A Phase 2 Randomized, Open-label, Parallel-group, Multicenter Study to Assess Intrahepatic and Peripheral Changes of Immunologic and Virologic Markers in Response to Combination Regimens Containing JNJ-73763989 and Nucleos(t)Ide Analog With or Without JNJ-56136379 in Patients With Chronic Hepatitis B Virus Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 10
- 主要终点
- Panel 1 and 2: Absolute Change From Baseline in the Percentage of Hepatitis B Surface Antigen (HBsAg) Hepatocytes at Week 40
研究概览
简要总结
The purpose of this study is to assess changes in intrahepatic hepatitis B surface antigen (HBsAg) between baseline and on-treatment liver biopsy in response to JNJ-3989-based combination treatment.
详细描述
The title of protocol reflects the original study design. The study design section is reflecting that the design as of protocol amendment 5 is non-randomized.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 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
- •Medically stable on the basis of physical examination, medical history, vital signs, and triplicate 12-lead electrocardiogram (ECG) performed at screening
- •Hepatitis B virus (HBV) infection with documentation at least 6 months prior to screening: participants be either currently not treated with HBeAg positive status or virologically (nucleos[t]ide analog [NA]) suppressed with HBeAg negative status
- •Hepatitis B surface antigen (HBsAg) greater than (>) 100 International Units per Milliliter (IU/mL) at screening
- •Body mass index (BMI) between 18.0 and 35.0 kilogram per meter square (kg/m^2), extremes included
- •Highly effective contraceptive measures in place for female participants of childbearing potential or male participants with female partners of childbearing potential
- •Fibroscan liver stiffness measurement less than and equal to (<=) 9 Kilopascal (kPa) within 6 months prior to screening or at the time of screening
排除标准
- •Evidence of infection with hepatitis A, C, D or E virus infection or evidence of human immunodeficiency, virus type 1 (HIV-1) or HIV-2 infection at screening
- •History or evidence of clinical signs/symptoms of hepatic decompensation including but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal varices
- •History or signs of cirrhosis or portal hypertension, signs of hepatocellular carcinoma (HCC) or clinically relevant renal abnormalities on an abdominal ultrasound performed within 6 months prior to screening or at the time of screening
- •Presence of coagulopathy or bleeding disorder as indicated by: (a) International normalized ratio (INR) greater than or equal to (>=) 1.1* upper limit of normal (ULN); (b) Partial thromboplastin time >1.1*ULN; (c) Any signs of prolonged bleeding (>10 minutes)
- •Presence of hemoglobinopathy (including sickle cell disease, thalassemia)
- •Liver biopsy performed prior to screening that led to complications and that in the opinion of the investigator would prohibit another liver biopsy
研究组 & 干预措施
Panel 1: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: JNJ-73763989 (Drug)
Panel 1: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: JNJ-56136379 (Drug)
Panel 1: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: Entecavir (ETV) (Drug)
Panel 1: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: Tenofovir disoproxil (Drug)
Panel 1: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: Tenofovir alafenamide (TAF) (Drug)
Panel 1: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: PegIFN-alpha-2a (Optional) (Drug)
Panel 2: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: JNJ-73763989 (Drug)
Panel 2: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: JNJ-56136379 (Drug)
Panel 2: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: Entecavir (ETV) (Drug)
Panel 2: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: Tenofovir disoproxil (Drug)
Panel 2: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: Tenofovir alafenamide (TAF) (Drug)
Panel 2: JNJ-73763989+ NA
Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
干预措施: PegIFN-alpha-2a (Optional) (Drug)
结局指标
主要结局
Panel 1 and 2: Absolute Change From Baseline in the Percentage of Hepatitis B Surface Antigen (HBsAg) Hepatocytes at Week 40
时间窗: Baseline, Week 40
Absolute change from baseline to on-treatment liver biopsy timepoint (Week 40) in terms of the percentage of HBsAg-positive hepatocytes (at Week 40) were reported.
Panel 3: Liver Concentrations of JNJ-73763989 (JNJ-73763976, JNJ-73763924 and JNJ-87719164 [M65; Deaminated Metabolite of JNJ-73763976]) at Week 12
时间窗: At Week 12 (at the time of liver biopsy: 24 hours post dose of JNJ-73763989)
Liver concentrations of JNJ-73763989 (JNJ-73763976, JNJ-73763924 - Molecules of JNJ-73763989 and JNJ-87719164 \[M65; deaminated metabolite of JNJ-73763976\]) at Week 12 were reported.
Panel 3: Liver Concentrations of JNJ-73763989 (JNJ-73763976, and JNJ-73763924 and JNJ-87719164 [M65; Deaminated Metabolite of JNJ-73763976]) at Week 40
时间窗: At Week 40 (at the time of liver biopsy: 24 hours post dose of JNJ-73763989)
Liver concentrations of JNJ-73763989 (JNJ-73763976, and JNJ-73763924 and JNJ-87719164 \[M65; deaminated metabolite of JNJ-73763976\]) at Week 40 were reported.
Panel 3: Plasma Concentration of JNJ-73763989 (JNJ-73763976, and JNJ-73763924) at Week 12
时间窗: At Week 12 (at the time of liver biopsy: 24 hours post dose of JNJ-73763989)
Plasma concentration of JNJ-73763989 (JNJ-73763976 and JNJ-73763924-molecules of JNJ-73763989) at Week 12 were reported.
Panel 3: Plasma Concentrations of JNJ-73763989 (JNJ-73763976 and JNJ-73763924) at Week 40
时间窗: At Week 40 (at the time of liver biopsy: 24 hours post dose of JNJ-73763989)
Plasma concentrations of JNJ-73763989 (JNJ-73763976 and JNJ-73763924-molecules of JNJ-73763989) at Week 40 were reported.
Panel 3: Correlation of Liver Concentration to Plasma Concentration of JNJ-73763989 (JNJ-73763976 and JNJ-73763924) and Liver Concentration of JNJ-87719164 (M65: Deaminated Metabolite of JNJ-73763976) to Liver Concentration JNJ-73763976 at Week 12
时间窗: Week 12 (at the time of liver biopsy: 24 hours post dose of JNJ-73763989)
Correlation of liver concentration to plasma concentration of JNJ-73763989 (JNJ-73763976 and JNJ-73763924) and liver concentration of JNJ-87719164 (M65: Deaminated metabolite of JNJ-73763976) to liver concentration JNJ-73763976 at Week 12 were reported.
Panel 3: Correlation of Liver to Plasma Concentration of JNJ-73763989 (JNJ-73763976 and JNJ-73763924) and Liver Concentration of JNJ-87719164 (M65: Deaminated Metabolite of JNJ-73763976) to Liver Concentration JNJ-73763976 at Week 40
时间窗: Week 40 (at the time of liver biopsy: 24 hours post dose of JNJ-73763989)
Correlation of liver concentration to plasma concentration of JNJ-73763989 (JNJ-73763976 and JNJ-73763924) and liver concentration of JNJ-87719164 (M65: Deaminated metabolite of JNJ-73763976) to liver concentration JNJ-73763976 at Week 40 were reported.
次要结局
- Panel 1, 2 and 3: Percentage of Participants With Sustained (Reduction) Serum HBsAg Response Per Definition 3 at Follow-up Week 48(From follow-up Week 24 up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Sustained (Reduction) Serum HBsAg Response Per Definition 4 at Follow-up Week 48(Follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants Who Achieved HBsAg Seroconversion(From baseline (Day 1) up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants Who Achieved HBeAg Seroconversion(From baseline (Day 1) up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Off-treatment Virologic Flares Per Derivation 1(From baseline (Day 1) up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Off-treatment and On-treatment Biochemical Flares(From baseline (Day 1) up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Off-treatment Clinical Flares(From baseline (Day 1) up to follow-up Week 48)
- Panel 1, 2 and 3: Time to First Occurence of HBsAg Seroclearance(From baseline (Day 1) up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Virologic Breakthrough(From baseline (Day 1) up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)(Open-label: Day 1 (Week 1) up to Week 48; Follow-up Phase: Follow-up Week 1 up to follow-up Week 48)
- Panel 1, 2 and 3: Number of Participants With HBV-Specific Peripheral Blood T-cell Responses(Open-label: Weeks 40, 44, and 48; Follow-up Phase: Follow-up Weeks 2, 12 and 24)
- Panel 1, 2 and 3: Percentage of Participants With Worst (Grade 3 and 4) Treatment-emergent Division of Acquired Immunodeficiency Syndrome (DAIDS) Toxicity Grade in Clinical Laboratory Tests(Open-label: Day 1 (Week 1) up to Week 48; Follow-up Phase: Follow-up Week 1 up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Worst (Abnormally Low/High)Treatment-emergent DAIDS Toxicity Grade in Electrocardiogram (ECG)(Open-label: Day 1 (Week 1) up to Week 48; Follow-up Phase: Follow-up Week 1 up to follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants With Worst (Abnormally Low/High) Treatment-emergent DAIDS Toxicity Grade in Vital Signs(Open-label: Day 1 (Week 1) up to Week 48; Follow-up Phase: Follow-up Week 1 up to follow-up Week 48)
- Panel 1, 2 and 3: Number of Participants With Clinically Significant Treatment-emergent Abnormalities in Physical Examination(Open-label: Day 1 (Week 1) up to Week 48; Follow-up Phase: Follow-up Week 1 up to follow-up Week 48)
- Panel 2 and 3: Plasma Trough Concentration (C[0hour]) of JNJ-73763989 (JNJ-73763976, JNJ-73763924)(Week 4 : Pre-dose on Day 29)
- Panel 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-73763989 (JNJ-73763976, JNJ-73763924)(Week 4 (Day 29): Pre-dose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose)
- Panel 3: Maximum Observed Plasma Concentration (Cmax) of JNJ-73763989 (JNJ-73763976, JNJ-73763924)(Week 4 (Day 29): Pre-dose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose)
- Panel 2 and 3: Minimum Observed Plasma Concentration (Cmin) of JNJ-73763989 (JNJ-73763976, JNJ-73763924)(Week 4 (Day 29): Pre-dose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose)
- Panel 2: Time to Reach the Maximum Observed Plasma Concentration (Tmax) of JNJ-73763989 (JNJ-73763976,JNJ-73763924)(Week 4 (Day 29): Post dose (15 minutes, 30 minutes, 1, 2, 3, 4, 6, and 24 hours))
- Panel 3:Time to Reach the Maximum Observed Plasma Concentration (Tmax) of JNJ-73763989 (JNJ-73763976, JNJ-73763924)(Week 4 (Day 29): Post dose (15 minutes, 30 minutes, 1, 2, 3, 4, 6, and 24 hours))
- Panel 2: Area Under the Plasma Concentration-time Curve From Time Zero to 24hours (AUC0 to 24h) of JNJ-73763989 (JNJ-73763976, JNJ-73763924)(Week 4 (Day 29): Pre-dose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose)
- Panel 3: Area Under the Plasma Concentration-time Curve From Time Zero to 24hours (AUC0 to 24h) of JNJ-73763989 (JNJ-73763976, JNJ-73763924)(Week 4 (Day 29): Pre-dose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 24 hours post dose)
- Panel 1, 2 and 3: Percentage of Participants With Sustained (Reduction) Serum HBsAg Response Per Definition 2 at Follow-up Week 48(Follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants Who Achieved HBsAg Seroclearance(Follow-up Week 48)
- Panel 1, 2 and 3: Percentage of Participants Who Achieved HBeAg Seroclearance(Follow-up Week 48)
- Panel 1 and 2: Change From Baseline in Percentage of Intrahepatic Viral Parameter: Hepatitis B Core Antigen Positive (HBcAg+) Hepatocytes at Week 40(Baseline, Week 40)
- Panel 1,and 2: Change From Baseline in Percentage of Intrahepatic Viral Parameter: Covalently Closed Circular Deoxyribonucleic Acid Positive (cccDNA+) Hepatocytes at Week 40(Baseline, Week 40)
- Panel 1 and 2: Change From Baseline in Percentage of Intrahepatic Viral Parameter: HBsAg Positive (HBsAg+) Hepatocytes at Week 40(Baseline, Week 40)
- Panel 1 and 2: Change From Baseline in Percentage of Intrahepatic Viral Parameter: Pre-genomic Ribonucleic Acid Positive (pgRNA+) Hepatocytes at Week 40(Baseline, Week 40)
- Panel 1 and 2: Change From Baseline in Transcriptional Activity (Ratio of pg RNA/cccDNA) at Week 40(Baseline, Week 40)
- Panel 1, 2: Change From Baseline in Percentage of Intrahepatic Viral Parameter: Silent Infected Hepatocytes at Week 40(Baseline, Week 40)
- Panel 1, 2 and 3: Percentage of Participants With HBsAg Seroclearance at Week 72 Without Restarting Nucleos(t)Ide Analog (NA) Treatment(At Week 72 (24 weeks after completion of all study drugs at Week 48))
- Panel 1, 2 and 3: Percentage of Participants With Sustained (Reduction) Serum HBsAg Response Per Definition 1 at Follow-up Week 48(Follow-up Week 48)