A Phase 2b, Multicenter, Double-blind, Active-controlled, Randomized Study to Investigate the Efficacy and Safety of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 471
- 试验地点
- 108
- 主要终点
- Percentage of Participants Meeting the Nucleos(t)Ide Analog (NA) Treatment Completion Criteria at Week 48
研究概览
简要总结
The purpose of this study is to establish the dose-response relationship for antiviral activity of 3 dose levels of JNJ-73763989+nucleos(t)ide analog (NA) and to evaluate the efficacy of combination regimens of JNJ-73763989+NA (with and without JNJ-56136379) and of JNJ-56136379+NA.
详细描述
Hepatitis B virus (HBV) is a small deoxyribonucleic acid virus that specifically infects the human liver. The acute phase of infection is either followed by an immune controlled state or progresses to chronic hepatitis B. The worldwide estimated prevalence of chronic HBV infection is about 292 million people affected. Hepatitis B surface antigen (HBsAg) seroclearance is currently considered to be associated with the most thorough suppression of HBV replication (termed functional cure). With current available NA treatment strategies, rate of HBsAg seroclearance remains very low (around 3 percent [%]) even under long-term treatment. Also, with the persistently high global prevalence of HBV-associated mortality, there is a medical need for more effective finite treatment options that lead to sustained HBsAg seroclearance. JNJ-73763989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic HBV infection via ribonucleic acid interference mechanism. JNJ-56136379 is an orally administered capsid assembly modulator that is being developed for the treatment of chronic HBV infection. The aim of the study is to evaluate efficacy as measured by proportion of participants who completed 48-week study intervention and qualified for stopping NA treatment at Week 48. The study includes: Screening phase (4 weeks), Double-blind study intervention phase (from Day 1 up to Week 48), and Follow-up phase (48 weeks after end of investigational intervention with a maximum duration of 96 weeks). The duration of individual study participation will be between 100 and 150 weeks. Safety and tolerability (including adverse events [AEs] and Serious AEs, laboratory assessments, electrocardiogram [ECG], vital signs, physical examination), efficacy (including HBsAg seroclearance), and pharmacokinetics will be assessed 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
- Double (Participant, Investigator)
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 based on physical examination, medical history, vital signs, electrocardiogram (ECG) at screening
- •Chronic hepatitis B virus (HBV) infection with documentation at least 6 months prior to screening
- •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
- •Liver fibrosis stage 0-2 (Metavir) or Fibroscan less than (<) 9 Kilopascal (kPa) at 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 or any laboratory abnormalities indicating a reduced liver function as defined in the protocol
- •Evidence of liver disease of non-HBV etiology
- •Signs of hepatocellular carcinoma (HCC)
- •Significant laboratory abnormalities as defined in the protocol at screening
- •Participants with a history of malignancy within 5 years before screening
- •Abnormal sinus rhythm or ECG parameters at screening as defined in the protocol
- •History of or current cardiac arrhythmia or history or clinical evidence of significant or unstable cardiac disease
- •Participants with any current or previous illness for which, in the opinion of the investigator and/or sponsor, participation would not be in the best interest of the participant
- •History of or current clinically significant skin disease or drug rash
- •Participants with known allergies, hypersensitivity, or intolerance to JNJ-3989 and JNJ 6379 or their excipients or excipients of the placebo content
- •Contraindications to the use of entecavir (ETV), tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF) per local prescribing information
- •Participants who have taken any therapies disallowed per protocol
- •Female participants who are pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study intervention
- •Male participants who plan to father a child while enrolled
- •Participants who had or planned major surgery, (example, requiring general anesthesia) or who have received an organ transplant
- •Vulnerable participants (example, incarcerated individuals, individuals under a legal protection measure)
研究组 & 干预措施
Arm 1: JNJ-73763989 (medium dose) + JNJ-56136379 + NA
Participants will receive medium dose of JNJ-73763989 along with JNJ-56136379 and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil fumarate [TDF], or tenofovir alafenamide [TAF]) up to 48 weeks.
干预措施: JNJ-73763989 (Drug)
Arm 1: JNJ-73763989 (medium dose) + JNJ-56136379 + NA
Participants will receive medium dose of JNJ-73763989 along with JNJ-56136379 and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil fumarate [TDF], or tenofovir alafenamide [TAF]) up to 48 weeks.
干预措施: JNJ-56136379 (Drug)
Arm 1: JNJ-73763989 (medium dose) + JNJ-56136379 + NA
Participants will receive medium dose of JNJ-73763989 along with JNJ-56136379 and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil fumarate [TDF], or tenofovir alafenamide [TAF]) up to 48 weeks.
干预措施: Nucleos(t)ide Analog (NA) (Drug)
Arm 2: JNJ-73763989 (high dose) + Placebo + NA
Participants will receive high dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: JNJ-73763989 (Drug)
Arm 2: JNJ-73763989 (high dose) + Placebo + NA
Participants will receive high dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Placebo for JNJ-56136379 (Drug)
Arm 2: JNJ-73763989 (high dose) + Placebo + NA
Participants will receive high dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Nucleos(t)ide Analog (NA) (Drug)
Arm 3: JNJ-73763989 (medium dose) + Placebo + NA
Participants will receive medium dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: JNJ-73763989 (Drug)
Arm 3: JNJ-73763989 (medium dose) + Placebo + NA
Participants will receive medium dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Placebo for JNJ-56136379 (Drug)
Arm 3: JNJ-73763989 (medium dose) + Placebo + NA
Participants will receive medium dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Nucleos(t)ide Analog (NA) (Drug)
Arm 4: JNJ-73763989 (low dose) + Placebo + NA
Participants will receive low dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: JNJ-73763989 (Drug)
Arm 4: JNJ-73763989 (low dose) + Placebo + NA
Participants will receive low dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Placebo for JNJ-56136379 (Drug)
Arm 4: JNJ-73763989 (low dose) + Placebo + NA
Participants will receive low dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Nucleos(t)ide Analog (NA) (Drug)
Arm 5: Placebo + JNJ-56136379 + NA
Participants will receive placebo for JNJ-73763989 and a fixed dose of JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Placebo for JNJ-73763989 (Drug)
Arm 5: Placebo + JNJ-56136379 + NA
Participants will receive placebo for JNJ-73763989 and a fixed dose of JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: JNJ-56136379 (Drug)
Arm 5: Placebo + JNJ-56136379 + NA
Participants will receive placebo for JNJ-73763989 and a fixed dose of JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Nucleos(t)ide Analog (NA) (Drug)
Arm 6 (Control): Placebo + Placebo + NA
Participants will receive placebo for JNJ-73763989 and placebo for JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Placebo for JNJ-73763989 (Drug)
Arm 6 (Control): Placebo + Placebo + NA
Participants will receive placebo for JNJ-73763989 and placebo for JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Placebo for JNJ-56136379 (Drug)
Arm 6 (Control): Placebo + Placebo + NA
Participants will receive placebo for JNJ-73763989 and placebo for JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.
干预措施: Nucleos(t)ide Analog (NA) (Drug)
结局指标
主要结局
Percentage of Participants Meeting the Nucleos(t)Ide Analog (NA) Treatment Completion Criteria at Week 48
时间窗: Week 48
Percentage of participants meeting the NA treatment completion criteria at Week 48 were reported. A participant was defined as a responder in meeting the NA treatment completion criteria at Week 48, if the following criteria were met based on the clinical laboratory tests performed at Week 44: participants had alanine transaminase (ALT) less than (\<) 3\*upper limit of normal range (ULN); had hepatitis B virus deoxyribonucleic acid (HBV DNA) \< lower limit of quantification (LLOQ); was hepatitis B e antigen (HBeAg)-negative; had hepatitis B surface antigen (HBsAg) \<10 international units per milliliter (IU/mL). Multiple Imputation using a longitudinal multiple regression model was applied to impute missing data.
次要结局
- Follow-up Phase 1: Percentage of Participants With SAEs(From Week 48 up to Week 96)
- Time to Achieve HBsAg Seroclearance(Baseline (Day 1) up to Week 96)
- Time to Achieve HBeAg Seroclearance(Baseline (Day 1) up to Week 96)
- Percentage of Participants With HBsAg Levels <100 IU/mL(Baseline, Weeks 12, 24, 48, 60, 72, 96)
- Percentage of Participants With Undetectable HBV DNA Levels After Re-start of NA Treatment During Follow-up(Week 48 up to Week 96)
- Follow-up Phase 1: Percentage of Participants With TEAEs(From Week 48 up to Week 96)
- Extended Follow-up Phase: Percentage of Participants With TEAEs(Extended Follow up Week 1 to extended follow up Week 48)
- Double-blind Phase: Percentage of Participants With Serious Adverse Events (SAEs)(Baseline up to Week 48)
- Extended Follow-up Phase: Percentage of Participants With SAEs(Extended Follow up Week 1 to extended follow up Week 48)
- Double-blind Phase: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs)(Baseline up to Week 48)
- Percentage of Participants With HBsAg Seroclearance 48 Weeks After Completion of All Study Intervention at Week 48(Week 96)
- Follow-up Phase 2: Percentage of Participants With TEAEs(From Week 48 up to Week 96)
- Follow-up Phase 3: Percentage of Participants With TEAEs(From Week 48 up to Week 96)
- Percentage of Participants With Abnormalities in Clinical Laboratory Tests (Hematology)(Double blind (DB) phase: Baseline (Day 1) up to Week 48, Follow up (FU) phase: Week 48 up to Week 96)
- Percentage of Participants With Abnormalities in Vital Signs(Double blind (DB) phase: Baseline (Day 1) up to Week 48, Follow up (FU) phase: Week 48 up to Week 96)
- Change From Baseline in HBeAg Levels(Baseline, Weeks 12, 24, 48, 60, 72, 96)
- Follow-up Phase 2: Percentage of Participants With SAEs(From Week 48 up to Week 96)
- Follow-up Phase 3: Percentage of Participants With SAEs(From Week 48 up to Week 96)
- Percentage of Participants With Abnormalities in Electrocardiogram (ECG)(Double blind (DB) phase: Baseline (Day 1) up to Week 48, Follow up (FU) phase: Week 48 up to Week 96)
- Percentage of Participants With HBV DNA <LLOQ 24 and 48 Weeks After Completion of All Study Intervention at Week 48(Weeks 72 and 96)
- Percentage of Participants With HBsAg Seroclearance After Completion of NA Treatment at Weeks 60, 84, and 96(Weeks 60, 84, and 96)
- Percentage of Participants With Abnormalities in Clinical Laboratory Tests (Chemistry)(Double blind (DB) phase: Baseline up to Week 48, Follow up (FU) phase: Week 48 up to Week 96)
- Percentage of Participants With Abnormalities in Clinical Laboratory Tests (Urinalysis)(Double blind (DB) phase: Baseline up to Week 48, Follow up (FU) phase: Week 48 up to Week 96)
- Percentage of Participants With HBsAg Seroclearance 24 Weeks After Completion of All Study Intervention at Week 48(Week 72)
- Percentage of Participants With HBsAg Seroconversion(Weeks 48, 60, 72, and 96)
- Change From Baseline in HBV DNA Levels(Baseline, Weeks 12, 24, 48, 60, 72, 96)
- Percentage of Participants With HBV DNA Levels <LLOQ(Baseline, Weeks 12, 24, 48, 60, 72, 96)
- Change From Baseline in HBsAg Levels(Baseline, Weeks 12, 24, 48, 60, 72, 96)
- Percentage of Participants With ALT Normalization(Baseline, Weeks 12, 24, 48, 60, 72, 96)
- Percentage of Participants Meeting the NA Treatment Completion Criteria During Follow-up(Week 48 up to Week 96)
- Percentage of Participants Who Required NA Re-treatment During Follow-up(Week 48 up to Week 96)
- Percentage of Participants With Flares(Follow-up phase (Week 48 up to Week 96))
- Number of Participants With (Sustained) Reduction, Suppression, and/or Seroclearance Considering Single and Multiple Marker(Weeks 12, 24, 36 and 48)
- Percentage of Participants With HBeAg Seroconversion(Weeks 48, 60, 72, and 96)
- Percentage of Participants With HBsAg Levels >1 log10 IU/mL Reduction From Baseline(Weeks 12, 24, 48, 60, 72, 96)
- Percentage of HBeAg-positive Participants With HBeAg Levels <LLOQ(Weeks 12, 24, 48, 60, 72, 96)
- Percentage of HBeAg-positive Participants With HBeAg Levels >1 log10 IU/mL(Weeks 12, 24, 48, 60, 72, 96)
- Mean Change From Baseline in ALT at EOT (Week 48) in Participants With Elevated ALT at Baseline(Baseline and Week 48)
- Percentage of Participants With Virologic Breakthrough(Baseline (Day 1) up to Week 48)