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
- Conditions
- Hepatitis B, Chronic
- Interventions
- Other: PlaceboDrug: RO7020531
- Registration Number
- NCT02956850
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 160
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
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part I: SAD in Healthy Volunteers Placebo 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. Part I: SAD in Healthy Volunteers RO7020531 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. Part I: MAD in Healthy Volunteers Placebo 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. Part I: MAD in Healthy Volunteers RO7020531 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. Part II: CHB Participants Placebo 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. Part II: CHB Participants RO7020531 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.
- Primary Outcome Measures
Name Time Method Part 1: Percentage of MAD Participants With Abnormalities in Vital Signs From randomization up to Day 20 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).
Part 1: Percentage of SAD Participants With Adverse Events (AEs) From randomization up to Day 29 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.
Part 1: Percentage of MAD Participants With AEs From randomization up to Day 41 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.
Part 2: Percentage of Chronic Hepatitis B Participants With AEs From randomization up to Week 12 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.
Part 1: Percentage of SAD Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results From randomization up to Day 8 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.
Part 1: Percentage of MAD Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results From randomization up to Day 20 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.
Part 2: Percentage of Chronic Hepatitis B Participants With Laboratory Abnormalities Based on Hematology, Clinical Chemistry, Coagulation and Urinalysis Test Results From randomization up to Week 12 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.
Part 1: Percentage of SAD Participants With Abnormalities in Electrocardiograph (ECG) Parameters From randomization up to Day 8 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.
Part 1: Percentage of MAD Participants With Abnormalities in ECG Parameters From randomization up to Day 20 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.
Part 2: Percentage of Chronic Hepatitis B Participants With Abnormalities in ECG Parameters From randomization up to Week 12 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 msec or 60 msec longer than the pre-dose baseline.
Part 1: Percentage of SAD Participants With Abnormalities in Vital Signs From randomization up to Day 8 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).
Part 2: Percentage of Chronic Hepatitis B Participants With Abnormalities in Vital Signs From randomization up to Week 12 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).
- Secondary Outcome Measures
Name Time Method Part 1: Maximum Observed Plasma Concentration (Cmax) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD 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 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 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 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 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 Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41 Part 2: AUCinf of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805 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 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: AUClast of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805 Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41 Part 1: Half Life (t1/2) of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805: SAD and MAD 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: t1/2 of RO7020531 and Its Metabolites Including RO7011785, RO7018822 and RO7033805 Predose and 0.25, 1, 2, 4, 6, 8, and 24 hours post dose on Days 1 and 41 Part 1: Total Amount of RO7020531, RO7011785, RO7018822 and RO7033805 in Urine: SAD 0 to 24 hrs Postdose on Day 1 Total amount of the study drug and metabolites recovered in urine was reported.
Part 1:Mean Concentration of Interferon Alpha (IFN-alpha): SAD and MAD 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 Mean concentrations of IFN-alpha for SAD were calculated following single-dose and for MAD it was calculated following multiple doses. The standard deviation (SD) presented is actually the log transformed geometric standard deviation.
Part 2: Mean Concentration of IFN-alpha 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 Mean concentrations of IFN-alpha for Part 2 were calculated following multiple doses. The SD presented is actually the log transformed geometric standard deviation.
Part 1: Mean Fold Change From Baseline in Cytokine Markers: SAD and MAD 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 Cytokines markers include Chemokine (C-X-C Motif) Ligand 10 (IP-10), Interleukin 6 (IL-6), Interleukin 10 (IL-10), Interleukin 12 p40 (IL-12 p40), Neopterin, Tumor Necrosis Factor-Alpha (TNF-alpha). The SD presented is actually the log transformed geometric standard deviation.
Part 2: Mean Fold Change From Baseline in Cytokine Markers 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 Cytokines markers included IP- 10, IL- 6, IL-1 10, IL-12 p40, Neopterin and TNF -alpha. The SD presented is actually the log transformed geometric standard deviation.
Part 1:Mean Fold Change From Baseline in Markers of Transcriptional Responses: SAD and MAD 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 Markers of transcriptional responses includes messenger ribonucleic acid interferon-stimulated gene 15(mRNA ISG15), messenger RNA oligoadenylate synthetase 1 (mRNA OAS1), messenger RNA myxovirus resistance 1 gene (mRNA MX-1), messenger RNA Toll-like receptor (mRNA TLR7). The SD presented is actually the log transformed geometric standard deviation.
Part 2: Mean Fold Change From Baseline in Markers of Transcriptional Responses 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 Transcriptional markers include mRNA ISG15, mRNA OAS1, mRNA MX-1, mRNA TLR7. The SD presented is actually the log transformed geometric standard deviation.
Effect of RO7020531 Dosing on ECG Parameters (PR [PQ], QRS, QT, QTcF in Miliseconds [ms]) Using Exposure-response Analysis: SAD and MAD 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 Part 2: Plasma Concentrations of Tenofovir, Tenofovir Alafenamide, Entecavir, Adefovir and Telbivudine Pre-dose and 2-4 hours post-dose on Day 1, Day 21 and Day 41 Adefovir was not administered to any participants in the study. Hence, no data could be collected for plasma concentration of adefovir. As participants in each cohort received different NUCs the data for Cohorts 1, 2 and 3 have been reported separately.
Trial Locations
- Locations (18)
Academisch Medisch Centrum Universiteit Amsterdam; Dermatology and VU University Medical Center
🇳🇱Amsterdam, Netherlands
Gastroenterology department, Second clinic of internal diseases
🇧🇬Sofia, Bulgaria
Queen Mary Hospital
🇭🇰Hong Kong, Hong Kong
COMAC Medical; Clinical Research Unit for Phase I
🇧🇬Sofia, Bulgaria
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, Lombardia, Italy
Medicina Generale ed Epatologia (Humanitas-Rozzano)
🇮🇹Rozzano, Lombardia, Italy
Auckland Clinical Studies
🇳🇿Auckland, New Zealand
King College Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
Taipei Veterans General Hospital
🇨🇳Taipei City, Taiwan
Maharaj Nakorn Chiang Mai Hospital
🇹🇭Chiang Mai, Thailand
King Chulalongkorn Memorial Hospital
🇹🇭Bangkok, Thailand
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
Chang Gung Memorial Hospital
🇨🇳Taoyuan, Taiwan
Taichung Veterans General Hospital
🇨🇳Xitun Dist., Taiwan
Siriraj Hospital
🇹🇭Bangkok, Thailand
Royal Liverpool University Hospital
🇬🇧Liverpool, United Kingdom