A Phase 2, Randomized, Open-label, Multicenter Study to Evaluate Efficacy, Pharmacokinetics, Safety, and Tolerability of Treatment With JNJ-73763989, Pegylated Interferon Alpha-2a, Nucleos(t)Ide Analog With or Without JNJ-56136379 in Treatment-naive Patients With HBeAg Positive Chronic Hepatitis B Virus Infection
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 54
- Locations
- 47
- Primary Endpoint
- Percentage of Participants With Functional Cure: Hepatitis B Surface Antigen (HBsAg) Seroclearance at 24 Weeks After Stopping All Study Interventions at the End of Consolidation Phase (CP) and Without Restarting Nucleos(t)Ide Analog (NA) Treatment
Study Overview
Brief Summary
The purpose of this study is to evaluate the efficacy of a treatment regimen of JNJ-73763989 + pegylated interferon alpha-2a (PegIFN-alpha-2a) + nucleos(t)ide analog (NA).
Detailed Description
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 a ribonucleic acid interference (RNAi) mechanism. JNJ-56136379 is an orally administered capsid assembly modulator (CAM) that is being developed for the treatment of chronic HBV infection. The aim of the study is to evaluate the efficacy of a treatment regimen of JNJ-73763989 + PegIFN-alpha-2a + NA with or without JNJ-56136379 in participants with hepatitis B e antigen (HBeAg) positive chronic infection. The study will be conducted in 4 phases: a screening phase, an induction phase with flexible duration, a consolidation phase with or without PegIFN-α2a and a follow-up phase. Safety assessments will include Adverse Events (AEs), serious AEs of the study interventions, clinical laboratory tests, Electrocardiograms (ECGs), vital signs, and physical examinations. The study title reflects the original study design and JNJ-56136379 (JNJ-6379) was initially part of the study intervention but was discontinued as per amendment 6 of the study.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Medically stable based on physical examination, medical history, vital signs, laboratory values, and 12-lead Electrocardiogram (ECG) at screening
- •Currently not treated chronic hepatitis B virus (HBV) infection with alanine transaminase (ALT) less than (<) 2* upper limit of normal (ULN) at screening and HBV deoxyribonucleic acid (DNA) greater than or equal to (>=) 20,000 international units per milliliter (IU/mL)
- •Body mass index (BMI) between 18.0 and 35.0 kilogram per meter square (kg/m^2), extremes included
- •Liver fibrosis stage 0-2 (Metavir) or Fibroscan less than or equal to (<=) 9 Kilopascal (kPa) at screening
Exclusion Criteria
- •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 or symptoms of hepatic decompensation, including but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal varices
- •Evidence of liver disease of non-HBV etiology
- •Participants with a history of malignancy within 5 years before screening
- •Participants who had or planned major surgery, (example, requiring general anesthesia) or who have received an organ transplant
- •Contraindications to the use of PegIFN-α2a
Arms & Interventions
Cohort 1: Participants Enrolled Prior to Protocol Amendment 5 is in Effect
During the Induction phase, participants will receive JNJ-73763989 subcutaneously along with JNJ-56136379 tablet orally with NA (either tenofovir disoproxil or tenofovir alafenamide tablets orally) treatment. At the start of consolidation phase, participants will be randomized to receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and JNJ-56136379 with NA in arm 1 and arm 2 (without PegIFN-alpha-2a). According to predefined criteria NA treatment may be continued during the follow up (FU) phase.
Intervention: JNJ-73763989 (Drug)
Cohort 1: Participants Enrolled Prior to Protocol Amendment 5 is in Effect
During the Induction phase, participants will receive JNJ-73763989 subcutaneously along with JNJ-56136379 tablet orally with NA (either tenofovir disoproxil or tenofovir alafenamide tablets orally) treatment. At the start of consolidation phase, participants will be randomized to receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and JNJ-56136379 with NA in arm 1 and arm 2 (without PegIFN-alpha-2a). According to predefined criteria NA treatment may be continued during the follow up (FU) phase.
Intervention: PegIFN-alpha-2a (Drug)
Cohort 1: Participants Enrolled Prior to Protocol Amendment 5 is in Effect
During the Induction phase, participants will receive JNJ-73763989 subcutaneously along with JNJ-56136379 tablet orally with NA (either tenofovir disoproxil or tenofovir alafenamide tablets orally) treatment. At the start of consolidation phase, participants will be randomized to receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and JNJ-56136379 with NA in arm 1 and arm 2 (without PegIFN-alpha-2a). According to predefined criteria NA treatment may be continued during the follow up (FU) phase.
Intervention: Tenofovir disoproxil (Drug)
Cohort 1: Participants Enrolled Prior to Protocol Amendment 5 is in Effect
During the Induction phase, participants will receive JNJ-73763989 subcutaneously along with JNJ-56136379 tablet orally with NA (either tenofovir disoproxil or tenofovir alafenamide tablets orally) treatment. At the start of consolidation phase, participants will be randomized to receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and JNJ-56136379 with NA in arm 1 and arm 2 (without PegIFN-alpha-2a). According to predefined criteria NA treatment may be continued during the follow up (FU) phase.
Intervention: Tenofovir alafenamide (Drug)
Cohort 1: Participants Enrolled Prior to Protocol Amendment 5 is in Effect
During the Induction phase, participants will receive JNJ-73763989 subcutaneously along with JNJ-56136379 tablet orally with NA (either tenofovir disoproxil or tenofovir alafenamide tablets orally) treatment. At the start of consolidation phase, participants will be randomized to receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and JNJ-56136379 with NA in arm 1 and arm 2 (without PegIFN-alpha-2a). According to predefined criteria NA treatment may be continued during the follow up (FU) phase.
Intervention: JNJ-56136379 (Drug)
Cohort 2: Participants Enrolled After Protocol Amendment 5 is in Effect
Following implementation of protocol amendment- 5 and 6, all participants will receive JNJ-73763989 subcutaneously along with NA (tenofovir disoproxil tablets orally) for 36 weeks (induction phase). In the consolidation phase, participants will receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and NA for 12 weeks. According to predefined criteria NA treatment may be continued during the follow up (FU) phase. JNJ-56136379 (JNJ-6379) was discontinued as per amendment 6 of the study.
Intervention: JNJ-73763989 (Drug)
Cohort 2: Participants Enrolled After Protocol Amendment 5 is in Effect
Following implementation of protocol amendment- 5 and 6, all participants will receive JNJ-73763989 subcutaneously along with NA (tenofovir disoproxil tablets orally) for 36 weeks (induction phase). In the consolidation phase, participants will receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and NA for 12 weeks. According to predefined criteria NA treatment may be continued during the follow up (FU) phase. JNJ-56136379 (JNJ-6379) was discontinued as per amendment 6 of the study.
Intervention: PegIFN-alpha-2a (Drug)
Cohort 2: Participants Enrolled After Protocol Amendment 5 is in Effect
Following implementation of protocol amendment- 5 and 6, all participants will receive JNJ-73763989 subcutaneously along with NA (tenofovir disoproxil tablets orally) for 36 weeks (induction phase). In the consolidation phase, participants will receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and NA for 12 weeks. According to predefined criteria NA treatment may be continued during the follow up (FU) phase. JNJ-56136379 (JNJ-6379) was discontinued as per amendment 6 of the study.
Intervention: Tenofovir disoproxil (Drug)
Outcomes
Primary Outcomes
Percentage of Participants With Functional Cure: Hepatitis B Surface Antigen (HBsAg) Seroclearance at 24 Weeks After Stopping All Study Interventions at the End of Consolidation Phase (CP) and Without Restarting Nucleos(t)Ide Analog (NA) Treatment
Time Frame: At follow-up (FU) phase Week 24
Percentage of participants with functional cure (defined as percentage of participants with HBsAg seroclearance at 24 weeks after stopping all study interventions at the end of consolidation phase and without restarting NA treatment) were reported. Seroclearance HBsAg was defined as a (quantitative) HBsAg level \<lower limit of quantification (LLOQ; \<0.05 international units per milliliter \[IU/mL\]).
Secondary Outcomes
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(IP: From Day 1 up to end of IP (up to Week 52 for Cohort 1; up to Week 36 for Cohort 2); CP: CP Week 1 up to CP Week 12 (for Cohort 1 and 2); FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs)(IP: From Day 1 up to end of IP (up to Week 52 for Cohort 1; up to Week 36 for Cohort 2); CP: CP Week 1 up to CP Week 12 (for Cohort 1 and 2); FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Number of Participants With Worst (Grade 3 or 4) Treatment-emergent DAIDS Toxicity Grade in Clinical Laboratory Tests(IP: From Day 1 up to end of IP (up to Week 52 for Cohort 1; up to Week 36 for Cohort 2); CP: CP Week 1 up to CP Week 12 (for Cohort 1 and 2); FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Number of Participants With Worst Treatment-emergent Abnormality in Electrocardiogram (ECGs)(IP: From Day 1 up to end of IP (up to Week 52 for Cohort 1; up to Week 36 for Cohort 2); CP: CP Week 1 up to CP Week 12 (for Cohort 1 and 2); FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Number of Participants With Worst Treatment-emergent Abnormalities in Vital Signs(IP: From Day 1 up to end of IP (up to Week 52 for Cohort 1; up to Week 36 for Cohort 2); CP: CP Week 1 up to CP Week 12 (for Cohort 1 and 2); FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Number of Participants With Clinically Important Abnormalities in Physical Examination(IP: From Day 1 up to end of IP (up to Week 52 for Cohort 1; up to Week 36 for Cohort 2); CP: CP Week 1 up to CP Week 12 (for Cohort 1 and 2); FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Percentage of Participants Who Reached HBsAg Less Than (<) 10 (International Units Per Milliliter [IU/mL]) at the End of the Induction Phase (EOI)(At IP Week 36 and EOI; anytime up to IP Week 52 for Cohort 1; up to IP Week 36 for Cohort 2)
- Time to Achieve First Occurrence of HBsAg <10 IU/mL(From Baseline (Day 1 of IP) up to Follow-up phase Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Percentage of Participants Who Met Nucleos(t)Ide Analog (NA) Treatment Completion Criteria at the End of Consolidation Phase(At CP Week 12 (for Cohort 1 and 2))
- FU Phase: Percentage of Participants With HBsAg Seroclearance 48 Weeks After Stopping All Study Interventions of the Consolidation Phase and Without Restarting NA Treatment During Follow up Phase(FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- FU Phase: Percentage of Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <LLOQ 48 Weeks After Stopping All Study Interventions of the Consolidation Phase and Without Restarting NA Treatment During Follow up Phase(FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- FU Phase: Number of Participants With Off-treatment Virologic HBV Flares During Follow up Phase(FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- FU Phase: Number of Participants With Off-treatment Biochemical HBV Flares During Follow-up Phase(FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- FU Phase: Number of Participants With On-treatment Biochemical Flares During Follow-up Phase(FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- FU Phase: Number of Participants With Off-treatment Clinical Flares During Follow-up Phase(FU phase: FU Week 1 up to FU Week 48(up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- FU Phase: Percentage of Participants Who Required NA Re-treatment During Follow-Up Phase(FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- FU Phase: Percentage of Participants Who Achieved Reduction (Sustained) in HBsAg Response (Per Definition 1) at Follow-up Week 48(At FU Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants Who Achieved Reduction (Sustained) in HBsAg Response (Per Definition 2) at Follow-up Week 48(At FU Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants Who Achieved Reduction (Sustained) in HBsAg Response (Per Definition 3) at Follow-up Week 48(At FU Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants Who Achieved Reduction (Sustained) in HBsAg Response (Per Definition 4) at Follow-up Week 48(At FU Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants With HBsAg Seroclearance at Follow-up Week 48(At FU Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants With HBeAg Seroclearance at Follow-up Week 48(At FU Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants With HBsAg Seroconversion(IP Week 24; CP: Week 12, FU phase: Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants With HBeAg Seroconversion(CP: Week 12; FU phase: FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Change From Baseline Over Time in HBsAg Levels(Baseline (Day 1 of IP), IP: Week 36; CP: Week 12; FU phase: Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Change From Baseline Over Time in HBeAg Levels(Baseline (Day 1 of IP), IP: Week 36; CP: Week 12; FU phase: Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Change From Baseline Over Time in HBV DNA Levels(Baseline (Day 1 of IP), IP: Week 36; CP: Week 12; FU phase: Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Time to Achieve First HBsAg Seroclearance(From Baseline (Day 1 of IP) to Follow-up Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Time to Achieve First HBeAg Seroclearance(From Baseline (Day 1 of IP) to Follow-up Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Time to Achieve First HBV DNA <LLOQ(From Baseline (Day 1 of IP) to Follow-up Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Percentage of Participants With HBeAg Levels Below Different Cut-offs(IP: Week 36, CP: Week 12; FU phase: Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants With HBsAg Levels Below Different Cut-offs(IP: Week 36, CP: Week 12; FU phase: Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants With HBV DNA Levels Below Different Cut-offs(IP: Week 36; CP: Week 12; FU phase: Week 48 (Week 112 [Cohort 1]; Week 96 [Cohort 2]))
- Percentage of Participants With Virologic Breakthrough(IP: From Day 1 up to end of IP (up to Week 52 for Cohort 1; up to Week 36 for Cohort 2); CP: CP Week 1 up to CP Week 12 (for Cohort 1 and 2); FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Percentage of Participants Who Reached HBV DNA Undetectability After Re-start of NA Treatment During Follow-up(FU phase: FU Week 1 up to FU Week 48 (up to Week 112 [Cohort 1]; up to Week 96 [Cohort 2]))
- Maximum Observed Plasma Concentration (Cmax) of JNJ-73763989 (Molecules: JNJ-73763976 [JNJ3976], JNJ-73763924 [JNJ-3924])(IP : Predose (0 hour), post dose on 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 hours on IP Week 24; CP: Predose (0 hour), post dose on 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 hours on CP Week 8)
- Time to Reach the Maximum Observed Plasma Concentration (Tmax) of JNJ-73763989 (Molecules: JNJ-73763976 [JNJ3976], JNJ-73763924 [JNJ-3924])(IP : Predose (0 hour), post dose on 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 hours on IP Week 24; CP: Predose (0 hour), post dose on 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 hours on CP Week 8)
- Plasma Concentration 24 Hours After Administration (C24h) of JNJ-73763989 (Molecules: JNJ-73763976 [JNJ3976], JNJ-73763924 [JNJ-3924])(IP: 24 hours post dose on Week 24 visit; CP: 24 hours post dose on Week 8 visit)
- Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours [AUC (0- 24 Hours)] of JNJ-73763989 (Molecules: JNJ-73763976 [JNJ3976], JNJ-73763924 [JNJ-3924])(IP: 24 hours post dose on Week 24 visit; CP: 24 hours post dose on Week 8 visit)