A Randomized, Placebo-controlled,Observer-blinded Study, to Evaluate Safety,Tolerability, Pharmacokinetics and Pharmacodynamics of RO7239958 in Healthy Volunteers and Patients With Chronic Hepatitis B Virus Infection
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 55
- 试验地点
- 14
- 主要终点
- Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings
研究概览
简要总结
This study is designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending doses in healthy volunteers (HV) and participants diagnosed with chronic hepatitis B (CHB).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Female participants should be of non-childbearing potential and male participants who are with pregnant partners or partners of childbearing potential must agree to remain abstinent or use contraceptive measures
- •Part 1 (SAD HV only)
- •Healthy, as judged by the Investigator
- •Non-smoker (nor tobacco containing products) for at least 90 days prior to dosing on Day 1, and agrees to remain non-smoker during the study
- •Part 2 (CHB only)
- •Positive serum HBsAg status for > 6 months prior to screening
- •Serum HBsAg level ≥ 250 IU/mL at screening
- •On stable entecavir or tenofovir (alone or in combination) treatment and having received the same drug in the 3 months prior to randomisation
- •HBV DNA below the lower limit of quantification (LLQ) for ≥ 6 months prior to screening by local testing, and confirmed at screening
- •Screening laboratory values (including hematology, chemistry, urinalysis) within normal ranges
- •No past or current diagnosis of cirrhosis
排除标准
- •History or presence of significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological disorders, or diagnosed central or peripheral neurological disease, capable of altering the absorption, metabolism, or elimination of drugs, or constituting a risk when taking the study treatment, or of interfering with the interpretation of the data
- •History of lymphoma, leukemia, or malignancy within the past five years
- •Positive for human immunodeficiency virus (HIV) infection
- •Participant under judicial supervision, guardianship or curatorship
- •Part 1 (SAD HV only)
- •Screening ECG showing clinically relevant abnormalities
- •Abnormal blood pressure
- •History or presence of liver disease, or known hepatic or biliary abnormalities
- •Alanine aminotransferase (ALT) ≥1.5 × upper limit of normal (ULN)
- •Any clinically significant out of range findings in other laboratory test results or any other clinically significant (as judged by the Investigator) abnormalities in the physical examination at screening and on Day -1
- •Positive for hepatitis B surface antigen (HBsAg), or hepatitis B core total antibody [anti-HBc]), or hepatitis C virus (HCV) antibody test result
- •Part 2 (CHB only)
- •History or presence of bridging fibrosis or cirrhosis or decompensated liver disease
- •History or presence of a medical condition associated with liver disease other than HBV infection. Other known hepatic or biliary abnormalities
- •History of or suspicion of hepatocellular carcinoma or alpha fetoprotein (AFP) ≥13 ng/mL
- •History of having received (in the last six months) or currently receiving any systemic antineoplastic (including radiation) or immune-modulatory treatment (including systemic corticosteroids)
- •History of organ transplantation
- •Estimated glomerular filtration rate (eGFR) <70 mL/min/1.73m^2
- •Confirmed QT interval corrected using Fridericia's formula (QTcF) >450 ms
- •Expected to need any other systemic antiviral therapy at any time during participation in the study
- •Positive hepatitis C antibody test
研究组 & 干预措施
Part 1: Single Ascending Dose, HV
Healthy volunteers will be administered a single dose of RO7239958 or placebo subcutaneously (SC).
干预措施: RO7239958 (Drug)
Part 1: Single Ascending Dose, HV
Healthy volunteers will be administered a single dose of RO7239958 or placebo subcutaneously (SC).
干预措施: Placebo (Other)
Part 2a: Multi-dose, CHB
Participants with chronic hepatitis B will be administered different dose levels of RO7239958 or placebo SC. Dosages will be determined from data collected from Part 1.
干预措施: RO7239958 (Drug)
Part 2a: Multi-dose, CHB
Participants with chronic hepatitis B will be administered different dose levels of RO7239958 or placebo SC. Dosages will be determined from data collected from Part 1.
干预措施: Placebo (Other)
Part 2b: Multi-dose, CHB (Optional)
Additional study arm to open based on data collected from Part 2a. Participants with chronic hepatitis B will be administered different doses and frequencies of RO7239958 or placebo SC.
干预措施: RO7239958 (Drug)
Part 2b: Multi-dose, CHB (Optional)
Additional study arm to open based on data collected from Part 2a. Participants with chronic hepatitis B will be administered different doses and frequencies of RO7239958 or placebo SC.
干预措施: Placebo (Other)
结局指标
主要结局
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Findings
时间窗: Up to approximately 16 months
Number of Participants With Clinically Significant Changes in Vital Signs
时间窗: Up to approximately 16 months
Number of participants with clinically significant abnormalities in vital signs such as systolic and diastolic blood pressure, heart rate, body temperature were evaluated.
Number of Participants With Adverse Events (AEs)
时间窗: Up to approximately 16 months
An adverse event (AE) was defined as any untoward medical occurrence in a participant who was administered a pharmaceutical product (including investigational drug) during the course of a clinical investigation. An AE could therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease that was temporally associated with the use of the investigational product, regardless of whether it was considered to be related to the investigational product or not.
Number of Participants With Clinically Significant Changes in Clinical Laboratory Results
时间窗: Up to approximately 16 months
Number of participants with clinically significant abnormalities in clinical laboratory parameters such as serum chemistry, hematology, coagulation, viral serology, urinalysis were evaluated.
Number of Participants With Injection Site Reactions (ISRs)
时间窗: Up to approximately 16 months
Injection site reactions (ISRs) referred to any localized sign or symptom, including pain, erythema, swelling and pruritus and were graded as follows: Grade 1: mild, Grade 2: moderate; Grade 3: severe. Adverse events related to ISRs were reported.
次要结局
- Cumulative Amount of Drug Excreted in Urine (Ae)(Part 1: 0-4 h, 0-8 h, 0-12 h and 0-24 h on Day 1; Part 2a: 0-4 h and 0-8 h on Days 1 and 29)
- Part 2a: Number of Participants With HBsAg Loss(Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks))
- Part 2a: Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) Below the Assay Lower Limit of Quantification(Part 2a: Day 1 (pre-dose), 15, 29 (pre-dose); at discontinuation (DC), rebound and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks))
- Time to Cmax (Tmax) of RO7239958(Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.)
- Area Under the Curve From Time 0 to the Last Measurable Concentration (AUClast) of RO7239958(Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.)
- Part 2a: Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels(Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks))
- Part 2a: Change From Baseline in Hepatitis B Surface Antibody (Anti-HBs) Levels(Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks))
- Part 2a: Number of Participants With Hepatitis B e Antibody (Anti-HBe) Seroconversion in HBeAg-positive Participants(Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks))
- Maximum Plasma Concentration (Cmax) of RO7239958(Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.)
- Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of RO7239958(Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.)
- Half-life (t1/2) of RO7239958(Part 1: pre-dose on Day 1 and post-dose at 15 minutes (min), 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, 72, 96, 120, 168 hours. Part 2a: pre-dose on Days 1 and 29 and post-dose at 30 min, 1, 2, 4, 6, 8, 24 hours.)
- Part 2a: Number of Participants With Hepatitis B Envelope Antigen (HBeAg) Loss in HBeAg-positive Participants(Part 2a: Days 1 (pre-dose), 8, 15, 22, 29 (pre-dose); at discontinuation (DC) and at follow-up visits 14, 28, 56, and 84 days after the last dose of study drug (up to 16 weeks))