A Study of JNJ-73763989 + Nucleos(t)Ide Analog in Participants Co-Infected With Hepatitis B and Hepatitis D Virus

Study Overview
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Brief Summary
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The purpose of the study is to evaluate on-treatment efficacy against hepatitis D virus (HDV) of JNJ-73763989 + nucleos(t)ide analog (NA) regimen compared to NA alone.

Detailed Description
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JNJ-73763989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic hepatitis B virus (HBV) infection via ribonucleic acid interference mechanism. This phase 2 study is designed to evaluate safety and efficacy of JNJ-73763989 in HBV infected patients who are co-infected with HDV. The study consists of 2 parts: Part 1 will evaluate safety, tolerability and antiviral activity of JNJ-73763989 + NA while Part 2 will evaluate the safety and efficacy of the JNJ-73763989 + NA regimen in the treatment of HBV/HDV co-infection. Each part includes 3 phases: Screening phase (from 4 Week up to maximum of 8 weeks), Intervention phase (144 Week for Arm A and 148 Week for Arm B) and Follow-up phase (48 Week). The duration of individual study participation will be between 196 and 204 weeks. Safety and tolerability (including adverse events [AEs] and Serious AEs, laboratory assessments, electrocardiogram [ECG], vital signs, physical examination), efficacy (including HDV ribonucleic acid [RNA], HBV deoxyribonucleic acid [DNA] and antigens) , and pharmacokinetics will be assessed throughout the study.

Official Title
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A Phase 2, Multicenter, Randomized, Double-blind, Placebo-Controlled Study With Deferred Active Treatment to Investigate the Efficacy, Safety, and Pharmacokinetics of JNJ-73763989 + Nucleos(t)Ide Analog in Participants Co-Infected With Hepatitis B and Hepatitis D Virus

Conditions
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Hepatitis D, Chronic

Intervention / Treatment
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* Drug: JNJ-73763989
* Drug: Placebo
* Drug: Entecavir (ETV) monohydrate
* Drug: Tenofovir disoproxil
* 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) and hepatitis D virus (HDV) co-infection with documentation at least 6 months prior to screening For Part 1: hepatitis D RNA (HDV RNA) greater than or equal to (>=) 1000 international units per milliliter (IU/mL) at screening. For Part 2: must have HDV RNA values >= 500 IU/mL, and must have hepatitis B surface antigen (HBsAg) values less than or equal to (<=) 10000 IU/mL at screening or HDV RNA values at screening are <= 100000 IU/mL Alanine aminotransferase (ALT) greater than upper limit normal (ULN) but less than 10 times (ULN) 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 Non-cirrhotic participants and participants with compensated cirrhosis (Child Pugh class A) at screening (Part 1) and participants must have absence of cirrhosis and platelet count of >= 140000 per deciliter (dL) for enrollment into Part-2 Exclusion Criteria: Evidence of infection with hepatitis A, C, 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/HDV 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 or its excipients or excipients of the placebo content Contraindications to the use of entecavir (ETV), tenofovir disoproxil, 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: Immediate Active Treatment arm: JNJ-73763989 + NA<br>Participants will receive JNJ-73763989 subcutaneous (SC) injection every 4 weeks (Q4W) along with NA (entecavir [ETV], tenofovir disoproxil, or tenofovir alafenamide [TAF]) once daily for 144 Weeks in Part 1 and 2. | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered as a SC injection.<br>* Other names: JNJ-3989;Drug: Entecavir (ETV) monohydrate<br>* ETV monohydrate film coated tablet will be administered orally.<br>Drug: Tenofovir disoproxil<br>* Tenofovir disoproxil film-coated tablet will be administered orally.<br>Drug: Tenofovir alafenamide (TAF)<br>* TAF film coated tablet will be administered orally.<br>|
| Placebo Comparator: Deferred Active Treatment arm: Placebo+NA+JNJ-73763989+NA<br>Participants will receive matching placebo to JNJ-73763989 SC injection Q4W along with NA (ETV, tenofovir disoproxil, or TAF) once daily for 52 Weeks followed by JNJ-73763989 SC injection Q4W along with NA once daily for 96 weeks in Part 1 and 2. | Drug: JNJ-73763989<br>* JNJ-73763989 will be administered as a SC injection.<br>* Other names: JNJ-3989;Drug: Placebo<br>* Matching placebo to JNJ-73763989 will be administered as a SC injection.<br>Drug: Entecavir (ETV) monohydrate<br>* ETV monohydrate film coated tablet will be administered orally.<br>Drug: Tenofovir disoproxil<br>* Tenofovir disoproxil film-coated tablet will be administered orally.<br>Drug: Tenofovir alafenamide (TAF)<br>* TAF 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 HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND in Combination with Normal ALT at Week 48 | Percentage of participants with hepatitis D virus (HDV) ribonucleic acid (RNA) greater than or equal to (>=) 2 log10 international units per milliliter (IU/mL) decline from baseline or HDV RNA target not detected (TND) in combination with normal alanine aminotransferase (ALT) at Week 48 will be reported. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND at Week 48 | Percentage of participants with HDV RNA >=2 log10 IU/mL decline from baseline or HDV RNA TND at Week 48 will be reported. | Week 48 | 
| Percentage of Participants With Normal ALT at Week 48 | Percentage of participants with normal ALT at Week 48 will be reported. | Week 48 | 
| Percentage of Participants with HBsAg Seroclearance at Week 48 | Percentage of participants with hepatitis B s antigen (HBsAg) seroclearance at Week 48 will be reported. | Week 48 | 
| Percentage of Participants with >=2 kPa Reduction From Baseline in LSM assessed by VCTE (FibroScan) at Week 48 | Percentage of participants with >=2 kilopascal (kPa) reduction from baseline in liver stiffness measurement (LSM) assessed by vibration-controlled transient elastography (VCTE) (FibroScan) at Week 48 will be reported. | Week 48 | 
| Percentage of Participants with HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND in Combination with Normal ALT | Percentage of participants with HDV RNA >=2 log10 IU/mL decline from baseline or HDV RNA TND in combination with normal ALT will be reported. | Up to Week 204 | 
| Percentage of Participants with HDV RNA >=2 log10 IU/mL Decline From Baseline in Combination with Normal ALT | Percentage of participants with HDV RNA >=2 log10 IU/mL decline from baseline in combination with normal ALT will be reported. | Up to Week 204 | 
| Percentage of Participants with HDV RNA TND in Combination with Normal ALT | Percentage of participants with HDV RNA TND in combination with normal ALT will be reported. | Up to Week 204 | 
| Percentage of Participants with HDV RNA >=2 log10 IU/mL Decline From Baseline or HDV RNA TND | Percentage of participants with HDV RNA >=2 log10 IU/mL decline from baseline or HDV RNA TND will be reported. | Up to Week 204 | 
| Percentage of Participants with HDV RNA >=2 log10 IU/mL Decline From Baseline | Percentage of participants with HDV RNA >=2 log10 IU/mL decline from baseline will be reported. | Up to Week 204 | 
| Percentage of Participants with HDV RNA TND | Percentage of participants with HDV RNA TND will be reported. | Up to Week 204 | 
| Percentage of Participants with Normal ALT | Percentage of participants with normal ALT will be reported. | Up to Week 204 | 
| Time to Reach HDV RNA >=2 log10 IU/mL Decline or HDV RNA TND | Time to reach HDV RNA >=2 log10 IU/mL decline or HDV RNA TND will be reported. | Up to Week 204 | 
| Change from Baseline in HDV RNA | Change from baseline in HDV RNA will be reported. | Baseline and up to Week 204 | 
| Changes from Baseline in ALT | Changes from baseline in ALT will be reported. | Baseline and up to Week 204 | 
| Percentage 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 204 | 
| Percentage of Participants with Abnormalities in Laboratory Parameters | Percentage of participants with abnormalities in laboratory parameters (hematology, blood biochemistry, blood coagulation, urinalysis, urine chemistry, and renal biomarkers) will be reported. | Up to Week 204 | 
| Percentage of Participants with Abnormalities in 12-lead Electrocardiogram (ECGs) | Percentage of participants with abnormalities in 12-lead electrocardiogram (ECGs) will be reported. | Up to Week 204 | 
| Percentage of Participants with Abnormalities in Vital Signs | Percentage of participants with abnormalities in vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) will be reported. | Up to Week 204 | 
| Percentage of Participants with Abnormalities in Physical Examination | Percentage of participants with abnormalities in physical examination will be reported. | Up to Week 204 | 
| Percentage of Participants with HBsAg Seroclearance and/or Seroconversion | Percentage of participants with HBsAg seroclearance and/or seroconversion will be reported. | Up to Week 204 | 
| Change from Baseline Over Time in HBsAg | Change from baseline over time in HBsAg will be reported. | Baseline and up to Week 204 | 
| Change from Baseline Over Time in HBeAg | Change from baseline over time in HBeAg will be reported. | Baseline and up to Week 204 | 
| Change from Baseline Over Time in HBV DNA | Change from baseline over time in HBV DNA will be reported. | Baseline and up to Week 204 | 
| Percentage of Participants with HBsAg levels below/above different cut-offs | Percentage of participants with HBsAg levels below/above different cut-offs will be reported. | Up to Week 204 | 
| Percentage of Participants with HBeAg levels below/above different cut-offs | Percentage of participants with HBeAg levels below/above different cut-offs will be reported. | Up to Week 204 | 
| Percentage of Participants with HBV DNA levels below/above different cut-offs | Percentage of participants with HBV DNA levels below/above different cut-offs will be reported. | Up to Week 204 | 
| Percentage of Participants with HBsAg Change From Baseline Below/Above Different Cut-offs | Percentage of participants with HBsAg change from baseline below/above different cut-offs will be reported. | Baseline and up to Week 204 | 
| Percentage of Participants with HBeAg Change From Baseline Below/Above Different Cut-offs | Percentage of participants with HBeAg change from baseline below/above different cut-offs will be reported. | Baseline and up to Week 204 | 
| Percentage of Participants with HBV DNA Change From Baseline Below/Above Different Cut-offs | Percentage of participants with HBV DNA change from baseline below/above different cut-offs will be reported. | Baseline and up to Week 204 | 
| Time to Reach Efficacy Thresholds such as HBsAg <1 IU/mL | Time to reach efficacy thresholds such as HBsAg <1 IU/mL will be reported. | Up to Week 204 | 
| Percentage of Participants with HBV DNA 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 < lower limit of quantification [LLOQ] of the HBV DNA assay) will be reported. | Up to Week 204 | 
| Area Under the Plasma Concentration-time Curve (AUC) of JNJ-73763989 | Area under the plasma concentration-time curve (AUC) of JNJ-73763989 will be reported. | Up to Week 124 | 
| Percentage of Participants with >=2 kPa Reduction from Baseline in LSM Assessed by VCTE (FibroScan) | Percentage of participants with >=2 kPa reduction from baseline in LSM assessed by VCTE (FibroScan) will be reported. | Up to Week 204 | 
| Change from Baseline in LSM Over Time Assessed by VCTE (FibroScan) | Change from baseline in LSM over time assessed by VCTE (FibroScan) will be reported. | Baseline and up to Week 204 | 
| Percentage of Participants with Sustained HDV Response Off-treatment Post end of JNJ-73763989 Treatment | Percentage of participants with sustained HDV response off-treatment post end of JNJ-73763989 treatment will be reported. | Up to Week 204 | 
| Percentage of Participants with HDV Relapse Post End of JNJ 73763989 Treatment | Percentage of participants with HDV relapse post end of JNJ 73763989 treatment will be reported. | Up to Week 204 | 
| Percentage of Participants with Sustained HBV Response Off-Treatment Post End of JNJ-73763989 Treatment. | Percentage of participants with sustained HBV response off-treatment post end of JNJ-73763989 treatment will be reported. | Up to Week 204 | 
| Percentage of Participants with HBV Flare (Virologic, Biochemical, and Clinical) Post End of Treatment | Percentage of participants with HBV flare (virologic, biochemical, and clinical) post end of treatment will be reported. | Up to Week 204 |