A Safety, Tolerability, Pharmacokinetics and Efficacy Study of ro7049389 in: (1) Single- (With or Without Food) and Multiple- (With Midazolam) Ascending Doses in Healthy Volunteers; (2) Patients Chronically Infected With Hepatitis b Virus (3) Patients With Chronic Hepatitis B.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 192
- 试验地点
- 21
- 主要终点
- Part 1: Percentage of Participants With Adverse Events
研究概览
简要总结
This study is a multicenter, three-part study. Parts 1 and 2 are randomized, investigator- and participant-blinded, placebo-control, single-ascending dose (SAD) and multiple-ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RO7049389 following oral administration in healthy volunteers and chronic HBV infected participants. Part 3 is a non-randomized, non-controlled, open-label part to assess the efficacy and safety of RO7049389 when administered in combination with standard-of-care therapies for up to 48 weeks in nucleos(t)ide (NUC)-suppressed and treatment-naive chronic hepatitis B (CHB) participants.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Part 1- Healthy Volunteers only:
- •Absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead Electrocardiogram (ECG), hematology, blood chemistry, serology and urinalysis
- •A Body Mass Index (BMI) between 18 to 30 kilograms per square meter (kg/m^2) inclusive
- •Female participants must be either surgically sterile or post-menopausal for at least one year
- •For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
- •Part 2- Chronic HBV-infected participants only:
- •A BMI between 18 to 30 kg/m^2 inclusive
- •Chronic Hepatitis B infection, defined as positive test for Hepatitis B surface antigen (HBsAg) for more than 6 months prior to randomization
- •HBV DNA at screening greater than or equal to (>/=) 2 × 10^4 international units per milliliter (IU/mL) for Hepatitis B e antigen (HBeAg) positive participants, or >/=2 × 10^3 IU/mL for HBeAg-negative participants
- •Liver biopsy, fibroscan or equivalent test obtained within the past 6 months demonstrating liver disease consistent with chronic HBV infection with absence of extensive bridging fibrosis and absence of cirrhosis
- •For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
- •For women of childbearing potential: agreement to remain abstinent or use non-hormonal contraceptive methods that result in a failure rate of less than (<)1 percent (%) per year during the treatment period and for at least 3 months after the last dose of study drug
- •Part 3- Chronic HBV Participants Only:
- •A BMI between 18 to 32 kg/m^2 inclusive
- •Chronic hepatitis B infection, defined as positive test for HBsAg or HBV DNA, or positive HBeAg, for more than 6 months prior to screening
- •For Cohorts only enrolling NUC-suppressed CHB participants (e.g. POM Cohort A), participants must have been treated with a single NUC (entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate) for at least 12 months. Participants must be on the same NUC therapy for at least 3 months prior to screening
- •For Cohorts only enrolling anti-HBV treatment-naive and immune-active participants (e.g. POM Cohort B and Cohort C), previous anti-HBV treatments <30 days in total, and did not receive any anti-HBV treatments within 3 months prior to the first study dose
- •Liver biopsy, fibroscan, or equivalent test obtained within the past 6 months demonstrating liver disease consistent with chronic HBV infection with absence of extensive bridging fibrosis and absence of cirrhosis
- •For men: agreement to remain abstinent or use contraceptive measures, and agree to refrain from donating sperm
- •For women of childbearing potential: agreement to remain abstinent or to use two approved contraceptive methods during the study and for at least 6 months after the last dose of study drug
排除标准
- •Part 1- Healthy Volunteers only:
- •History or symptoms of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, hematological or allergic disease, metabolic disorder, cancer or cirrhosis
- •History of Gilbert's syndrome
- •Participants who have had significant acute infection, e.g., influenza, local infection, acute gastrointestinal symptoms or any other clinically significant illness within two weeks of dose administration
- •Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies
- •Any clinically significant concomitant diseases or condition that could interfere with, or treatment of which 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 test at screening of any of the following: Hepatitis A (HAV IgM Ab), Hepatitis B (HBsAg), Hepatitis C (HCV RNA or HCV Ab) or human immunodeficiency virus (HIV Ab)
- •Acute narrow-angle glaucoma (for MAD-midazolam cohorts)
- •Part 2- Chronic HBV-infected participants only:
- •History or other evidence of bleeding from esophageal varices
- •Evidence of liver cirrhosis or decompensated liver disease such as ascites, esophageal or gastric varices, splenomegaly, nodular liver, jaundice, hepatic encephalopathy
- •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 steatohepatitis, etc.)
- •Documented history or other evidence of metabolic liver disease within one year of randomization
- •Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, or human immunodeficiency virus
- •History of or suspicion of hepatocellular carcinoma or alphafetoprotein >/= Upper limit of normal (ULN) at screening
- •History of clinically significant gastrointestinal, cardiovascular, endocrine, renal, ocular, pulmonary, psychiatric or neurological disease
- •History of organ transplantation
- •Previous or concurrent HBV treatments in the past 6 months
- •Significant acute infection (e.g., influenza, local infection) or any other clinically significant illness within 2 weeks of randomization
- •Part 3- Chronic Hepatitis B Participants Only:
- •History or other evidence of bleeding from esophageal varices
- •Evidence of liver cirrhosis or decompensated liver disease such as ascites, esophageal or gastric varices, splenomegaly, nodular liver, jaundice, or hepatic encephalopathy
- •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 statohepatitis, etc.)
- •History of thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests
- •Documented history or other evidence of metabolic liver disease within one year of screening
- •Positive test for hepatitis A (IgM anti-HAV), hepatitis C, hepatitis D, HEV, or HIV
- •Diagnosed or suspected hepatocellular carcinoma
- •History of clinically significant gastrointestinal, cardiovascular, endocrine, renal, ocular, pulmonary, psychiatric, or neurological disease
- •History of organ transplantation
- •Significant acute infection (e.g. influenza, local infection) or any other clinically significant illness within 2 weeks of screening
研究组 & 干预措施
Parts 1a and 1b: SAD in Healthy Volunteers (Placebo)
In Part 1a, participants will receive a single oral dose of placebo matching to RO7049389 film coated tablet on Day 1. In Part 1b, minimum 8 participants from Part 1a will be selected and 2 of whom will receive another single dose of placebo matching to RO7049389 on Day 16 after eating the standard United States - Food and Drug Administration (US FDA)-recommended high-fat and high-calorie breakfast.
干预措施: Placebo (Other)
Parts 1a and 1b: SAD in Healthy Volunteers (RO7049389)
In Part 1a, participants will receive a single oral dose of RO7049389 film coated tablet on Day 1 in dose-escalation cohorts with a starting dose of 150 milligrams (mg). The doses for subsequent cohorts will be defined by an adaptive approach based on the safety and PK data in previously-dosed healthy volunteers. In Part 1b, minimum 8 participants from Part 1a will be selected and 6 of whom will receive another single dose of RO7049389 on Day 16 after eating the standard US FDA-recommended high-fat and high-calorie breakfast.
干预措施: RO7049389 (Drug)
Part 1c: MAD in Healthy Volunteers (Placebo)
Participants will receive placebo matching to RO7049389 film coated tablet from Days 1 to 13 (either once a day [QD] or twice a day [BID]) and a single dose of placebo matching to RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 micrograms [mcg]) on Day -1 and Day 14.
干预措施: Midazolam (Drug)
Part 1c: MAD in Healthy Volunteers (Placebo)
Participants will receive placebo matching to RO7049389 film coated tablet from Days 1 to 13 (either once a day [QD] or twice a day [BID]) and a single dose of placebo matching to RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 micrograms [mcg]) on Day -1 and Day 14.
干预措施: Placebo (Other)
Part 1c: MAD in Healthy Volunteers (RO7049389)
Participants will receive RO7049389 film coated tablet from Days 1 to 13 (either QD or BID; dose and regimen will be decided based on the available PK and safety data) and a single dose of RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 mcg) on Day -1 and Day 14.
干预措施: Midazolam (Drug)
Part 1c: MAD in Healthy Volunteers (RO7049389)
Participants will receive RO7049389 film coated tablet from Days 1 to 13 (either QD or BID; dose and regimen will be decided based on the available PK and safety data) and a single dose of RO7049389 film coated tablet in the morning of Day 14. Participants will also receive a single dose of midazolam solution (100 mcg) on Day -1 and Day 14.
干预措施: RO7049389 (Drug)
Part 2: POM in Chronic HBV Participants (Placebo)
Participants will receive placebo matching to RO7049389 film coated tablet from Days 1 to 27 (either QD or BID) and a single dose of placebo matching to RO7049389 film coated tablet in the morning of Day 28.
干预措施: Placebo (Other)
Part 2: POM in Chronic HBV Participants (RO7049389)
Participants will receive RO7049389 film coated tablet from Days 1 to 27 (either QD or BID; dose and regimen will be decided based on the available PK and safety data) and a single dose of RO7049389 film coated tablet in the morning of Day 28.
干预措施: RO7049389 (Drug)
Part 3: POM in NUC-Suppressed CHB Participants (Cohort A)
Participants will receive RO7049389 on top of a NUC for 48 weeks at a dose determined from Part 2. NUC therapy will be administered per local label or guidelines.
干预措施: RO7049389 (Drug)
Part 3: POM in Treatment-Naive CHB Participants (Cohort B)
Participants will receive RO7049389 for 4 weeks, followed by RO7049389 with an added NUC for 44 weeks. RO7049389 will be administered at a dose determined from Part 2. NUC therapy will be administered per local label or guidelines.
干预措施: RO7049389 (Drug)
Part 3: POM in Treatment-Naive CHB Participants (Cohort C)
Participants will receive RO7049389 + NUC + Pegylated-Interferon (Peg-IFN) for 48 weeks. RO7049389 will be administered at a dose determined from Part 2. NUC and Peg-IFN therapy will be administered per local label or guidelines.
干预措施: RO7049389 (Drug)
结局指标
主要结局
Part 1: Percentage of Participants With Adverse Events
时间窗: Up to Day 29 (Part 1a), Day 44 (Part 1b), Day 42 (Part 1c)
Parts 1a and 1b: SAD Cohort: Time to Reach Maximum Concentration (Tmax) of RO7049389
时间窗: Up to 28 days
Parts 1a and 1b: SAD Cohort: Maximum Observed Plasma Concentration (Cmax) of RO7049389
时间窗: Up to 28 days
Parts 1a and 1b: SAD Cohort: AUC From Time Zero to Infinity (AUC0-inf) of RO7049389
时间窗: Up to 28 days
Parts 1a and 1b: SAD Cohort: Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of RO7049389
时间窗: Up to 28 days
Parts 1a and 1b: SAD Cohort: Half-life (T1/2) of RO7049389
时间窗: Up to Day 28
Parts 1a and 1b: SAD Cohort: Apparent Oral Clearance (CL/F) of RO7049389
时间窗: Up to Day 28
Parts 1a and 1b: SAD Cohort: Cumulative Amount Excreted Unchanged in Urine (Ae) of RO7049389
时间窗: Up to Day 28
Parts 1a and 1b: SAD Cohort: Renal Clearance (CLr) of RO7049389
时间窗: Up to Day 28
Part 2: Percentage of Participants With Adverse Events
时间窗: Up to Day 112
Part 2: Quantitative Plasma HBV DNA Level
时间窗: Baseline - Day 112
Part 3: Proportion of Patients Achieving Functional Cure
时间窗: Every 2-4 weeks from Baseline through Week 72
Functional cure is defined as HBV DNA \< lower limit of quantification (LLOQ, 20 IU/mL) with HBsAg loss (\< 0.05 IU/mL) at 24 weeks post-treatment.
次要结局
- Part 1c: CLr of RO7049389(Up to Day 14)
- Part 1b: Food Effect on Cmax of RO7049389(Day 16)
- Part 1b: Food Effect on AUCinf of RO7049389(Day 16)
- Part 1c: Cmax of Midazolam(Up to Day 14)
- Part 1c: AUCinf of Midazolam(Up to Day 14)
- Part 1c: Tmax of RO7049389(Up to Day 14)
- Part 1c: Cmax of RO7049389(Up to Day 14)
- Part 1c: AUC0-12hr of RO7049389(Up to Day 14)
- Part 1c: Accumulation Ratio of RO7049389(Day 1, Day 14)
- Part 1c: T1/2 of RO7049389(Up to Day 14)
- Part 1c: Ae of RO7049389(Up to Day 14)
- Part 1c: Ctrough of RO7049389(Up to Day 14)
- Part 2: HBV DNA < Lower Limit of Quantification (LLOQ)(Baseline - Day 112/Follow-up Day 84)
- Part 2: Tmax of RO7049389(Up to Day 28)
- Part 2: Cmax of RO7049389(Up to Day 28)
- Part 2: AUCtau of RO7049389(Up to Day 28)
- Part 2: Accumulation Ratio of RO7049389(Day 1, Day 28)
- Part 2: T1/2 of RO7049389(Up to Day 28)
- Part 2: Ctrough of RO7049389(Up to Day 28)
- Part 3: Percentage of Participants With AEs(72 weeks)
- Part 3: Hepatitis B Surface Antigen (HBsAg) Level(Baseline - Week 72)
- Part 3: Hepatitis B e-Antigen (HBeAg) Levels(Baseline - Week 72)
- Part 3: HBV RNA Level(Baseline - Week 72)
- Part 3: HBV Core-Related Antigen (HBcrAg) Levels(Baseline - Week 72)
- Part 3: Alanine Transaminase (ALT) Normalization in Participants With Baseline ALT Elevation(Week 12 - Week 72)
- Part 3: Percentage of Participants With Anti-Hepatitis B Core Antigen (HBc) Antibodies(Up to Week 72)
- Part 3: HBV DNA Level(Baseline - Week 72)
- Part 3: HBV DNA < Lower Limit of Quantification (LLOQ)(Baseline - Week 72)
- Part 3: Tmax of RO7049389(Day 1 - Week 48)
- Part 3: Cmax of RO7049389(Day 1 - Week 48)
- Part 3: AUCtau of RO7049389(Day 1 - Week 48)
- Part 3: T1/2 of RO7049389(Day 1 - Week 48)