A Study to Assess Intrahepatic and Peripheral Changes of Immunologic and Virologic Markers in Chronic Hepatitis B Virus Infection

Hepatitis B Clinical Trial

— INSIGHT  

Official title:

A Phase 2 Randomized, Open-label, Parallel-group, Multicenter Study to Assess Intrahepatic and Peripheral Changes of Immunologic and Virologic Markers in Response to Combination Regimens Containing JNJ-73763989 and Nucleos(t)Ide Analog With or Without JNJ-56136379 in Patients With Chronic Hepatitis B Virus Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04585789
• Other study ID #: CR108790
• Secondary ID: 2019-004475-3973
• Status: Completed
• Phase: Phase 2
• Start date: March 11, 2021
• Est. completion date: January 9, 2024

Study information

• Verified date: February 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess changes in intrahepatic hepatitis B surface antigen (HBsAg) between baseline and on-treatment liver biopsy in response to JNJ-3989-based combination treatment.

Description:

The title of protocol reflects the original study design. The study design section is reflecting that the design as of protocol amendment 5 is non-randomized.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: January 9, 2024
• Est. primary completion date: February 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Medically stable on the basis of physical examination, medical history, vital signs, and triplicate 12-lead electrocardiogram (ECG) performed at screening

• Hepatitis B virus (HBV) infection with documentation at least 6 months prior to screening: participants be either currently not treated with HBeAg positive status or virologically (nucleos[t]ide analog [NA]) suppressed with HBeAg negative status

• 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

• Fibroscan liver stiffness measurement less than and equal to (<=) 9 Kilopascal (kPa) within 6 months prior to screening or at the time of 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

• History or signs of cirrhosis or portal hypertension, signs of hepatocellular carcinoma (HCC) or clinically relevant renal abnormalities on an abdominal ultrasound performed within 6 months prior to screening or at the time of screening

• Presence of coagulopathy or bleeding disorder as indicated by: (a) International normalized ratio (INR) greater than or equal to (>=) 1.1* upper limit of normal (ULN); (b) Partial thromboplastin time >1.1*ULN; (c) Any signs of prolonged bleeding (>10 minutes)

• Presence of hemoglobinopathy (including sickle cell disease, thalassemia)

• Liver biopsy performed prior to screening that led to complications and that in the opinion of the investigator would prohibit another liver biopsy

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Herpesviridae Infections
• Virus Diseases

Intervention

Drug:
• JNJ-73763989
JNJ-73763989 will be administered subcutaneously once every 4 weeks up to Week 44.
• JNJ-56136379
JNJ-56136379 tablets will be administered orally once daily up to 48 weeks.
• Entecavir (ETV)
ETV tablet will be administered orally once daily up to 48 weeks as NA treatment.
• Tenofovir disoproxil
Tenofovir disoproxil will be administered orally once daily up to 48 weeks as NA treatment.
• Tenofovir alafenamide (TAF)
TAF will be administered orally once daily up to 48 weeks as NA treatment.
• PegIFN-alpha-2a (Optional)
PegIFN-alpha-2a injection will be administered subcutaneously once weekly after Week 40 for either 12 or 24 weeks.

Locations

Country	Name	City	State
Belgium	UZ Antwerpen	Edegem
Canada	Toronto General Hospital	Toronto	Ontario
France	Hopital Beaujon	Clichy
Germany	University Medical Center	Hamburg
Italy	Irccs Ospedale Maggiore Di Milano	Milano
New Zealand	New Zealand Clinical Research	Auckland
Poland	ID Clinic	Myslowice
United Kingdom	Grahame Hayton Unit	London
United Kingdom	Kings College Hospital	London
United States	Johns Hopkins University	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Italy,  New Zealand,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Panel 1 and 2: Absolute Change From Baseline in the Percentage of Hepatitis B Surface Antigen (HBsAg) Hepatocytes at Week 40	The absolute change from baseline to on-treatment liver biopsy timepoint (Week 40) in terms of the percentage of HBsAg-positive hepatocytes (at Week 40) were reported.	Baseline, Week 40
Secondary	Panel 1 and 2: Change From Baseline in Intrahepatic Immune Response	Variation in major cell populations (CD4+ T-cells, CD8+ T-cells, CD45+ T-cells, natural killer cells, and dendritic cells, defined by single cell transcriptomics [in FNABs] and immunofluorescence staining [in core needle biopsies]) assessed at Week 40 will be reported.	Baseline, Week 40
Secondary	Panel 1 and 2: Change From Baseline in Intrahepatic Viral Parameters: HBsAg and Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA)	Change from baseline in intrahepatic viral parameters (HBsAg and HBV DNA, measured in International units [IU/ml]) will be reported.	Baseline, Week 40
Secondary	Panel 1 and 2: Change From Baseline in Intrahepatic Covalently Closed Circular DeoxyriboNucleic Acid (cccDNA) and Pre-genomic RiboNucleic Acid (pgRNA) Levels	Change from baseline in intrahepatic cccDNA and pgRNA levels will be reported.	Baseline, Week 40
Secondary	Panel 1 and 2: Percentage of Participants With HBsAg Seroclearance at Week 72 Without Restarting Nucleos(t)Ide Analog (NA)Treatment	Percentage of participants with HBsAg seroclearance (defined as quantitative HBsAg less than lower limit of quantification [	Week 72 (extended follow-up, ie, 24 weeks after completion of all study interventions at Week 48)
Secondary	Panel 1 and 2: Percentage of Participants With (Sustained) Reduction, Suppression, and/or Seroclearance	Percentage of participants with HBsAg seroclearance (defined as quantitative HBsAg [	Up to Week 120 (included participants who received optional PegIFN-alpha-2a)
Secondary	Panel 1 and 2: Percentage of Participants With HBsAg and Hepatitis B e Antigen (HBeAg) Seroconversion	Seroconversion of HBsAg is defined as having achieved HBsAg seroclearance (defined as quantitative HBsAg	Up to Week 120 (included participants who received optional PegIFN-alpha-2a)
Secondary	Panel 1 and 2: Percentage of Participants With Flares	Virologic flare (VF;for off-treatment):Derivation 1: HBV DNA	Up to Week 120 (included participants who received optional PegIFN-alpha-2a)
Secondary	Panel 1 and 2: Time to Achieve First HBsAg Seroclearance	Time to achieve first HBsAg seroclearance (defined as quantitative HBsAg less than lower limit of quantification [	Up to Week 120 (included participants who received optional PegIFN-alpha-2a)
Secondary	Panel 1 and 2: Percentage of Participants With Virologic Breakthrough	Virological breakthrough was defined as confirmed on-treatment HBV DNA increase by >1 log10 IU/mL from nadir level (lowest level reached during treatment) in participants who did not have on-treatment HBV DNA level < LLOQ (20 IU/mL) or confirmed on-treatment HBV DNA level >200 IU/mL in participants who had on-treatment HBV DNA level	Up to Week 48
Secondary	Panel 1 and 2: Change From Baseline in HBV-Specific Peripheral Blood T-cell Responses During the Study Intervention and Follow-up Phases	Change from baseline in HBV-specific peripheral blood T-cell responses during the study intervention and follow-up phases will be reported. HBV-specific T-cells were characterized in peripheral blood mononuclear cell immune analyss by binding assays (multimer staining) combined with downstream TCR and transcriptome profiling.	Baseline up to Week 48
Secondary	Panel 1 and 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	From Day 1 (Week 0) up to Week 120 (included participants who received optional PegIFN-alpha-2a)
Secondary	Panel 1 and 2: Percentage of Participants With Abnormalities in Selected Clinical Laboratory Tests, Electrocardiogram (ECG), Vital Signs And Physical Examination	Percentage of participants with abnormalities in clinical laboratory tests, ECG, vital signs and physical examination will be reported.	From Day 1 (Week 0) up to Week 120 (included participants who received optional PegIFN-alpha-2a)
Secondary	Panel 1 and 2: Plasma Concentration of JNJ-73763989 (JNJ-73763976 and JNJ-73763924) and Optionally of JNJ-56136379, NA and/or Pegylated Interferon Alpha-2a (PegIFN-alpha-2a)	Plasma samples will be analyzed to determine concentrations of JNJ-73763989 (JNJ-73763976 and JNJ-73763924) and optionally of JNJ-56136379, NA and/or PegIFN-alpha-2a.	Panel 1 and 2: post-dose on Days 1, 29, 85, 169, 337