A Study of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus Infection

Hepatitis B, Chronic Clinical Trial

— REEF-1  

Official title:

A Phase 2b, Multicenter, Double-blind, Active-controlled, Randomized Study to Investigate the Efficacy and Safety of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03982186
• Other study ID #: CR108608
• Secondary ID: 2019-000622-2273
• Status: Completed
• Phase: Phase 2
• Start date: August 1, 2019
• Est. completion date: April 26, 2022

Study information

• Verified date: May 2023
• Source: Janssen Sciences Ireland UC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to establish the dose-response relationship for antiviral activity of 3 dose levels of JNJ-73763989+nucleos(t)ide analog (NA) and to evaluate the efficacy of combination regimens of JNJ-73763989+NA (with and without JNJ-56136379) and of JNJ-56136379+NA.

Description:

Hepatitis B virus (HBV) is a small deoxyribonucleic acid virus that specifically infects the human liver. The acute phase of infection is either followed by an immune controlled state or progresses to chronic hepatitis B. The worldwide estimated prevalence of chronic HBV infection is about 292 million people affected. Hepatitis B surface antigen (HBsAg) seroclearance is currently considered to be associated with the most thorough suppression of HBV replication (termed functional cure). With current available NA treatment strategies, rate of HBsAg seroclearance remains very low (around 3 percent [%]) even under long-term treatment. Also, with the persistently high global prevalence of HBV-associated mortality, there is a medical need for more effective finite treatment options that lead to sustained HBsAg seroclearance. JNJ-73763989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic HBV infection via ribonucleic acid interference mechanism. JNJ-56136379 is an orally administered capsid assembly modulator that is being developed for the treatment of chronic HBV infection. The aim of the study is to evaluate efficacy as measured by proportion of participants who completed 48-week study intervention and qualified for stopping NA treatment at Week 48. The study includes: Screening phase (4 weeks), Double-blind study intervention phase (from Day 1 up to Week 48), and Follow-up phase (48 weeks after end of investigational intervention with a maximum duration of 96 weeks). The duration of individual study participation will be between 100 and 150 weeks. Safety and tolerability (including adverse events [AEs] and Serious AEs, laboratory assessments, electrocardiogram [ECG], vital signs, physical examination), efficacy (including HBsAg seroclearance), and pharmacokinetics will be assessed throughout the study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 471
• Est. completion date: April 26, 2022
• Est. primary completion date: March 29, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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 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
• 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
• 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 and JNJ 6379 or their excipients or excipients of the placebo content
• Contraindications to the use of entecavir (ETV), tenofovir disoproxil fumarate (TDF), 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)

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 as medium dose (Arms 1 and 3), high dose (Arm 2), and low dose (Arm 4) as subcutaneous injection.
• Placebo for JNJ-73763989
Placebo for JNJ-73763989 will be administered as subcutaneous injection.
• JNJ-56136379
JNJ-56136379 tablets will be administered orally.
• Placebo for JNJ-56136379
Placebo for JNJ-56136379 tablets will be administered orally.
• Nucleos(t)ide Analog (NA)
NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc	Brussel
Belgium	UZ Antwerpen	Edegem
Belgium	UZA-SGS	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	UZ Leuven	Leuven
Brazil	Fundacao de Medicina Tropical Doutor Heitor Vieira Dourado - FMT	Manaus
Brazil	Universidade Federal da Bahia - Hospital Professor Edgard Santos	Salvador
Brazil	Hospital Das Clinicas Da Faculdade De Medicina Da USP	Sao Paulo
Canada	University of Calgary	Calgary	Alberta
Canada	University of Alberta - Faculty of Medicine & Dentistry	Edmonton	Alberta
Canada	Toronto General Hospital	Toronto
Canada	GI Research Institute (G.I.R.I.)	Vancouver	British Columbia
Canada	Vancouver ID Research and Care Centre Society	Vancouver	British Columbia
China	Nanfang Hospital	Guangzhou
Czechia	FN Hradec Kralove	Hradec Kralove
Czechia	RESEARCH SITE s.r.o.	Plzen
Czechia	IKEM	Praha
Czechia	KLIN MED s.r.o	Praha 2
France	Hopital Beaujon	Clichy
France	CHU de Grenoble - Hopital Albert Michallon	Grenoble
France	Hopital de La Croix Rousse	Lyon
France	Hopital Saint Joseph	Marseille
France	CHU de Nantes hôtel-Dieu	Nantes
France	Hopital Saint-Antoine	Paris
France	Chu Rennes - Hopital Pontchaillou	Rennes
France	Hopital Paul Brousse	Villejuif
Germany	EPIMED GmbH	Berlin
Germany	Universitatsklinikum Essen	Essen
Germany	Universitätsklinikum Johann Wolfgang Goethe- Universität Frankfurt Medizinische Klinik 1	Frankfurt
Germany	ICH Study Center GmbH & Co. KG	Hamburg
Germany	University Medical Center	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitatsklinikum Leipzig	Leipzig
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Hong Kong	The University of Hong Kong	Hong Kong
Hong Kong	The Chinese University of Hong Kong	Shatin
Italy	Azienda Ospedaliera Universitaria Policlinico G. Martino	Messina
Italy	Irccs Ospedale Maggiore Di Milano	Milano
Italy	Azienda Ospedaliero-Universitaria di Modena, Ospedale di Baggiovara	Modena
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	Universita degli Studi di Roma 'La Sapienza' - Umberto I Policlinico di Roma	Rome
Japan	Tokyo Medical and Dental University Hospital	Bunkyo-Ku
Japan	Chiba University Hospital	Chiba
Japan	Fukui-ken Saiseikai Hospital	Fukui City
Japan	Fukuyama City Hospital	Fukuyama
Japan	Hiroshima University Hospital	Hiroshima-shi
Japan	Kagawa Prefectural Central Hospital	Kagawa
Japan	Nara Medical University Hospital	Kashihara
Japan	Musashino Red Cross Hospital	Musashino
Japan	National Hospital Organization Nagasaki Medical Center	Nagasaki
Japan	Nagoya City University Hospital	Nagoya
Japan	The Hospital of Hyogo College of Medicine	Nishinomiya
Japan	Hokkaido University Hospital	Sapporo-shi
Japan	Osaka University Hospital	Suita-shi
Japan	Toranomon Hospital	Tokyo
Japan	Fujita Health University Hospital	Toyoake
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Malaysia	Hospital Sultanah Bahiyah	Alor Setar
Malaysia	Hospital Selayang	Batu Caves
Malaysia	Hospital University Sains Malaysia	Kota Bharu
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Poland	Wojewodzki Szpital Obserwacyjno-Zakazny im. Tadeusza Browicza w Bydgoszczy	Bydgoszcz
Poland	Neutrum Lekarze M.Hlebowicz i Partnerzy spolka partnerska	Gdansk
Poland	ID Clinic	Myslowice
Poland	Wojewodzki Szpital Zakazny w Warszawie	Warszawa
Poland	SP ZOZ Wroclawskie Centrum Zdrowia	Wroclaw
Russian Federation	Ural State Medical University	Chelyabinsk
Russian Federation	Sverdlovsk Regional Clinical Hospital #1	Ekaterinburg
Russian Federation	Krasnoyarsk Regional Center For AIDS And Infectious Diseases Treatment And Prophylaxis	Krasnoyarsk
Russian Federation	Clinic of the Modern Medicine	Moscow
Russian Federation	Medical Center SibNovoMed LLC	Novosibirsk
Russian Federation	Republican Clinical Infectious Hospital	Saint Petersburg
Russian Federation	St. Petersburg City Center for AIDS and Infectious Diseases Treatment and Prophylaxis	Saint Petersburg
Russian Federation	Clinical Infectious Diseases Hospital n. a. S.P. Botkin	Saint-Petersburg
Russian Federation	Medical Company Hepatolog Ltd	Samara
Russian Federation	Smolensk Regional Clinical Hospital	Smolensk
Russian Federation	Stavropol State Medical University	Stavropol
Spain	Hosp. Clinic I Provincial de Barcelona	Barcelona
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hospital Puerta De Hierro	Madrid
Spain	Hosp. Univ. Marques de Valdecilla	Santander
Spain	Hosp. Gral. Univ. Valencia	Valencia
Thailand	King Chulalongkorn Memorial Hospital	Bangkok
Thailand	Siriraj Hospital	Bangkok
Thailand	Chiang Mai University Hospital	Chiang Mai
Thailand	Prince Of Songkla University	Songkla
Turkey	Ankara Sehir Hastanesi	Ankara
Turkey	Ankara University Medical Faculty	Ankara
Turkey	Hacettepe University Hospital	Ankara
Turkey	Istanbul University Cerrahpasa Medical Faculty	Istanbul
Turkey	Ege University Medical of Faculty, Department of Gastroenterology	Izmir
Turkey	Karadeniz Teknik University Medical Faculty	Trabzon
United Kingdom	NHS Greater Glasgow and Clyde - Gartnavel General Hospital	Glasgow
United Kingdom	Grahame Hayton Unit	London
United Kingdom	Kings College Hospital	London
United Kingdom	St George's, University of London and St George's University Hospitals NHS Foundation Trust	London
United States	The Office of Franco Felizarta, MD	Bakersfield	California
United States	Johns Hopkins University	Baltimore	Maryland
United States	I.D. Care, Inc.	Hillsborough	New Jersey
United States	Ruane Clinical Research Group Inc	Los Angeles	California
United States	NYU Hepatology Associates	New York	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Southern California GI and Liver Center	San Clemente	California
United States	Johns Hopkins Office of Capital Region Research - Sibley Memorial Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Sciences Ireland UC

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  China,  Czechia,  France,  Germany,  Hong Kong,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Poland,  Russian Federation,  Spain,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Meeting the Nucleos(t)ide Analog (NA) Treatment Completion Criteria at Week 48	Percentage of participants meeting the NA treatment completion criteria at week 48 will be reported.	Week 48
Secondary	Number of Participants with Adverse Events (AE) and Serious Adverse Events (SAE) as a Measure of Safety and Tolerability	An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. 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 follow-up (maximum up to 150 weeks)
Secondary	Number of Participants with Abnormalities in Clinical Laboratory Tests, 12-Lead Electrocardiogram (ECG), and Vital Signs	Number of participants with abnormalities in clinical laboratory tests, 12-lead ECG, and vital signs will be reported.	Up to follow-up (maximum up to 150 weeks)
Secondary	Percentage of Participants with HBsAg Seroclearance After Completion of all Study Intervention	Percentage of participants with hepatitis B surface antigen (HBsAg) seroclearance after completion of all study intervention will be reported.	Week 72 and Week 96
Secondary	Percentage of Participants with HBV DNA less than (<) Lower Limit of Quantification (LLOQ) After Completion of all Study Intervention	Percentage participants with hepatitis B virus (HBV) deoxyribonucleic acid (DNA)	Week 72 and Week 96
Secondary	Percentage of Participants Meeting the NA Treatment Completion Criteria During Follow-up	Percentage of participants meeting the NA treatment completion criteria during follow-up will be reported.	Up to 96 weeks
Secondary	Percentage of Participants with HBsAg Seroclearance After Completion of NA Treatment at any Time During Follow-up	Percentage of participants with HBsAg seroclearance after completion of NA treatment at any time during follow-up will be reported.	Up to 150 weeks
Secondary	Percentage of Participants Requiring NA Re-treatment During Follow-up	Percentage of participants requiring NA re-treatment during follow-up will be reported.	Up to 150 weeks
Secondary	Percentage of Participants with Relapse	Percentage of participants with relapse will be reported.	Up to 150 weeks
Secondary	Percentage of Participants with (Sustained) Reduction, Suppression, and/or Seroclearance Considering Single and Multiple Markers	Percentage of participants with (sustained) reduction, suppression, and/or seroclearance considering single and multiple markers (such as hepatitis B surface antigen [HBsAg], hepatitis B e antigen [HBeAg], HBV DNA and alanine aminotransferase [ALT]) will be reported.	Up to Week 96
Secondary	Percentage of Participants with HBsAg Seroconversion	Percentage of participants with HBsAg seroconversion will be reported.	Up to 150 weeks
Secondary	Percentage of Participants with HBeAg Seroconversion	Percentage of participants with HBeAg seroconversion will be reported.	Up to 150 weeks
Secondary	Change From Baseline in HBsAg Levels	Change from baseline in HBsAg levels will be determined.	Baseline up to follow up (up to Week 150)
Secondary	Change From Baseline in HBeAg Levels	Change from baseline in HBeAg levels will be determined.	Baseline up to follow up (up to Week 150)
Secondary	Change from Baseline in HBV DNA Levels	Change from baseline in HBV DNA levels will be determined.	Baseline up to follow up (up to Week 150)
Secondary	Time to Achieve HBsAg Seroclearance	Time to achieve HBsAg seroclearance will be determined.	Up to Week 96
Secondary	Time to Achieve HBeAg Seroclearance	Time to achieve HBeAg seroclearance will be determined.	Up to Week 96
Secondary	Percentage of Participants with <100 IU/mL or >1 log10 IU/mL Reduction in HBsAg From Baseline	Percentage of participants with less than (<) 100 international units per milliliter (IU/mL) or greater than (>) 1 log10 IU/mL reduction in HBsAg from baseline will be assessed.	Baseline up to Week 150
Secondary	Percentage of HBeAg-positive Participants with HBeAg Levels	Percentage of HBeAg-positive participants with HBeAg levels will be reported.	Baseline up to Week 150
Secondary	Percentage of Participants with ALT Decrease and Normalization	Percentage of participants with alanine aminotransferase (ALT) decrease and normalization will be reported.	Up to follow-up (maximum up to 150 weeks)
Secondary	Percentage of Participants with Virologic Breakthrough	Percentage of participants with virologic breakthrough defined as confirmed on-treatment HBV DNA increase by >1 log10 IU/mL from nadir level or confirmed on treatment level >200 IU/mL in participants who had HBV DNA level below	Up to Week 48
Secondary	Percentage of Participants with Undetectable HBV DNA Levels After Re-start of NA Treatment During Follow-up	Percentage of participants who reach HBV DNA undetectability after re-start of NA treatment during follow-up will be reported.	Up to 150 weeks
Secondary	Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of JNJ-73763989	The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state.	Days 1, 29, 85, 169 and 337
Secondary	Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of JNJ-56136379	The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state.	Days 1, 29, 85, 169 and 337
Secondary	Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of NA	The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state.	Days 1, 29, 85, 169 and 337