A Study of JNJ 73763989+JNJ 56136379+Nucleos(t)Ide Analog (NA) Regimen Compared to NA Alone in e Antigen Negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of 48-week study intervention with JNJ-73763989+JNJ-56136379+nucleos(t)ide analog (NA) regimen compared to NA alone assessed by HBsAg levels. This study is part of HepB Wings Platform Trial (PLATFORMPAHPB2001).

Detailed Description
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Hepatitis B virus (HBV) is a small deoxyribonucleic acid (DNA) virus that infects the liver and can cause either acute or chronic infection. It consists of a so-called nucleocapsid in which viral DNA is packed with hepatitis B core protein (HBc) and membranous envelope containing hepatitis B surface antigen (HBsAg). Chronic HBV infection may lead to serious illnesses like cirrhosis and hepatocellular carcinoma (HCC). Oral treatment with NAs is effective at suppressing viral DNA formation and lowering virus concentration in blood to levels below lower limit of quantification (LLOQ). JNJ-73763989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic HBV infection via ribonucleic acid interference mechanism but rarely lead to functional cure defined as sustained loss of HBs Ag and HBV DNA in serum. JNJ-56136379 is an orally administered capsid assembly modulator that is being developed for treatment of chronic HBV infection. The aim of study is to evaluate efficacy of 48-week study intervention with JNJ-3989+JNJ-6379+NA regimen compared to NA alone, assessed by HBsAg seroclearance at Week 72 (i.e., 24 weeks after completion of all study interventions at Week 48) without restarting NA treatment in HBeAg negative virologically suppressed chronic hepatitis B (CHB) infected participants who received NA treatment for at least 2 years prior to screening. The study will be 2.3 years and will be conducted in 3 phases: a screening phase (4 weeks), a study intervention phase (48 weeks), and a follow-up phase (48 weeks). Safety will be evaluated by AEs including AEs of special interest to any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical examinations.

Official Title
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A Randomized, Double Blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy, Pharmacokinetics, and Safety of 48-week Study Intervention With JNJ 73763989+JNJ 56136379+Nucleos(t)Ide Analog (NA) Regimen Compared to NA Alone in e Antigen Negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: JNJ-73763989
* Drug: JNJ-56136379
* Drug: Placebo for JNJ-73763989
* Drug: Placebo for JNJ-56136379
* Drug: Entecavir (ETV) monohydrate
* Drug: Tenofovir disoproxil fumarate (TDF)
* Drug: Tenofovir alafenamide (TAF)


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 e (antigen) (HBeAg)-negative on stable nucleotide analogue (NA) treatment for at least 24 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 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 History or signs of cirrhosis or portal hypertension (nodules, no smooth liver contour, no normal portal vein, spleen size ≥12 cm) or 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 Known allergies, hypersensitivity, or intolerance to JNJ-73763989 and JNJ-56136379 or their excipients or to 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

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: JNJ-73763989+ JNJ-56136379+ NA<br>Participants will receive fixed dose of JNJ-73763989 subcutaneous injection once every 4 weeks along with fixed dose of JNJ-56136379 tablet once daily and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil fumarate [TDF], or tenofovir alafenamide [TAF]) once daily up to 48 weeks. | Drug: JNJ-73763989<br>* JNJ-73763989 injection will be administered subcutaneously once every 4 weeks up to 48 weeks.<br>Drug: JNJ-56136379<br>* JNJ-56136379 tablets will be administered orally once daily up to 48 weeks.<br>Drug: Entecavir (ETV) monohydrate<br>* ETV tablet will be administered orally once daily up to 48 weeks as NA treatment.<br>Drug: Tenofovir disoproxil fumarate (TDF)<br>* TDF will be administered orally once daily up to 48 weeks as NA treatment.<br>Drug: Tenofovir alafenamide (TAF)<br>* TAF will be administered orally once daily up to 48 weeks as NA treatment.<br>|
| Placebo Comparator: Placebo for JNJ-73763989+ Placebo for JNJ-56136379+ NA<br>Participants will receive matching placebo for JNJ-73763989 subcutaneous injection once every 4 weeks with matching placebo for JNJ-56136379 once daily and NA treatment (either ETV, TDF or TAF) once daily up to 48 weeks. | Drug: Placebo for JNJ-73763989<br>* Matching placebo for JNJ-73763989 will be administered as subcutaneous injection up to 48 weeks.<br>Drug: Placebo for JNJ-56136379<br>* Matching placebo for JNJ-56136379 tablets will be administered orally up to 48 weeks.<br>Drug: Entecavir (ETV) monohydrate<br>* ETV tablet will be administered orally once daily up to 48 weeks as NA treatment.<br>Drug: Tenofovir disoproxil fumarate (TDF)<br>* TDF will be administered orally once daily up to 48 weeks as NA treatment.<br>Drug: Tenofovir alafenamide (TAF)<br>* TAF will be administered orally once daily up to 48 weeks as NA treatment.<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 at Week 72 (24 weeks after completion of all study interventions at Week 48) Without Restarting NA Treatment | Percentage of participants with HBsAg seroclearance at week 72 (24 weeks after completion of all study interventions at Week 48) without restarting nucleos(t)ide analog (NA) treatment will be reported. | Week 72 | 

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 clinical study participant administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. 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 102 weeks | 
| Number of Participants with Abnormalities in Clinical Laboratory Tests | Number of participants with abnormalities in clinically significant laboratory findings (urine chemistry and renal biomarkers) will be reported. | Up to 102 weeks | 
| Percentage of Participants with HBsAg Seroclearance at Week 48 | Percentage of participants with HBsAg seroclearance at week 48 will be reported. | Week 48 | 
| Percentage of Participants with HBV DNA less than (<) Lower Limit of Quantification (LLOQ) at Week 48 | Percentage of participants with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) <LLOQ at week 48 will be reported. | Week 48 | 
| Percentage of Participants with HBsAg Seroclearance at Week 96 (48 Weeks After Completion of all Study Intervention) Without Restarting NA Treatment | Percentage of participants with HBsAg seroclearance up to week 96 (48 weeks after completion of all study intervention) without restarting NA treatment will be reported. | Up to Week 96 | 
| 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 96 | 
| Time to Achieve First HBsAg Seroclearance | Time to achieve first HBsAg seroclearance will be reported. | Up to Week 96 | 
| Percentage of participants with HBV DNA levels with <LLOQ | Percentage of participants with HBV DNA levels with lower limit of quantification (<LLOQ) assay will be reported. | Up to Week 96 | 
| 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 48 | 
| Percentage of Participants with Flares | Percentage of participants with flares (virologic, biochemical and clinical flares) will be reported. | Up to week 96 | 
| 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 week 96 | 
| Association Between Baseline Characteristics and On-Treatment Viral Blood Markers with Selected Off-Treatment Responses | Identification of baseline characteristics and on treatment viral blood markers (e.g., HBV DNA, HBsAg, ALT) associated with sustained off-treatment responses will be reported. | Baseline to week 72 | 
| 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 |