A Study of JNJ-73763989, Pegylated Interferon Alpha-2a, Nucleos(t)Ide Analog (NA) With or Without JNJ-56136379 in Treatment-naive Participants With Hepatitis B e Antigen (HBeAg) Positive Chronic Hepatitis B Virus (HBV) Infection

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: JNJ-73763989
* Drug: PegIFN-alpha-2a
* Drug: Tenofovir disoproxil
* Drug: Tenofovir alafenamide
* Drug: JNJ-56136379


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Participants Enrolled Prior to Protocol Amendment 5 is in Effect<br>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. | Drug: JNJ-73763989<br>* JNJ-73763989 injection will be administered subcutaneously.<br>* Other names: JNJ-3989;Drug: PegIFN-alpha-2a<br>* PegIFN-alpha-2a injection will be administered subcutaneously.<br>Drug: Tenofovir disoproxil<br>* Tenofovir disoproxil film-coated tablet will be administered orally.<br>Drug: Tenofovir alafenamide<br>* Tenofovir alafenamide film-coated tablet will be administered orally.<br>Drug: JNJ-56136379<br>* JNJ-56136379 will be administered orally.<br>* Other names: JNJ-6379;|
| Experimental: Cohort 2: Participants Enrolled After Protocol Amendment 5 is in Effect<br>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. | Drug: JNJ-73763989<br>* JNJ-73763989 injection will be administered subcutaneously.<br>* Other names: JNJ-3989;Drug: PegIFN-alpha-2a<br>* PegIFN-alpha-2a injection will be administered subcutaneously.<br>Drug: Tenofovir disoproxil<br>* Tenofovir disoproxil film-coated tablet will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) Seroclearance 24 Weeks After Stopping all Study Interventions of Consolidation Phase and Without Restarting NA Treatment | Percentage of participants with HBsAg seroclearance 24 weeks after stopping all study interventions of consolidation phase and without restarting nucleos(t)ide analog (NA) treatment will be reported. | Up to Follow-up Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) and Serious AEs | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Up to Week 102 | 
| Number of Participants with Clinically Significant Abnormalities in Laboratory Parameters | Number of participants with clinically significant abnormalities in laboratory parameters (hematology, blood biochemistry, blood coagulation, urinalysis, urine chemistry, and renal biomarkers) will be reported. | Up to Week 102 | 
| Number of Participants with Clinically Significant Abnormalities in Electrocardiogram (ECGs) | Number of participants with clinically significant abnormalities in electrocardiogram (ECGs) will be reported. | Up to Week 102 | 
| Number of Participants with Clinically Significant Abnormalities in Vital Signs | Number of participants with clinically significant abnormalities in vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) will be reported. | Up to Week 102 | 
| Number of Participants with Clinically Significant Abnormalities in Physical Examination | Number of participants with clinically significant abnormalities in physical examination will be reported. | Up to Week 102 | 
| Percentage of Participants Reaching HBsAg less than (<) 10 IU/mL at the End of Induction Phase (Week 36) | Percentage of participants reaching HBsAg <10 international units per milliliter (IU/mL) at the end of induction phase (Week 36) will be reported. | Up to Week 48 | 
| Time to Reach Hepatitis B Surface Antigen (HBsAG) < 10 IU/mL | Time to Reach HBsAG < 10 IU/mL will be reported. | Up to Week 102 | 
| Percentage of Participants Meeting NA Treatment Completion Criteria at the end of Consolidation Phase | Percentage of participants meeting NA treatment completion criteria at the end of consolidation phase will be reported. | Up to Week 60 | 
| Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) Seroclearance | Percentage of participants with HBsAg Seroclearance will be reported. | Up to Week 102 | 
| Percentage of Participants with HBV DNA less than (<) Lower Limit of Quantification (LLOQ) | Percentage of participants with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) <LLOQ will be reported. | Up to Week 102 | 
| Number of Participants with Flares | Number of participants with flares (virologic, biochemical and clinical flares) will be reported. | Up to Week 102 | 
| Percentage of Participants Requiring NA Re-treatment | Percentage of participants requiring NA re-treatment based on failure in NA treatment completion criteria will be reported. | Up to Week 102 | 
| Percentage of Participants with (Sustained) Reduction, Suppression, and/or Seroclearance | Percentage of participants with (sustained) reduction, suppression, and/or seroclearance considering single and multiple markers (such as hepatitis B surface antigen [HBsAg], hepatitis B e antigen [HBeAg], HBV DNA and alanine aminotransferase [ALT]) will be reported. | Up to Week 102 | 
| Percentage of Participants with Hepatitis B Surface Antigen (HBsAg) and Hepatitis B e Antigen (HBeAg) Seroconversion | Percentage of participants with HBsAg and HBeAg seroconversion will be reported. | Up to Week 102 | 
| Time to Achieve Hepatitis B Surface Antigen (HBsAg) Seroclearance | Time to achieve HBsAg seroclearance will be reported. | Up to Week 102 | 
| Time to Achieve Hepatitis B e Antigen (HBeAg) Seroclearance | Time to achieve hepatitis B e antigen (HBeAg) seroclearance will be reported. | Up to Week 102 | 
| Time to Achieve Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <LLOQ | Time to achieve HBV DNA <LLOQ will be reported. | Up to Week 102 | 
| Percentage of participants with Hepatitis B e Antigen (HBeAg), Hepatitis B Surface Antigen (HBsAg), and Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels | Percentage of participants with HBeAg, HBsAg, and HBV DNA Levels will be reported. | Up to Week 102 | 
| Change from Baseline in Hepatitis B e Antigen (HBeAg) | Change from baseline in HBeAg will be reported. | Baseline and Week 102 | 
| Change from Baseline in Hepatitis B Surface Antigen (HBsAg) | Change from baseline in HBsAg will be reported. | Baseline and Week 102 | 
| Change from Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels | Change from baseline in HBV DNA levels will be reported. | Baseline and Week 102 | 
| Percentage of Participants with Virologic Breakthrough | Percentage of participants with virologic breakthrough (defined as confirmed on-treatment HBV DNA increase by greater than (>) 1 log10 IU/mL from nadir level or confirmed on treatment level >200 IU/mL in participants who had HBV DNA level below <LLOQ of the HBV DNA assay) will be reported. | Up to Week 102 | 
| Percentage of Participants who Reach Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Undetectability After Re-start of NA Treatment During Follow-up | Percentage of participants who reach HBV DNA undetectability after re-start of NA treatment during follow-up will be reported. | Up to Week 102 | 
| Maximum Observed Plasma Concentration (Cmax) | Cmax is the maximum observed plasma concentration. | Up to Day 253 postdose | 
| Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours [AUC (0- 24 hours)] | AUC (0- 24 hours) is the area under the plasma concentration-time curve from time zero to 24 hours. | Up to 24 hours postdose |