A Phase 2b, Multi-centre, Randomized, Partially Placebo-controlled, Double-blind Study to Investigate the Safety and Efficacy of Sequential Therapy With Daplusiran/Tomligisiran Followed by Bepirovirsen in Participants With Chronic Hepatitis B Virus on Background Nucleos(t)Ide Analogue Therapy (B-United)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 283
- 试验地点
- 81
- 主要终点
- Number of participants achieving functional cure
研究概览
简要总结
The study is intended to evaluate the efficacy and safety of 2 different doses of DAP/TOM followed by bepirovirsen in participants living with CHB on standard of care nucleos(t)ide analogue (NA) therapy. The study also aims to identify an optimal dose of DAP/TOM for sequenced therapy with bepirovirsen for further clinical development and to assess the contribution of DAP/TOM to the sequential regimen. The study will also include an optional long-term follow-up (LTFU) extension stage for eligible participants.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: At least 18 years of age at the time of signing the informed consent
- •Documented chronic HBV infection greater than or equal to (>=) 6 months prior to Screening AND currently receiving stable NA therapy defined as receiving an NA regimen form at least 6 months prior to Screening and with no planned changes to their stable regimen over the duration of the study.
- •Plasma or serum HBsAg concentration greater than (>) 100 international units per milliliter (IU/mL)
- •Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA less than (<) 90 IU/mL
- •Alanine aminotransferase less than or equal to (<=) 2* upper limit of normal (ULN)
- •Participants who are willing and able to cease their NA treatment in accordance with the protocol.
- •Male and Female
排除标准
- •Clinically significant abnormalities, aside from chronic HBV infection in medical history (e.g., moderate-severe liver disease other than chronic HBV, acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening, significant/unstable cardiac disease, uncontrolled diabetes, bleeding diathesis coagulopathy) or clinically significant physical examination findings.
- •Coinfection with Hepatitis C (cured <12 months at the time of screening), Human immunodeficiency virus or hepatitis D virus
- •History of or suspected liver cirrhosis and/or evidence of cirrhosis.
- •Diagnosed or suspected hepatocellular carcinoma.
- •History of malignancy within the past 5 years with the exception of specific cancers that are cured by surgical resection (example, skin cancer). Participants under evaluation for possible malignancy are not eligible.
- •History of vasculitis or presence of symptoms and signs of potential vasculitis (e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause), current or history of an autoimmune condition or history/presence of other diseases that may be associated with vasculitis condition (example, systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex).
- •History of extrahepatic disorders possibly related to HBV immune conditions (example, nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).
- •History of alcohol or drug abuse/dependence:
- •Currently taking, or took within 3 months of screening, any immunosuppressing drugs (example, prednisone), other than a short course of therapy (<=2 weeks) or topical/inhaled steroid use.
- •Participants, to whom immunosuppressive treatment (including therapeutic doses of steroids) is contraindicated, should not be considered for enrollment in the study.
- •Currently taking, or has taken within 6 months of Screening, any interferon-containing therapy.
- •Participants requiring anti-coagulation therapies (example, warfarin, Factor Xa inhibitors) or anti-platelet agents (like clopidogrel or aspirin) unless treatment can safely be discontinued throughout duration of Investigational medicinal product (IMP) treatment, by the discretion of the investigator. Occasional use is permitted.
- •Prior hepatitis B treatment with bepirovirsen, DAP/TOM, or another oligonucleotide or small interfering RNA (siRNA).
- •Prior non-hepatitis B treatment with an oligonucleotide or siRNA within 12 months prior to the first dosing day.
- •Fridericia's QT correction formula (QTcF) >=450 millisecond (msec) (if single electrocardiogram [ECG] at screening shows QTcF >=450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).
- •History of/sensitivity to bepirovirsen, DAP/TOM or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
- •Participants who do not wish to discontinue taking NA therapy for their chronic HBV infection.
研究组 & 干预措施
Treatment Arm 1A: DAP/TOM + Bepirovirsen
Participants with high Hepatitis B surface antigen (HBsAg) level will receive dose level 1 of DAP/TOM in Treatment Stage 1. After DAP/TOM Treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Bepirovirsen (Drug)
Treatment Arm 1A: DAP/TOM + Bepirovirsen
Participants with high Hepatitis B surface antigen (HBsAg) level will receive dose level 1 of DAP/TOM in Treatment Stage 1. After DAP/TOM Treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Daplusiran/Tomligisiran Dose Level 1 (Drug)
Treatment Arm 1B: DAP/TOM + Bepirovirsen
Participants with high HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Bepirovirsen (Drug)
Treatment Arm 2A: DAP/TOM + Bepirovirsen
Participants with low HBsAg level will receive dose level 1 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Bepirovirsen (Drug)
Treatment Arm 2B: DAP/TOM + Bepirovirsen
Participants with low HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Bepirovirsen (Drug)
Treatment Arm 2C: Placebo + Bepirovirsen
Participants with low HBsAg level will receive Placebo in Treatment Stage 1. After Placebo treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Bepirovirsen (Drug)
Treatment Arm 2C: Placebo + Bepirovirsen
Participants with low HBsAg level will receive Placebo in Treatment Stage 1. After Placebo treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Placebo (Drug)
Treatment Arm 1B: DAP/TOM + Bepirovirsen
Participants with high HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Daplusiran/Tomligisiran Dose Level 2 (Drug)
Treatment Arm 2A: DAP/TOM + Bepirovirsen
Participants with low HBsAg level will receive dose level 1 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Daplusiran/Tomligisiran Dose Level 1 (Drug)
Treatment Arm 2B: DAP/TOM + Bepirovirsen
Participants with low HBsAg level will receive dose level 2 of DAP/TOM in Treatment Stage 1. After DAP/TOM treatment, eligible participants will receive bepirovirsen in Treatment Stage 2. All participants will continue background NA treatment throughout these treatment stages. After bepirovirsen Treatment Stage, participants will be observed during the NA Only Stage, while maintaining background NA treatment. Eligible participants will then discontinue background NA treatment.
干预措施: Daplusiran/Tomligisiran Dose Level 2 (Drug)
结局指标
主要结局
Number of participants achieving functional cure
时间窗: Up to 100 Weeks
The functional cure for HBV is defined as sustained suppression (24 weeks or longer) of HBV deoxyribonucleic acid (DNA) \<lower limit of quantification (LLOQ) and HBsAg not detected with or without HBsAb after a finite duration of therapy and off all HBV treatment. The number of participants achieving functional cure after discontinuation of all chronic HBV treatments (DAP/TOM, bepirovirsen, and NA treatment) will be reported.
次要结局
- Number of participants with undetected HBsAg and HBV DNA <LLOQ(Up to 48 Weeks)
- Number of participants achieving functional cure with high Baseline HBsAg level(Up to 100 Weeks)
- Number of participants achieving functional cure with low Baseline HBsAg level(Up to 100 Weeks)
- Number of participants achieving functional cure with low Baseline HBsAg level compared against placebo + bepirovirsen arm(Up to 100 Weeks)