An Efficacy and Safety Study of a Combination of JNJ-73763989, Nucleos(t)Ide Analogs (NA), and a Programmed Cell Death Protein Receptor-1 (PD-1) Inhibitor in Chronic Hepatitis B Participants
- Conditions
- Hepatitis B, Chronic
- Interventions
- Registration Number
- NCT05275023
- Lead Sponsor
- Janssen Research & Development, LLC
- Brief Summary
The purpose of this study is to evaluate efficacy of the study intervention, based on hepatitis B surface antigen (HBsAg) levels at follow-up (FU) Week 24.
- Detailed Description
JNJ-73763989 (JNJ-3989) is a small interfering ribonucleic acid (siRNA) targeting all hepatitis B virus (HBV) messenger ribonucleic acid (mRNAs). The programmed cell death protein receptor-1 (PD-1) inhibitor aims at preventing the interaction of PD-1 with its ligands. The purpose of this study to determine whether at least one of the combination regimens of JNJ-3989 + PD-1 inhibitor + Nucleos(t)ide analog (NA) is more efficacious than JNJ-3989 + NA treatment. This study will be conducted in 3 periods: screening period, treatment period and follow-up (FU) period. Safety assessments will include adverse events (AEs), serious AEs, clinical safety laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. Total duration of individual participation will be up to 78 weeks (including screening period).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 37
- Participants must have chronic hepatitis B virus (HBV) infection
- Participants must have fibroscan liver stiffness measurement less than or equal to (<=) 9.0 kilopascal (kPa) or a liver biopsy result classified as metavir F0-F2
- Participants with evidence of hepatitis A virus infection (hepatitis A antibody immunoglobulin IgM), hepatitis C virus (HCV) infection (HCV antibody), hepatitis D virus (HDV) infection (HDV antibody), hepatitis E virus (HEV) infection (hepatitis E antibody IgM), or human immunodeficiency virus type 1 (HIV-1) or human immunodeficiency virus type 2 (HIV-2) infection (laboratory confirmed) 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
- Participants with history or signs of cirrhosis or portal hypertension or signs of hepatocellular carcinoma (HCC) or clinically relevant renal abnormalities
- Participants with personal/familial history/indicative of immune-mediated disease risk
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 2: JNJ-73763989 + PD-1 Inhibitor + NA PD-1 inhibitor Participants will receive JNJ-73763989 SC injections and multiple doses of PD-1 inhibitor as IV infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, TAF or ETV). Arm 1: JNJ-73763989 + PD-1 Inhibitor + Nucleos(t)ide analog (NA) JNJ-73763989 Participants will receive JNJ-73763989 subcutaneous (SC) injections and single dose of programmed cell death protein receptor-1 (PD-1) inhibitor as intravenous (IV) infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, tenofovir alafenamide \[TAF\] or entecavir \[ETV\]). Arm 1: JNJ-73763989 + PD-1 Inhibitor + Nucleos(t)ide analog (NA) PD-1 inhibitor Participants will receive JNJ-73763989 subcutaneous (SC) injections and single dose of programmed cell death protein receptor-1 (PD-1) inhibitor as intravenous (IV) infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, tenofovir alafenamide \[TAF\] or entecavir \[ETV\]). Arm 2: JNJ-73763989 + PD-1 Inhibitor + NA JNJ-73763989 Participants will receive JNJ-73763989 SC injections and multiple doses of PD-1 inhibitor as IV infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, TAF or ETV). Arm 2: JNJ-73763989 + PD-1 Inhibitor + NA Tenofovir Alafenamide Participants will receive JNJ-73763989 SC injections and multiple doses of PD-1 inhibitor as IV infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, TAF or ETV). Arm 1: JNJ-73763989 + PD-1 Inhibitor + Nucleos(t)ide analog (NA) Tenofovir Disoproxil Participants will receive JNJ-73763989 subcutaneous (SC) injections and single dose of programmed cell death protein receptor-1 (PD-1) inhibitor as intravenous (IV) infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, tenofovir alafenamide \[TAF\] or entecavir \[ETV\]). Arm 1: JNJ-73763989 + PD-1 Inhibitor + Nucleos(t)ide analog (NA) Entecavir Participants will receive JNJ-73763989 subcutaneous (SC) injections and single dose of programmed cell death protein receptor-1 (PD-1) inhibitor as intravenous (IV) infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, tenofovir alafenamide \[TAF\] or entecavir \[ETV\]). Arm 1: JNJ-73763989 + PD-1 Inhibitor + Nucleos(t)ide analog (NA) Tenofovir Alafenamide Participants will receive JNJ-73763989 subcutaneous (SC) injections and single dose of programmed cell death protein receptor-1 (PD-1) inhibitor as intravenous (IV) infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, tenofovir alafenamide \[TAF\] or entecavir \[ETV\]). Arm 2: JNJ-73763989 + PD-1 Inhibitor + NA Tenofovir Disoproxil Participants will receive JNJ-73763989 SC injections and multiple doses of PD-1 inhibitor as IV infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, TAF or ETV). Arm 2: JNJ-73763989 + PD-1 Inhibitor + NA Entecavir Participants will receive JNJ-73763989 SC injections and multiple doses of PD-1 inhibitor as IV infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, TAF or ETV).
- Primary Outcome Measures
Name Time Method Percentage of Participants Who Achieved Hepatitis B Surface Antigen (HBsAg) Seroclearance at Follow-up (FU) Week 24 At FU Week 24 Percentage of participants who achieved HBsAg seroclearance at FU Week 24 were reported. Seroclearance of HBsAg was defined as a (quantitative) HBsAg level less than (\<) lower limit of quantification (LLOQ) (0.05 international unit per milliliters \[IU/mL\]).
- Secondary Outcome Measures
Name Time Method Number of Participants With Abnormalities in Vital Signs IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Number of participants with abnormalities in vital signs measurements (including pulse rate: abnormally low: less than or equal to \[\<=\] 45 beats per minute \[bpm\], abnormally high: greater than or equal to \[\>=\] 120 bpm; diastolic blood pressure \[BP\]: abnormally low: \<=50 millimeters of mercury \[mmHg\], mild: \>90 to \<100 mmHg, moderate: \>=100 to \<110 mmHg, and severe: \>=110 mmHg; systolic BP: abnormally low: \<=90 mmHg, mild: \>140 to \<160 mmHg, moderate: \>=160 to \<180 mmHg, and severe: \>=180 mmHg) were reported.
Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) of Special Interest IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 An AE was any untoward medical occurrence in a participant participating in a clinical study that does not necessarily had a causal relationship with the pharmaceutical/biological agent under study. Any AE occurring at or after the initial administration of study intervention was considered to be treatment emergent. AEs of interest were significant AEs that are judged to be of special interest because of clinical importance, known class effects or based on nonclinical signals.
Number of Participants With Abnormalities in Physical Examinations IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Number of participants with abnormalities in physical examinations were reported.
Number of Participants With Abnormalities in Clinical Laboratory Parameters: Urinalysis IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Number of participants with abnormalities in clinical laboratory parameters (including specific gravity high and urine hyaline casts high) were reported. Abnormalities with at least 1 participant is included. Low and high categorization depend on investigator's discretion.
Percentage of Participants With HBsAg Seroconversion IP: Week 0 to Week 24; FU Phase: FU Week 1 up to FU Week 48 Percentage of participants with HBsAg seroconversion were reported. Seroconversion of HBsAg was defined as having achieved HBsAg seroclearance and appearance of anti-HBs antibodies (baseline anti-HBs antibodies \<LLOQ and a post-baseline assessment \>=LLOQ).
Number of Participants With TEAEs by Severity IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Number of participants with TEAEs by severity were reported. An AE was any untoward medical occurrence in a participant participating in a clinical study that did not necessarily had a causal relationship with the pharmaceutical/biological agent under study. Any AE occurring at or after the initial administration of study intervention was considered to be treatment emergent. Severity of AE were graded by using Division of Acquired Immunodeficiency Syndrome (DAIDS) grading scale that ranges from Grade 1 to Grade 5. Grade 1 indicates a mild event, Grade 2 indicates a moderate event, Grade 3 indicates a severe event, Grade 4 indicated a potentially life-threatening event, Grade 5 indicated death.
Number of Participants With Immune Related TEAEs IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Number of participants with immune related TEAEs were reported. An AE was any untoward medical occurrence in a participant participating in a clinical study that did not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. Any AE occurring at or after the initial administration of study intervention was considered to be treatment emergent. Immune-related AEs (irAEs) were alanine aminotransferase/alanine aminotransferase (ALT/AST) elevations including immune-related hepatic AEs, infusion-related reaction (IRRs) and other irAEs (including gastrointestinal AEs, neurological AEs, pulmonary AEs, renal AEs, endocrinopathies, rash, uveitis and visual complaints, lipase/amylase elevations, and infection), hematological abnormalities and injection site reactions.
Number of Participants With Abnormalities in 12-lead Electrocardiogram (ECGs) IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Number of participants with abnormalities in 12-lead ECGs: heart rate (abnormally low: \<45 beats per minute \[bpm\], abnormally high: greater than or equal \[\>=\] 120 bpm), PR interval (abnormally high: greater than \[\>\] 220 millisecond \[msec\]), QRS interval (abnormally high: \>=120 msec), QTc interval Fridericia (Borderline prolonged QT: 450\< QTc \<=480 msec; Prolonged QT: 480 \< QTc \<=500; Pathologically prolonged QT: QTc \>500) were reported.
Percentage of Participants With Abnormalities in Clinical Laboratory Parameters: Hematology IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Percentage of participants with abnormalities in hematology parameters (including basophils/Leukocytes high, erythrocytes mean corpuscular volume high, erythrocytes high and low, lymphocytes/leukocytes high and low, monocytes/leukocytes high and low, neutrophils, segmented+band form high and low, reticulocytes/erythrocytes high and low, basophils/leukocytes, eosinophils/leukocytes high, erythrocyte mean corpuscular hemoglobin low, reticulocytes/erythrocytes high and low, lymphocytes atypical/leukocytes high, lymphocytes atypical high, hematocrit high, monocytes low and high) were reported. Abnormalities with at least 1 participant is included. Low and high categorization depend on investigator's discretion.
Number of Participants With Abnormalities in Clinical Laboratory Parameters: Clinical Chemistry IP: Week 0 up to Week 24; FU Phase: FU Week 1 up to FU Week 48 Number of participants with abnormalities in clinical chemistry parameters (including C reactive protein high, cystatin C low and high, gamma glutamyl transferase low, high density lipoprotein \[HDL\] cholesterol low and high, indirect bilirubin high, lactate dehydrogenase high, protein high, thyrotropin low and high, free thyroxine high, free triiodothyronine low and high, and urea nitrogen high) were reported. Abnormalities with at least 1 participant is included. Low and high categorization depend on investigator's discretion.
Time to Achieve HBsAg Seroconversion Week 0 up to FU Week 48 (up to Week 72) Time to achieve HBsAg seroconversion were reported. Seroconversion of HBsAg was defined as having achieved HBsAg seroclearance and appearance of anti-HBs antibodies (baseline anti-HBs antibodies \<LLOQ and a post-baseline assessment \>=LLOQ).
Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels IP: Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, and End of Study Intervention (EOSI; Week 24); FU Phase: FU Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, and EOS (last visit at FU Week 48) Change from baseline in HBsAg levels were reported. International units per milliliters=IU/mL. End of Study Intervention (EOSI) was the last post-baseline visit in study intervention period. End of study (EOS) was the last visit in the study.
Percentage of Participants With Change in HBsAg Levels Below/Above Different Cut-offs Over Time IP: Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, and EOSI (Week 24); FU Phase: FU Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, and EOS (last visit at FU Week 48) Percentage of participants with change in HBsAg levels below/above different cut-offs (\<0.05 IU/mL, \<1 U/mL, \<10 IU/mL, \<100 IU/mL , \<1000 IU/mL) over time were reported. EOSI was the last post-baseline visit in study intervention period. EOS was the last visit in the study.
Percentage of Participants With HBsAg Seroclearance IP: Week 0 to Week 24; FU Phase: FU Week 1 up to FU Week 48 Percentage of participants with HBsAg seroclearance were reported. Seroclearance of HBsAg was defined as a HBsAg level \<lower limit of quantification (LLOQ) (0.05 IU/mL).
Time to Achieve HBsAg Seroclearance Week 0 up to FU Week 48 (up to Week 72) Time to achieve HBsAg seroclearance was reported. Seroclearance of HBsAg was defined as a (quantitative) HBsAg level \<LLOQ (0.05 IU/mL).
Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels Over Time IP: Baseline, Weeks 2, 4, 8, 12, 16, 20 and EOSI (Week 24); FU Phase: FU Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, and EOS (last visit at FU Week 48) HBV DNA levels over time were reported. EOSI was the last post-baseline visit in study intervention period. EOS was the last visit in the study.
Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) Level Below/Above Different Cut-offs Over Time IP: Baseline, Weeks 2, 4, 8, 12, 16, 20, and EOSI (Week 24); FU Phase: FU Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, and EOS (last visit at FU Week 48) Percentage of participants with HBV DNA level below/above different cut-offs over time were reported. HBV DNA cut offs: \<LLOQ target detected (TD): that is, traces of HBV DNA were detected/found but were too low to be quantified; \<LLOQ target not detected (TND): that is, no traces of HBV DNA were detected/found. EOSI was the last post-baseline visit in study intervention period. EOS was the last visit in the study. The LLOQ for HBV DNA was 20 IU/mL. As indicated in the data table, the sum of percentage values of each sub-categories within the specific timepoints "IP: Week 2" and "FU Phase: Week 4", shows a slight deviation from 100% due to rounding.
Percentage of Participants With Hepatitis B e Antigen (HBeAg) Level Below/Above Different Cut-offs Over Time IP: Baseline, Weeks 2, 4, 8, 12, 20, and EOSI (Week 24); FU Phase: FU Weeks 12, 16, 20, 24, 32, 40, 48, and EOS (last visit at FU Week 48) Percentage of participants with HBeAg level below/above different cut-offs over time were reported. HBeAg cut-offs: \<LLOQ (0.11 IU/mL). EOSI was the last post-baseline visit in study intervention period. EOS was the last visit in the study.
Percentage of Participants With Virologic Breakthrough IP: Week 0 to Week 24; FU Phase: FU Week 1 up to FU Week 48 Percentage of participants with virologic breakthrough (confirmed on-treatment HBV DNA increase by \>1 log10 IU/mL from nadir in participants who did not have on-treatment HBV DNA level below LLOQ or a confirmed on-treatment HBV DNA level \>200 IU/mL in participants who had on-treatment HBV DNA level below LLOQ) were reported.
Trial Locations
- Locations (26)
Hosp. Univ. Pta. de Hierro Majadahonda
🇪🇸Madrid, Spain
Imperial College London and Imperial College Healthcare NHS Trust
🇬🇧London, United Kingdom
Hopital Beaujon
🇫🇷Clichy, France
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Hacettepe University Medical Faculty
🇹🇷Ankara, Turkey
Universita degli Studi di Roma 'La Sapienza' - Umberto I Policlinico di Roma
🇮🇹Rome, Italy
China Medical University Hospital
🇨🇳Taichung, Taiwan
Karadeniz Teknik University Medical Faculty
🇹🇷Trabzon, Turkey
Hopital Saint Joseph
🇫🇷Marseille, France
Linkou Chang Gung Memorial Hospital
🇨🇳Taoyuan, Taiwan
IKEM
🇨🇿Prague 4, Czechia
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Chu Rennes Hopital Pontchaillou
🇫🇷Rennes, France
Fondazione IRCCS Ca Granda Ospedale Policlinico Di Milano
🇮🇹Milano, Italy
CHRU Nancy Brabois
🇫🇷Vandoeuvre-les-nancy, France
Azienda Ospedaliero Universitaria Pisana
🇮🇹Pisa, Italy
Hosp Univ Vall D Hebron
🇪🇸Barcelona, Spain
Istanbul University Cerrahpasa Medical Faculty
🇹🇷Istanbul, Turkey
Hosp. Montecelo
🇪🇸Pontevedra, Spain
Hosp. Gral. Univ. Valencia
🇪🇸Valencia, Spain
E-DA Hospital
🇨🇳Kaohsiung, Taiwan
Kaohsiung Medical University Chung Ho Memorial Hospital
🇨🇳Kaohsiung, Taiwan
Kocaeli University Medical Faculty
🇹🇷Kocaeli, Turkey
Ege University Medical Faculty
🇹🇷Izmir, Turkey
Glasgow Royal Infirmary
🇬🇧Glasgow, United Kingdom
Kings College Hospital
🇬🇧London, United Kingdom