A Study of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus Infection

Study Overview
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Brief Summary
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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.

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 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.

Official Title
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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

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: JNJ-73763989
* Drug: Placebo for JNJ-73763989
* Drug: JNJ-56136379
* Drug: Placebo for JNJ-56136379
* Drug: Nucleos(t)ide Analog (NA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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/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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: JNJ-73763989 (medium dose) + JNJ-56136379 + NA<br>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. | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered as medium dose (Arms 1 and 3), high dose (Arm 2), and low dose (Arm 4) as subcutaneous injection.<br>Drug: JNJ-56136379<br>* JNJ-56136379 tablets will be administered orally.<br>Drug: Nucleos(t)ide Analog (NA)<br>* NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.<br>|
| Experimental: Arm 2: JNJ-73763989 (high dose) + Placebo + NA<br>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. | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered as medium dose (Arms 1 and 3), high dose (Arm 2), and low dose (Arm 4) as subcutaneous injection.<br>Drug: Placebo for JNJ-56136379<br>* Placebo for JNJ-56136379 tablets will be administered orally.<br>Drug: Nucleos(t)ide Analog (NA)<br>* NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.<br>|
| Experimental: Arm 3: JNJ-73763989 (medium dose) + Placebo + NA<br>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. | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered as medium dose (Arms 1 and 3), high dose (Arm 2), and low dose (Arm 4) as subcutaneous injection.<br>Drug: Placebo for JNJ-56136379<br>* Placebo for JNJ-56136379 tablets will be administered orally.<br>Drug: Nucleos(t)ide Analog (NA)<br>* NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.<br>|
| Experimental: Arm 4: JNJ-73763989 (low dose) + Placebo + NA<br>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. | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered as medium dose (Arms 1 and 3), high dose (Arm 2), and low dose (Arm 4) as subcutaneous injection.<br>Drug: Placebo for JNJ-56136379<br>* Placebo for JNJ-56136379 tablets will be administered orally.<br>Drug: Nucleos(t)ide Analog (NA)<br>* NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.<br>|
| Experimental: Arm 5: Placebo + JNJ-56136379 + NA<br>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. | Drug: Placebo for JNJ-73763989<br>* Placebo for JNJ-73763989 will be administered as subcutaneous injection.<br>Drug: JNJ-56136379<br>* JNJ-56136379 tablets will be administered orally.<br>Drug: Nucleos(t)ide Analog (NA)<br>* NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.<br>|
| Placebo Comparator: Arm 6 (Control): Placebo + Placebo + NA<br>Participants will receive placebo for JNJ-73763989 and placebo for JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks. | Drug: Placebo for JNJ-73763989<br>* Placebo for JNJ-73763989 will be administered as subcutaneous injection.<br>Drug: Placebo for JNJ-56136379<br>* Placebo for JNJ-56136379 tablets will be administered orally.<br>Drug: Nucleos(t)ide Analog (NA)<br>* NA treatment that is either of ETV, TDF or TAF tablets 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 Meeting the Nucleos(t)ide Analog (NA) Treatment Completion Criteria at Week 48 | Percentage of participants meeting the NA treatment completion criteria at week 48 will be reported. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AE) and Serious Adverse Events (SAE) as a Measure of Safety and Tolerability | An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. 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 follow-up (maximum up to 150 weeks) | 
| Number of Participants with Abnormalities in Clinical Laboratory Tests, 12-Lead Electrocardiogram (ECG), and Vital Signs | Number of participants with abnormalities in clinical laboratory tests, 12-lead ECG, and vital signs will be reported. | Up to follow-up (maximum up to 150 weeks) | 
| Percentage of Participants with HBsAg Seroclearance After Completion of all Study Intervention | Percentage of participants with hepatitis B surface antigen (HBsAg) seroclearance after completion of all study intervention will be reported. | Week 72 and Week 96 | 
| Percentage of Participants with HBV DNA less than (<) Lower Limit of Quantification (LLOQ) After Completion of all Study Intervention | Percentage participants with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) <LLOQ after completion of all study intervention will be reported. | Week 72 and Week 96 | 
| Percentage of Participants Meeting the NA Treatment Completion Criteria During Follow-up | Percentage of participants meeting the NA treatment completion criteria during follow-up will be reported. | Up to 96 weeks | 
| Percentage of Participants with HBsAg Seroclearance After Completion of NA Treatment at any Time During Follow-up | Percentage of participants with HBsAg seroclearance after completion of NA treatment at any time during follow-up will be reported. | Up to 150 weeks | 
| Percentage of Participants Requiring NA Re-treatment During Follow-up | Percentage of participants requiring NA re-treatment during follow-up will be reported. | Up to 150 weeks | 
| Percentage of Participants with Relapse | Percentage of participants with relapse will be reported. | Up to 150 weeks | 
| Percentage of Participants with (Sustained) Reduction, Suppression, and/or Seroclearance Considering Single and Multiple Markers | 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 96 | 
| Percentage of Participants with HBsAg Seroconversion | Percentage of participants with HBsAg seroconversion will be reported. | Up to 150 weeks | 
| Percentage of Participants with HBeAg Seroconversion | Percentage of participants with HBeAg seroconversion will be reported. | Up to 150 weeks | 
| Change From Baseline in HBsAg Levels | Change from baseline in HBsAg levels will be determined. | Baseline up to follow up (up to Week 150) | 
| Change From Baseline in HBeAg Levels | Change from baseline in HBeAg levels will be determined. | Baseline up to follow up (up to Week 150) | 
| Change from Baseline in HBV DNA Levels | Change from baseline in HBV DNA levels will be determined. | Baseline up to follow up (up to Week 150) | 
| Time to Achieve HBsAg Seroclearance | Time to achieve HBsAg seroclearance will be determined. | Up to Week 96 | 
| Time to Achieve HBeAg Seroclearance | Time to achieve HBeAg seroclearance will be determined. | Up to Week 96 | 
| Percentage of Participants with <100 IU/mL or >1 log10 IU/mL Reduction in HBsAg From Baseline | Percentage of participants with less than (<) 100 international units per milliliter (IU/mL) or greater than (>) 1 log10 IU/mL reduction in HBsAg from baseline will be assessed. | Baseline up to Week 150 | 
| Percentage of HBeAg-positive Participants with HBeAg Levels | Percentage of HBeAg-positive participants with HBeAg levels will be reported. | Baseline up to Week 150 | 
| Percentage of Participants with ALT Decrease and Normalization | Percentage of participants with alanine aminotransferase (ALT) decrease and normalization will be reported. | Up to follow-up (maximum up to 150 weeks) | 
| Percentage of Participants with Virologic Breakthrough | Percentage of participants with virologic breakthrough defined as confirmed on-treatment HBV DNA increase by >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 48 | 
| Percentage of Participants with Undetectable HBV DNA Levels 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 150 weeks | 
| Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of JNJ-73763989 | The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state. | Days 1, 29, 85, 169 and 337 | 
| Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of JNJ-56136379 | The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state. | Days 1, 29, 85, 169 and 337 | 
| Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of NA | The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state. | Days 1, 29, 85, 169 and 337 |