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
Overview
- Phase
- Phase 2
- Intervention
- JNJ-73763989
- Conditions
- Hepatitis B, Chronic
- Sponsor
- Janssen Sciences Ireland UC
- Enrollment
- 130
- Locations
- 41
- Primary Endpoint
- Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Seroclearance at Week 72 Without Restarting NA Treatment
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
JNJ-73763989+ JNJ-56136379+ NA
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.
Intervention: JNJ-73763989
JNJ-73763989+ JNJ-56136379+ NA
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.
Intervention: JNJ-56136379
JNJ-73763989+ JNJ-56136379+ NA
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.
Intervention: Entecavir (ETV) monohydrate
JNJ-73763989+ JNJ-56136379+ NA
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.
Intervention: Tenofovir disoproxil fumarate (TDF)
JNJ-73763989+ JNJ-56136379+ NA
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.
Intervention: Tenofovir alafenamide (TAF)
Placebo for JNJ-73763989+ Placebo for JNJ-56136379+ NA
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.
Intervention: Placebo for JNJ-73763989
Placebo for JNJ-73763989+ Placebo for JNJ-56136379+ NA
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.
Intervention: Placebo for JNJ-56136379
Placebo for JNJ-73763989+ Placebo for JNJ-56136379+ NA
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.
Intervention: Entecavir (ETV) monohydrate
Placebo for JNJ-73763989+ Placebo for JNJ-56136379+ NA
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.
Intervention: Tenofovir disoproxil fumarate (TDF)
Placebo for JNJ-73763989+ Placebo for JNJ-56136379+ NA
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.
Intervention: Tenofovir alafenamide (TAF)
Outcomes
Primary Outcomes
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Seroclearance at Week 72 Without Restarting NA Treatment
Time Frame: Week 72
Percentage of participants with HBsAg seroclearance at Week 72 (24 weeks after completion of all study interventions at Week 48) without restarting NA treatment was reported. Seroclearance at Week 72 of the treatment defined as a confirmed loss of HBsAg at Week 72. Loss is defined as a baseline HBsAg with a repeat reactive, confirmed or positive result and a post-baseline assessment with a negative result.
Secondary Outcomes
- Percentage of Participants With HBsAg Seroclearance at Week 48(Week 48)
- Percentage of Participants With HBsAg Seroconversion at Week 96(Week 96)
- Change From Baseline in HBsAg Values at Weeks 48, 72, and 96(Baseline (Day 1), Weeks 48, 72, and 96)
- Percentage of Participants With HBV DNA Levels Less Than (<) LLOQ From Baseline up to Week 96 (End of Study)(Baseline (Day 1) up to Week 96)
- Correlation Coefficient Between On-treatment HBsAg Change From Baseline With On-treatment HBV Blood Markers and Baseline Characteristics(Baseline (Day 1) to Week 96)
- Maximum Observed Analyte Concentration (Cmax) of JNJ-73763976 (Molecule of JNJ-73763989)(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Maximum Observed Analyte Concentration (Cmax) of JNJ-73763924 (Molecule of JNJ-73763989) Dose Normalized to 1 mg (Cmax[Dose Normalized])(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Area Under the Analyte Concentration Versus Time Curve From Time 0 to 24 Hours of JNJ-73763924 (Molecule of JNJ-73763989) Dose Normalized to 1 mg (AUC[0-24h], Dose Normalized)(0 to 24 hours postdose at Weeks 4, 8, 12, and 16)
- Percentage of Participants With Virologic Breakthrough(Baseline (Day 1) up to Week 48)
- Observed Plasma Concentration at Predose (C[Predose]) of JNJ-73763976 (Molecule of JNJ-73763989)(Predose at Weeks 4, 8, 12, and 16)
- Percentage of Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Less Than (<) Lower Limit of Quantification (LLOQ) at Week 48(Week 48)
- Percentage of Participants With HBsAg Seroclearance at Week 96 (48 Weeks After Stopping All Study Interventions at Week 48 Without Restarting NA Treatment)(Week 96)
- Percentage of Participants With Flares(Baseline (Day 1) up to Week 96)
- Time to Reach the Maximum Observed Plasma Concentration (Tmax) of JNJ-73763976 (Molecule of JNJ-73763989)(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Area Under the Analyte Concentration Versus Time Curve From Time 0 to 24 Hours (AUC[0-24h]) of JNJ-73763976 (Molecule of JNJ-73763989)(0 to 24 hours postdose at Weeks 4, 8, 12, and 16)
- Area Under the Analyte Concentration Versus Time Curve From Time 0 to 24 Hours of JNJ-73763976 (Molecule of JNJ-73763989) Dose Normalized to 1 mg (AUC[0-24h], Dose Normalized)(0 to 24 hours post-dose at Weeks 4, 8, 12, and 16)
- Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)(From screening up to Week 102)
- Percentage of Participants With (Sustained) Reduction, Suppression, and/or Seroclearance(Baseline (Day 1) up to Week 96)
- Change From Baseline in HBV DNA Values at Weeks 48, 72, and 96(Baseline (Day 1), Weeks 48, 72, and 96)
- Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs)(From screening up to 102 weeks)
- Time to Achieve First HBsAg Seroclearance(Baseline (Day 1) up to Week 96)
- Percentage of Participants With Reduction of More Than (>) 1 log10 IU/mL in HBsAg Levels From Baseline(Baseline (Day 1) up to Week 96)
- Maximum Observed Analyte Concentration (Cmax) of JNJ-73763976 (Molecule of JNJ-73763989) Dose Normalized to 1 mg (Cmax[Dose Normalized])(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Observed Plasma Concentration at 24 Hour Postdose (C[24h]) of JNJ-73763924 (Molecule of JNJ-73763989)(24 hours postdose at Weeks 4, 8, 12, and 16)
- Time to Reach the Maximum Observed Plasma Concentration (Tmax) of JNJ-56136379(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Observed or Predicted Concentration at the End of a Dosing Interval (Ctau) of JNJ-56136379(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Percentage of Participants With HBsAg Levels Less Than (<) 100 IU/mL at Weeks 48, 72, and 96(Weeks 48, 72, and 96)
- Percentage of Participants Requiring NA Re-Treatment During Follow-up(Baseline (Day 1) up to Week 96)
- Observed Plasma Concentration at 24 Hour Postdose (C[24h]) of JNJ-73763976 (Molecule of JNJ-73763989)(24 hours postdose at Weeks 4, 8, 12, and 16)
- Maximum Observed Analyte Concentration (Cmax) of JNJ-73763924 (Molecule of JNJ-73763989)(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Maximum Observed Analyte Concentration (Cmax) of JNJ-56136379(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Observed Plasma Concentration at Predose (C[Predose]) of JNJ-56136379(Predose at Weeks 4, 8, 12, and 16)
- Observed Plasma Concentration at Predose (C[Predose]) of JNJ-73763924 (Molecule of JNJ-73763989)(Predose at Weeks 4, 8, 12, and 16)
- Time to Reach the Maximum Observed Plasma Concentration (Tmax) of JNJ-73763924 (Molecule of JNJ-73763989)(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)
- Area Under the Analyte Concentration Versus Time Curve From Time 0 to 24 Hour (AUC[0-24h]) of JNJ-73763924 (Molecule of JNJ-73763989)(0 to 24 hours postdose at Weeks 4, 8, 12, and 16)
- Area Under the Analyte Concentration Versus Time Curve During a Dosing Interval at Steady State (AUCtau) of JNJ-56136379(Weeks 4, 8, 12, and 16: at Predose, 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose)