A Phase 2, Open-label, Multicenter Study to Assess Efficacy, Safety, Tolerability, and Pharmacokinetics of Treatment With JNJ-73763989, Nucleos(t)Ide Analogs, and Pegylated Interferon Alpha-2a in Patients With Chronic Hepatitis B Virus Infection
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 12
- 主要终点
- Percentage of Participants With a Reduction of at Least 2log10 International Units Per Milliliter (IU/mL) in Hepatitis B Surface Antigen (HBsAg) Levels From Baseline at Week 24 (End of Study Intervention [EOSI])
研究概览
简要总结
The purpose of this study is to evaluate the efficacy in terms of hepatitis B surface antigen (HBsAg) changes from baseline for the treatment regimens of 24 weeks of JNJ-73763989 + 24 weeks of nucleos(t)ide analog (NA) + 12 or 24 weeks of pegylated interferon alpha-2a (PegIFN-alpha-2a) (with immediate or delayed start of PegIFN-alpha-2a treatment).
详细描述
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic hepatitis B virus (HBV) infection via a ribonucleic acid interference (RNAi) mechanism. Combination treatment with JNJ-73763989 and NA has the potential to specifically decrease HBV viral antigen levels and inhibit viral replication. Since HBsAg is immune suppressive, the direct reduction of HBsAg levels by JNJ-73763989 is anticipated to contribute to the restoration of the immune response that is impaired in chronic HBV infection. Pegylated interferon (PegIFN) is an approved drug for the treatment of chronic HBV infection and after a finite treatment duration of 48 weeks results in slightly increased HBsAg seroclearance rates. The primary hypothesis of this study is that at least one of the combination regimens of JNJ-73763989+NA+PegIFN-alpha-2a is more efficacious than NA treatment alone (standard of care), as measured by the primary efficacy endpoint. This study will be conducted in 3 periods: Screening Period (4 weeks), Treatment Period (24 weeks) and Follow-up (FU) Period (48 weeks), starting at Week 24. Safety assessments will include adverse events (AEs), serious AEs, clinical safety laboratory tests, electrocardiograms (ECGs), vital signs, ophthalmologic examinations and physical examinations. Total duration of individual participation will be up to 76 weeks (including screening period).
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
- •Medically stable based on physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening
- •Participants must have a body mass index between 18.0 and 35.0 kilograms per meter square (kg/m^2) inclusive
- •Participants with chronic hepatitis B who should: a) be chronic hepatitis B e antigen (HBeAg) -negative; b) be anti-HBe antibody-positive; c) be currently receiving nucleos(t)ide analog (NA) treatment for at least 2 years prior to screening; d) have serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) less than (<) 60 international unit/milliliter (IU/mL) on 2 sequential measurements at least 6 months apart; e) have alanine aminotransferase (ALT) values < 2.0x upper limit of normal (ULN) on 2 sequential measurements at least 6 months apart
- •Hepatitis B surface antigen (HBsAg) greater than (>) 5 IU/mL at screening
- •Fibroscan liver stiffness measurement less than or equal to (<=) 9.0 kilopascal (kPa) within 6 months prior to screening
排除标准
- •History or signs of cirrhosis or portal hypertension
- •Evidence of hepatitis A, C, D, E virus infection, or human immunodeficiency virus (HIV) infection
- •Liver disease of non-HBV etiology
- •Clinically relevant alcohol or drug abuse within 12 months of screening
- •Participants who meet any of the additional exclusion criteria for pegylated interferon alpha-2a (PegIFN- α2a) as described in local prescribing information (example, refer to Pegasys SmPC or Pegasys USPI) per the investigator's discretion. Key exclusion criteria for PegIFN- α2a include: a) Participants with signs or symptoms compatible with autoimmune disorders. b) Participants with bone marrow suppression. c) Participants with hypoglycaemia, hyperglycaemia, and/or diabetes mellitus, who cannot be effectively controlled by medication. d) Participants with pre-existing ophthalmologic disorders. e) Participants with one or more of the following laboratory abnormalities: i) Absolute neutrophil count less than (<)1,500 cells/mm3 (<1,000 cells/mm³ for black or African American participants). ii) Serum creatinine >1.5x ULN. iii) Inadequately controlled thyroid function (thyroid stimulating hormone [TSH] and thyroxine [T4]). f) Participants with a history of a severe psychiatric disorder including severe depression, suicidal ideation and attempted suicide, or a current depression or other psychiatric disorder that is not adequately controlled on a stable medication regimen
研究组 & 干预措施
Arm 1: JNJ-73763989 + nucleos(t)ide analog (NA) + pegylated interferon alpha-2a (PegIFN-alpha-2a)
Participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks for 24 weeks plus NA treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly for 24 weeks.
干预措施: JNJ-73763989 (Drug)
Arm 1: JNJ-73763989 + nucleos(t)ide analog (NA) + pegylated interferon alpha-2a (PegIFN-alpha-2a)
Participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks for 24 weeks plus NA treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly for 24 weeks.
干预措施: PegIFN-alpha-2a (Drug)
Arm 1: JNJ-73763989 + nucleos(t)ide analog (NA) + pegylated interferon alpha-2a (PegIFN-alpha-2a)
Participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks for 24 weeks plus NA treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly for 24 weeks.
干预措施: Tenofovir disoproxil (Drug)
Arm 1: JNJ-73763989 + nucleos(t)ide analog (NA) + pegylated interferon alpha-2a (PegIFN-alpha-2a)
Participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks for 24 weeks plus NA treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly for 24 weeks.
干预措施: TAF (Drug)
Arm 1: JNJ-73763989 + nucleos(t)ide analog (NA) + pegylated interferon alpha-2a (PegIFN-alpha-2a)
Participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks for 24 weeks plus NA treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly for 24 weeks.
干预措施: ETV (Drug)
Arm 2: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil, or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from Week 12 till Week 24.
干预措施: JNJ-73763989 (Drug)
Arm 2: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil, or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from Week 12 till Week 24.
干预措施: PegIFN-alpha-2a (Drug)
Arm 2: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil, or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from Week 12 till Week 24.
干预措施: Tenofovir disoproxil (Drug)
Arm 2: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil, or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from Week 12 till Week 24.
干预措施: TAF (Drug)
Arm 2: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil, or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from Week 12 till Week 24.
干预措施: ETV (Drug)
Arm 3: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from baseline till Week 12.
干预措施: JNJ-73763989 (Drug)
Arm 3: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from baseline till Week 12.
干预措施: PegIFN-alpha-2a (Drug)
Arm 3: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from baseline till Week 12.
干预措施: Tenofovir disoproxil (Drug)
Arm 3: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from baseline till Week 12.
干预措施: TAF (Drug)
Arm 3: JNJ-73763989 + NA + PegIFN-alpha-2a
Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from baseline till Week 12.
干预措施: ETV (Drug)
结局指标
主要结局
Percentage of Participants With a Reduction of at Least 2log10 International Units Per Milliliter (IU/mL) in Hepatitis B Surface Antigen (HBsAg) Levels From Baseline at Week 24 (End of Study Intervention [EOSI])
时间窗: Week 24
Percentage of participants with a reduction of at least 2log10 IU/mL in HBsAg levels from baseline at Week 24 (EOSI) were planned to be reported.
次要结局
- Percentage of Participants With Abnormalities in Vital Signs(Up to 1 month 26 days)
- Percentage of Participants With Abnormalities in Ophthalmologic Examination(Weeks 8 and 20)
- Percentage of Participants With Adverse Events (AEs)(Up to 1 month 26 days)
- Percentage of Participants With Serious Adverse Events (SAEs)(Up to 1 month 26 days)
- Percentage of Participants With Abnormalities in Clinical Laboratory Tests(Up to 1 month 26 days)
- Percentage of Participants With Abnormalities in 12-Lead Electrocardiograms (ECGs)(Up to 1 month 26 days)
- Percentage of Participants With HBsAg Seroclearance at Follow-up Weeks 24 and 48 Without Re-starting NA Treatment(Follow-up Weeks 24 and 48)
- Percentage of Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < (Less Than) LLOQ at Follow-up Weeks 24 and 48 Without Re-starting NA Treatment(Follow-up Weeks 24 and 48)
- Change From Baseline in HBsAg Over Time(Baseline up to Week 72)
- Time to Achieve HBsAg Seroclearance(Up to 72 weeks)
- Time to Achieve HBsAg Seroconversion(Up to 72 weeks)
- Time to Achieve HBV DNA <Lower Limit of Quantitation (LLOQ)(Up to 72 weeks)
- Percentage of Participants Meeting the Protocol-defined Nucleos(t)Ide Analog (NA) Treatment Completion Criteria Based on the Week 24 (EOSI) or Follow-up Week 2 Visits(Week 24 (EOSI) and follow-up Week 2)
- Percentage of Participants With Abnormalities in Physical Examination(Week 24)
- Percentage of Participants With Virologic Flares(Up to 1 month 26 days)
- Percentage of Participants With Biochemical Flares(Up to 1 month 26 days)
- Percentage of Participants Requiring Nucleos(t)Ide Analog (NA) Re-treatment(Up to 72 weeks)
- Percentage of Participants With HBsAg, Hepatitis B e Antigen (HBeAg), HBV DNA, and Alanine Aminotransferase (ALT) Levels Below/Above Different Cut-offs(Up to 72 weeks)
- Percentage of Participants With HBsAg Seroconversion(Up to 72 weeks)
- Percentage of Participants With Virologic Breakthrough(Up to Week 24)
- Serum Concentration of JNJ-73763989 (JNJ-73763924 and JNJ-73763976)(Up to 72 weeks)
- Serum Concentration of Nucleos(t)Ide Analog (NA) (Entecavir [ETV])(Up to 72 weeks)
- Serum Concentration of PegIFN-alpha-2a(Up to 72 weeks)