI XXIII; Epatologia e gastroenterologia pediatrica e dei trapianti
state: Lombardia
city: Rozzano
country: Italy
facility: Medicina Generale ed Epatologia (Humanitas-Rozzano)
state: Lombardia
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum Universiteit Amsterdam; Dermatology and VU University Medical Center
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital
city: Xitun Dist.
country: Taiwan
facility: Taichung Veterans General Hospital
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
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: King College Hospital NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: