A Phase II, Randomised, Adaptive, Open-Label Platform Trial To Evaluate Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 281
- 试验地点
- 33
- 主要终点
- Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT)
研究概览
简要总结
This is a study designed to evaluate the safety, tolerability and efficacy of New Molecular Entity (NME) combination therapies in Chronic Hepatitis B (CHB) participants with preserved liver function and without significant fibrosis/cirrhosis. The platform design allows comparison of multiple NME combination therapies against a common control, and introduction of additional treatment arms at later study time points. Each arm will consist of a screening phase (up to 8 weeks), treatment phase (up to 48 weeks) and post-treatment follow-up phase (48 weeks). The safety and efficacy will be monitored throughout the study.
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
- None
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
- 否
入选标准
- •Body mass index between 18 and 32 kg/m2 inclusive.
- •Participants with Chronic Hepatitis B (CHB) infection (HBsAg positive for >=6 months) who are on established NUC (entecavir or tenofovir alafenamide/disoproxil fumarate) monotherapy for >=12 months, having received the same NUC therapy for >=3 months prior to screening.
- •HBV DNA below the lower LLOQ or < 20 IU/mL for > 6 months prior to screening and confirmed at screening.
- •Alanine transaminase (ALT) <=1.5 x upper limit of normal (ULN) for > 6 months prior to screening and confirmed at screening.
- •Female Participants: Eligible to participate if she is not pregnant, not breastfeeding and agrees to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods.
- •Male Participants: During the treatment period and for at least 6 months after the final dose of study treatment, agrees to remain abstinent (refrain from heterosexual intercourse), use contraceptive measures and refrain from donating sperm.
排除标准
- •Pregnant or lactating women.
- •Co-infection with other pathogens such as Hepatitis A, C, D and E or Human Immunodeficiency Virus (HIV).
- •History of cirrhosis or current evidence of significant liver fibrosis or cirrhosis or decompensated liver disease.
- •History of or suspicion of Hepatocellular Carcinoma (HCC).
- •Thyroid disease poorly controlled on prescribed medications or clinically relevant abnormal thyroid function tests.
- •Clinically significant disease other than CHB that, in the opinion of the Investigator, makes the participant unsuitable for the study.
- •Pre-existing cardiac disease that in the opinion of the investigator would increase the risk for the participant to take part in the study.
- •History of alcohol abuse and/or drug abuse within one year of randomization.
- •History of having received (in the last 6 months) or currently receiving any systemic antineoplastic (including radiation) or immunosuppressive (including biologic immunosuppressors) or immune modulating treatment.
- •Currently taking, or have received within 3 months of Day 1, systemic corticosteroids.
- •Electrocardiogram (ECG) with clinically significant abnormalities.
- •Previous treatment with an investigational agent for Hepatitis B (HBV) within 6 months prior to screening.
研究组 & 干预措施
Nucleos(t)ide (NUC) Control Arm
Participants will continue their background NUC therapy for the 48-week treatment period. At the end of the treatment period, in line with current CHB treatment guidelines, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC
Participants will receive RO7049389 (600 mg once daily [QD]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day [QOD]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC
Participants will receive RO7049389 (600 mg once daily [QD]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day [QOD]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: CpAM (RO7049389) (Drug)
Core Protein Allosteric Modulator (CpAM; RO7049389) + Toll-like Receptor 7 (TLR7;RO7020531) + NUC
Participants will receive RO7049389 (600 mg once daily [QD]) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg once every other day [QOD]) will be administered during Weeks 1-12 and Weeks 25-36. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: TLR7 (RO7020531) (Drug)
Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC
Participants will receive RO7445482 (Dose 1) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
Short Interfering Ribonucleic acid (siRNA; RO7445482) (Dose1) + NUC
Participants will receive RO7445482 (Dose 1) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: siRNA (RO7445482) (Drug)
siRNA (RO7445482) (Dose 2) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
siRNA (RO7445482) (Dose 2) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: siRNA (RO7445482) (Drug)
siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: siRNA (RO7445482) (Drug)
siRNA (RO7445482) + Pegylated Interferon (PEG-IFN) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. PEG-IFN will be administered at a dose of 180 μg once weekly (QW) for 48 weeks. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: PEG-IFN (Drug)
siRNA (RO7445482) + CpAM (RO7049389) + NUC
Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
siRNA (RO7445482) + CpAM (RO7049389) + NUC
Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: CpAM (RO7049389) (Drug)
siRNA (RO7445482) + CpAM (RO7049389) + NUC
Participants will receive RO7445482 (Dose 2) and RO7049389 (600 mg QD) in addition to their background NUC therapy for the 48-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: siRNA (RO7445482) (Drug)
siRNA (RO7445482) + TLR7 (RO7020531) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
siRNA (RO7445482) + TLR7 (RO7020531) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: TLR7 (RO7020531) (Drug)
siRNA (RO7445482) + TLR7 (RO7020531) + NUC
Participants will receive RO7445482 (Dose 2) in addition to their background NUC therapy for the 48-week treatment period. RO7020531 (150 mg QOD) will be administered during Weeks 13-24 and Weeks 37-48 (i.e., 2 treatment cycles of 12 weeks' duration each and 42 doses of RO7020531 for each cycle). At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: siRNA (RO7445482) (Drug)
siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]
Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]
Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: siRNA (RO7445482) (Drug)
siRNA(RO7445482)+ Programmed Death Ligand-1 Locked Nucleic Acid (PD-L1 LNA; RO7191863) + NUC [1]
Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 13-24, in addition to their background NUC therapy for the 24-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: PD-L1 LNA (RO7191863) (Drug)
siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]
Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: Nucleos(t)ide (NUC) (Drug)
siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]
Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: siRNA (RO7445482) (Drug)
siRNA (RO7445482) + PD-L1 LNA (RO7191863) + NUC [2]
Participants will receive RO7445482 (Dose 2) during Weeks 1-24 and RO7191863 (Dose 1) will be administered during Weeks 25-36, in addition to their background NUC therapy for the 36-week treatment period. At the end of the treatment period, participants will continue NUC treatment during the follow-up unless the NUC discontinuation criteria have been met.
干预措施: PD-L1 LNA (RO7191863) (Drug)
结局指标
主要结局
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at 24 Weeks Post-End of Treatment (EOT)
时间窗: Follow-up Week (FUW) 24
HBsAg loss was defined as quantitative HBsAg \<0.05 international units/milliliters (IU/mL). The percentage of participants with HBsAg loss was calculated as number of participants with HBsAg loss / total number of participants \*100. 95% confidence interval (CI) was calculated using the Clopper-Pearson method. Percentages have been rounded off.
次要结局
- Percentage of Participants With HBsAg Loss(Combos 1 and 5: Weeks 24, 36, 48 and FUW 48; Combos 2, 3, 4, 6 and NUC Arm: Week 48 and FUW 48; Combo 7: Week 24; Combo 8: Week 36)
- Percentage of Participants With HBsAg Seroconversion(Combos 1 and 5: Weeks 24, 36, 48, FUW 24 and FUW 48; Combos 2, 3, 4, 6 and NUC Arm: Week 48, FUW 24 and FUW 48; Combo 7: Week 24 and FUW 24; Combo 8: Week 36 and FUW 24)
- Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss in Baseline HBeAg-positive Participants(Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48)
- Percentage of Participants With HBeAg Seroconversion in Baseline HBeAg-positive Participants(Weeks 12, 24, 36, and 48; FUW 12, 24, 36, and 48)
- Number of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantification (LLOQ), <200 IU/mL, and <2,000 IU/mL(FUW 12, 24, 36, and 48)
- Change From Baseline in HBsAg, Anti-HBs, HBeAg, HBV Ribonucleic Acid (RNA) and HBV DNA Levels Over Time(HBsAg, Anti-HBs, HBeAg & HBV RNA: Combo 1 to 6 and NUC arm: Weeks 24, 36, 48, FUW 24 and FUW 48; Combo 7: Week 24, FUW 24 & FUW 48; Combo 8: Weeks 24, 36, FUW 24 & FUW 48; HBV DNA: FUW 24 and FUW 48)
- Combos 7 and 8: Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Week 1 (AUC1-0-168h) of PD-L1 LNA(Predose on Day 1 and up to 168 hours post dose (Week 1))
- Combos 7 and 8: Maximum Plasma Concentration (Cmax) at Week 1 (Cmax1-0-168h) of PD-L1 LNA(Predose on Day 1 and up to 168 hours post dose (Week 1))
- Combos 7 and 8: AUC Over the Dosing Interval at Week 12 (AUC12-0-168h) of PD-L1 LNA(Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12))
- Combos 7 and 8: Cmax at Week 12 (Cmax12-0-168h) of PD-L1 LNA(Predose on Day 1 of Week 12 up to 168 hours post dose (Week 12))
- Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve (AUC) Over Days 1-28 of siRNA(Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28)
- Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 29-56 of siRNA(From Day 29 up to Day 56)
- Combos 2, 3, 4, 6, 7 and 8: Cmax Over Days 1-28 of siRNA(Predose on Day 1 and 1-3 and 4-6 hours post dose each day, up to Day 28)
- Combos 2, 3, 4, 6, 7 and 8: Area Under the Plasma Concentration Time Curve During the Dosing Interval (AUC Tau) Over Days 29-56 of siRNA(From Day 29 up to Day 56)
- Combos 1 and 6: AUC of TLR7(Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36)
- Combos 1 and 6: Cmax of TLR7(Predose and 1-3 and 4-6 hours post-dose on Days 1, 3, 5 on Weeks 12 and 36)
- Number of Participants With Adverse Events (AEs)(From Day 1 up to end of 48 weeks of follow up (up to approximately 1.8 years))
- Combos 2, 3, 4, 5, 6, 7 and 8: Number of Participants With Anti-siRNA Antibodies(From Day 1 up to end of follow up (up to approximately 4 years))
- Combos 7 and 8: Number of Participants With Anti-PD-L1 Antibodies(From Day 1 for Combo 7 and 8 up to end of follow up (Up to approximately 2 years))