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

• ClinicalTrials.gov Identifier: NCT04585789
• Recruitment Status: Completed
• First Posted: October 14, 2020
• Results First Posted: March 5, 2024
• Last Update Posted: March 5, 2024
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Hepatitis B	Drug: JNJ-73763989; Drug: JNJ-56136379; Drug: Entecavir (ETV); Drug: Tenofovir disoproxil; Drug: Tenofovir alafenamide (TAF); Drug: PegIFN-alpha-2a (Optional)	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: As per protocol amendment-5, JNJ-56136379 has been removed as study intervention and all participants are counted as single arm in each panel.
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Actual Study Start Date: March 11, 2021
• Actual Primary Completion Date: February 8, 2023
• Actual Study Completion Date: January 9, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Panel 1: JNJ-73763989+ NA; Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil or tenofovir alafenamide [TAF] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.	Drug: JNJ-73763989; JNJ-73763989 will be administered subcutaneously once every 4 weeks up to Week 44.; Drug: JNJ-56136379; JNJ-56136379 tablets will be administered orally once daily up to 48 weeks.; Drug: Entecavir (ETV); ETV tablet will be administered orally once daily up to 48 weeks as NA treatment.; Drug: Tenofovir disoproxil; Tenofovir disoproxil will be administered orally once daily up to 48 weeks as NA treatment.; Drug: Tenofovir alafenamide (TAF); TAF will be administered orally once daily up to 48 weeks as NA treatment.; Drug: PegIFN-alpha-2a (Optional); PegIFN-alpha-2a injection will be administered subcutaneously once weekly after Week 40 for either 12 or 24 weeks.
Experimental: Panel 2: JNJ-73763989+ NA; Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.	Drug: JNJ-73763989; JNJ-73763989 will be administered subcutaneously once every 4 weeks up to Week 44.; Drug: JNJ-56136379; JNJ-56136379 tablets will be administered orally once daily up to 48 weeks.; Drug: Entecavir (ETV); ETV tablet will be administered orally once daily up to 48 weeks as NA treatment.; Drug: Tenofovir disoproxil; Tenofovir disoproxil will be administered orally once daily up to 48 weeks as NA treatment.; Drug: Tenofovir alafenamide (TAF); TAF will be administered orally once daily up to 48 weeks as NA treatment.; Drug: PegIFN-alpha-2a (Optional); PegIFN-alpha-2a injection will be administered subcutaneously once weekly after Week 40 for either 12 or 24 weeks.

Outcome Measures

Primary Outcome Measures :

1. Panel 1 and 2: Absolute Change From Baseline in the Percentage of Hepatitis B Surface Antigen (HBsAg) Hepatocytes at Week 40 [ Time Frame: Baseline, 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.

Secondary Outcome Measures :

1. Panel 1 and 2: Change From Baseline in Intrahepatic Immune Response [ Time Frame: Baseline, Week 40 ]
   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.
2. Panel 1 and 2: Change From Baseline in Intrahepatic Viral Parameters: HBsAg and Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) [ Time Frame: Baseline, Week 40 ]
   Change from baseline in intrahepatic viral parameters (HBsAg and HBV DNA, measured in International units [IU/ml]) will be reported.
3. Panel 1 and 2: Change From Baseline in Intrahepatic Covalently Closed Circular DeoxyriboNucleic Acid (cccDNA) and Pre-genomic RiboNucleic Acid (pgRNA) Levels [ Time Frame: Baseline, Week 40 ]
   Change from baseline in intrahepatic cccDNA and pgRNA levels will be reported.
4. Panel 1 and 2: Percentage of Participants With HBsAg Seroclearance at Week 72 Without Restarting Nucleos(t)Ide Analog (NA)Treatment [ Time Frame: Week 72 (extended follow-up, ie, 24 weeks after completion of all study interventions at Week 48) ]
   Percentage of participants with HBsAg seroclearance (defined as quantitative HBsAg less than lower limit of quantification [<LLOQ; HBsAg 0.05 IU/mL]) at Week 72 without restarting NA treatment will be reported.
5. Panel 1 and 2: Percentage of Participants With (Sustained) Reduction, Suppression, and/or Seroclearance [ Time Frame: Up to Week 120 (included participants who received optional PegIFN-alpha-2a) ]
   Percentage of participants with HBsAg seroclearance (defined as quantitative HBsAg [<LLOQ; HBsAg 0.05 IU/mL]) at Week 72 without restarting NA treatment will be reported.
6. Panel 1 and 2: Percentage of Participants With HBsAg and Hepatitis B e Antigen (HBeAg) Seroconversion [ Time Frame: Up to Week 120 (included participants who received optional PegIFN-alpha-2a) ]
   Seroconversion of HBsAg is defined as having achieved HBsAg seroclearance (defined as quantitative HBsAg <LLOQ [0.05 IU/mL]) and appearance of anti-HBs antibodies (defined as a baseline anti-HBs antibodies [quantitative] <LLOQ [<10 milli-international units per milliliter (mIU/mL)] and a post-baseline assessment >=LLOQ [>=10 mIU/mL]). Seroconversion of HBeAg is defined as having achieved HBeAg seroclearance (defined as [quantitative] HBeAg <LLOQ [0.11 IU/mL]) together with appearance of anti-HBe antibodies (defined as a baseline anti-HBe antibodies [qualitative] with a "NEGATIVE" result and a post-baseline assessment with "POSITIVE" result).
7. Panel 1 and 2: Percentage of Participants With Flares [ Time Frame: Up to Week 120 (included participants who received optional PegIFN-alpha-2a) ]
   Virologic flare (VF;for off-treatment):Derivation 1: HBV DNA <LLOQ (200 IU/mL) at last observed point on-treatment. VF start:with HBV DNA >20 IU/mL and VF end:HBV DNA <=200 IU/mL or NA treatment restart. Derivation 2:HBV DNA >=LLOQ (20 IU/mL). VF start:HBV DNA log10 increase >1 log10 from EOT & VF end:HBV DNA log10 increase from EOT to <=1 log10 or NA treatment restart. Off-treatment biochemical flare (OTBF) start:ALT and/or AST >=3x ULN and >=3*nadir while participant received no study drugs. Same OTBF end:50% reduction from peak ALT and/or AST and <3*ULN. On-treatment BF start:ALT and/or AST >=3*ULN & >=3*nadir while participant received no study drugs. Same on-treatment BF end:50% reduction from peak ALT and/or AST and <3*ULN. Clinical flare (CF):VF & BF overlap in time/when BF starts within 4 weeks following VF end. CF start:minimum start of VF & BF & CF end:maximum end of VF & BF (HBV DNA <=200 IU/mL/<=1 log10) & 50% reduction from peak ALT and/or AST & <3*ULN reached during BF.
8. Panel 1 and 2: Time to Achieve First HBsAg Seroclearance [ Time Frame: Up to Week 120 (included participants who received optional PegIFN-alpha-2a) ]
   Time to achieve first HBsAg seroclearance (defined as quantitative HBsAg less than lower limit of quantification [<LLOQ; HBsAg 0.05 IU/mL]) will be reported. Time to HBsAg seroclearance is defined as the number of days between the date of first study intervention intake and the date of the first occurrence of HBsAg seroclearance (the date ofthe first HBsAg seroclearance - the date of first study intervention intake + 1). The participants who withdrew early from the study before achieving HBsAg seroclearance or who did not achieve HBsAg seroclearance will be censored at the last available HBsAg assessment.
9. Panel 1 and 2: Percentage of Participants With Virologic Breakthrough [ Time Frame: Up to Week 48 ]
   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 <LLOQ of the HBV DNA assay. Confirmed HBV DNA increase/level means that the criterion should be fulfilled at 2 or more consecutive time points or at the last observed on-treatment time point. On treatment is defined as the time period in which the participant receives any of the study interventions (JNJ-3989 and/or JNJ 6379 and/or NA and/or PegIFN-α2a). Percentage of participants with virologic breakthrough on treatment will be reported.
10. Panel 1 and 2: Change From Baseline in HBV-Specific Peripheral Blood T-cell Responses During the Study Intervention and Follow-up Phases [ Time Frame: Baseline up to Week 48 ]
    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.
11. Panel 1 and 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From Day 1 (Week 0) up to Week 120 (included participants who received optional PegIFN-alpha-2a) ]
    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.
12. Panel 1 and 2: Percentage of Participants With Abnormalities in Selected Clinical Laboratory Tests, Electrocardiogram (ECG), Vital Signs And Physical Examination [ Time Frame: From Day 1 (Week 0) up to Week 120 (included participants who received optional PegIFN-alpha-2a) ]
    Percentage of participants with abnormalities in clinical laboratory tests, ECG, vital signs and physical examination will be reported.
13. 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) [ Time Frame: Panel 1 and 2: post-dose on Days 1, 29, 85, 169, 337 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

Belgium

UZ Antwerpen

Edegem, Belgium, 2650

Canada, Ontario

Toronto General Hospital

Toronto, Ontario, Canada, ON M5G 2C4

France

Hopital Beaujon

Clichy, France, 92110

Germany

University Medical Center

Hamburg, Germany, D-20246

Italy

Irccs Ospedale Maggiore Di Milano

Milano, Italy, 20122

New Zealand

New Zealand Clinical Research

Auckland, New Zealand, 1010

Poland

ID Clinic

Myslowice, Poland, 41-400

United Kingdom

Grahame Hayton Unit

London, United Kingdom, E1 1BB

Kings College Hospital

London, United Kingdom, SE5 9RF

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:

Study Protocol  [PDF] November 25, 2021

Statistical Analysis Plan  [PDF] March 29, 2023

More Information

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT04585789
• Other Study ID Numbers: CR108790; 2019-004475-39 ( EudraCT Number ); 73763989HPB2003 ( Other Identifier: Janssen Research & Development, LLC )
• First Posted: October 14, 2020
• Results First Posted: March 5, 2024
• Last Update Posted: March 5, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency.

As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

• URL: https://www.janssen.com/clinical-trials/transparency

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Virus Diseases; Herpesviridae Infections; Hepatitis; Infections; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Tenofovir; Entecavir; JNJ-56136379; Peginterferon alfa-2a; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors