Clinical trial NCT03361956: An Efficacy, Safety, and Pharmacokinetics Study of JNJ-56136379 in Participants With Chronic Hepatitis B Virus Infection
Official title: A Phase 2a, Randomized, Partially-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Pharmacokinetics of Treatment With Multiple Doses of JNJ-56136379 as Monotherapy and in Combination With a Nucleos(t)Ide Analog in Subjects With Chronic Hepatitis B Virus Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis B
Lead sponsor: Janssen Sciences Ireland UC
Sponsor class: INDUSTRY
First posted: 2017-12-05
Enrollment: 232
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main purpose of this study is to evaluate efficacy of 24 weeks of study treatment, in terms of changes in hepatitis B surface antigen (HBsAg) levels.

Detailed description: The main study consists of 2-parts and each part will consist of 2 types of Chronic Hepatitis B-infected participant populations. Each part of the study will consist of screening phase (up to 8 weeks), treatment phase (24 weeks or 48 weeks, depending on treatment response), and post-treatment follow-up phase (24 weeks or 48 weeks, depending on treatment response). The duration of individual participation will be up to approximately 56 weeks (participants not eligible to continue treatment in extension phase), up to 80 weeks (participants continuing treatment in extension phase but not meeting treatment completion criteria), or up to 104 weeks (participants meeting treatment completion criteria). The safety and efficacy will be monitored throughout the study. In a separate substudy, at selected clinical sites, percutaneous core liver biopsy will be performed to evaluate changes of intrahepatic viral parameters.

Eligibility criteria: Inclusion Criteria:

* Participants must have a body mass index (weight in kilogram (kg) divided by the square of height in meters) of 18.0 to 35.0 kilogram / square meter (kg/m\^2), extremes included
* Participants must have chronic hepatitis B virus infection (CHB) infection documented by: Serum hepatitis B surface antigen (HBsAg)-positive at screening and serum HBsAg- or hepatitis B virus (HBV) deoxyribonucleic acid (DNA)-positive at least 6 months prior to screening; Serum immunoglobulin M (IgM) anti- hepatitis B core-related (HBc) antibody negative at screening
* In participants currently not being treated (Treatment Arms 1-2-3 and 6-7-8): Participants must not be receiving any CHB treatment at screening, that is, Have never received treatment with HBV antiviral medicines, including NAs or interferon (IFN) products, OR Have not been on treatment with HBV antiviral medicines, including nucleos(t)ide analog (NA)s or IFN products within 6 months prior to baseline (first intake of study drugs), and participants must be HBeAg-positive and have HBV DNA greater than or equal to (\>=) 20,000 International Units Per Milliliter (IU/mL), OR be hepatitis B e antigen (HBeAg)-negative and have HBV DNA \>=2,000 IU /mL at screening, and participants must have HBsAg greater than (\>) 250 IU/mL at screening, and participants must have alanine aminotransferase (ALT) \> upper limit of normal (ULN) and less than or equal to (\<=) 5 \* ULN at screening, determined in the central laboratory
* In virologically suppressed participants (Treatment Arms 4-5 and 9-10): Participants must be virologically suppressed by current NA treatment (entecavir (ETV) or tenofovir disoproxil fumarate (TDF)) as defined by HBV DNA less than (\<) 60 IU/mL at screening and at least 6 months prior to screening, and participants must be on the same NA treatment (ETV or TDF) and the same dose for \>=12 months prior to screening, and participants must have HBsAg \> 250 IU/mL at screening, and participants must have ALT \<=2\*ULN at screening
* Participants must have: A liver biopsy result classified as Metavir F0-F2 within 1 year prior to screening or at the time of screening, OR FibroScan liver stiffness measurement \<8.0 kilopascal (kPa) within 6 months prior to screening or at the time of screening

Exclusion Criteria:

Main Study:

* Participants who test positive for anti-hepatitis B surface (HBs) antibodies
* Participants with current hepatitis A virus infection (confirmed by hepatitis A antibody immunoglobulin M \[IgM\]), hepatitis D virus (HDV) infection (confirmed by HDV antibody), hepatitis E virus infection (confirmed by hepatitis E antibody IgM), or human immunodeficiency virus (HIV)-1 or HIV-2 infection (confirmed by antibodies) at screening; participants with a history of or current HCV infection (confirmed by HCV antibody). Evidence of other active infection (bacterial, viral, fungal, including acute tuberculosis) deemed clinically relevant by the investigator that would interfere with study conduct or its interpretation will also lead to exclusion
* Participants with any evidence of hepatic decompensation at any time point prior to or at the time of screening: Direct bilirubin \>1.2\* ULN, or International normalized ratio (INR) \>1.5\* ULN, or Serum albumin \< lower limit of normal (LLN), or documented history or current evidence of variceal bleeding, ascites, or hepatic encephalopathy
* Participants with a history of cardiac arrhythmia (example, extrasystoli, tachycardia at rest), history of risk factors for Torsades de Pointes syndrome (example, hypokalemia, family history of long QT syndrome) or history or other clinical evidence of significant or unstable cardiac disease (example, angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia, coronary heart disease, and/or clinically significant 12 lead electrocardiograms (ECGs) abnormalities), moderate to severe valvular disease, or uncontrolled hypertension at screening
* Participants with contraindications to the use of ETV or TDF per local prescribing information

Substudy:

* Presence of coagulopathy or hemoglobinopathy (including sickle cell disease, thalassemia)
* Use of any anti-coagulant, anti-platelet, or non-steroidal anti-inflammatory drug medications from 10 days before until 5 days after each liver biopsy
* Presence of ascites, focal liver lesions, and other findings that would be contraindications for liver biopsies

Primary outcomes:
measure: Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels in Currently Not Treated Population at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in HBsAg Levels in Virologically Suppressed Population at Week 24
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Number of Participants With Treatment- Emergent Adverse Events (AEs)
timeFrame: Up to Week 48
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: Up to Week 80
measure: Number of Participants With Clinically Significant Changes in Vital Signs, Physical Examinations, Electrocardiogram (ECG), and Clinical Laboratory Tests
timeFrame: Up to Week 80
measure: Change From Baseline in HBsAg Levels in Currently Not Treated Population Over Time
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Change From Baseline in HBsAg Levels in Virologically Suppressed Population Over Time
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With HBsAg Levels Less Than (<) 1,000 or <100 International Units Per Milliliter (IU/mL) in Currently Not Treated Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With HBsAg Levels <1,000 or <100 IU/mL in Virologically Suppressed Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With Greater Than (>) 0.5 log10 IU/mL or >1 log10 IU/mL Reduction in HBsAg From Baseline in Currently Not Treated Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With >0.5 log10 IU/mL or >1 log10 IU/mL Reduction in HBsAg From Baseline in Virologically Suppressed Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels in Currently Not Treated Population
timeFrame: Baseline up to Weeks 24, 48 and Follow-up Week 24
measure: Change From Baseline in HBV DNA Levels in Virologically Suppressed Population
timeFrame: Baseline up to Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With Undetectable HBV DNA Levels in Currently Not Treated Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With Undetectable HBV DNA Levels in Virologically Suppressed Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Change From Baseline in HBeAg Levels in Currently Not Treated Population
timeFrame: Baseline up to Weeks 24, 48 and Follow-up Week 24
measure: Change From Baseline in HBeAg Levels in Virologically Suppressed Population
timeFrame: Baseline up to Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With >0.5 log10 IU/mL and >1 log10 IU/mL Reduction in HBeAg From Baseline in Currently Not Treated Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With >0.5 log10 IU/mL and >1 log10 IU/mL Reduction in HBeAg From Baseline in Virologically Suppressed Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With HBsAg Seroclearance in Currently Not Treated Population
timeFrame: Weeks 24 and 48
measure: Percentage of Participants With HBsAg Seroclearance in Virologically Suppressed Population
timeFrame: Weeks 24 and 48
measure: Percentage of Participants With HBsAg Seroconversion in Currently Not Treated Population
timeFrame: Weeks 24 and 48
measure: Percentage of Participants With HBsAg Seroconversion in Virologically Suppressed Population
timeFrame: Weeks 24 and 48
measure: Percentage of Participants With Normalized Alanine Aminotransferase (ALT) Levels in Currently Not Treated Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With Normalized ALT Levels in Virologically Suppressed Population
timeFrame: Weeks 24, 48 and Follow-up Week 24
measure: Percentage of Participants With Virological Breakthrough in Currently Not Treated Population
timeFrame: Weeks 24 and 48
measure: Percentage of Participants With Virological Breakthrough in Virologically Suppressed Population
timeFrame: Weeks 24 and 48
measure: Plasma Concentrations of Entecavir [ETV] in Currently Not Treated Population
timeFrame: Day 1: 0 hours, 2 hours; Weeks 1, 2, 4, 8, 12, 20, 24, 28, 32, 36, 44, 48: 0 hours; Follow-up: Weeks 2 and 4
measure: Plasma Concentrations of ETV in Virologically Suppressed Population
timeFrame: Day 1: 0 hours, 2 hours; Weeks 1, 2, 4, 8, 12, 20, 24, 28, 32, 36, 44, 48: 0 hours; Follow-up: Weeks 2 and 4
measure: Plasma Concentrations of Tenofovir Disoproxil Fumarate (TDF) in Currently Not Treated Population
timeFrame: Day 1: 0 hours, 2 hours; Weeks 1, 2, 4, 8, 12, 20, 24, 28, 32, 36, 44, 48: 0 hours; Follow-up: Weeks 2 and 4
measure: Plasma Concentrations of TDF in Virologically Suppressed Population
timeFrame: Day 1: 0 hours, 2 hours; Weeks 1, 2, 4, 8, 12, 20, 24, 28, 32, 36, 44, 48: 0 hours; Follow-up: Weeks 2 and 4
measure: Plasma Concentrations of JNJ-56136379 in Currently Not Treated Population
timeFrame: Day 1: 0 hours, 2 hours; Weeks 1, 2, 4, 8, 12, 20, 24, 28, 32, 36, 44, 48: 0 hours; Follow-up: Weeks 2 and 4
measure: Plasma Concentrations of JNJ-56136379 in Virologically Suppressed Population
timeFrame: Day 1: 0 hours, 2 hours; Weeks 1, 2, 4, 8, 12, 20, 24, 28, 32, 36, 44, 48: 0 hours; Follow-up: Weeks 2 and 4
measure: Number of Participants With Treatment-Associated Mutations
timeFrame: From Week 0 to Week 24, From Week 25 to Week 48, Up to Follow-up Week 24
Other outcomes:
Locations:
city: Bakersfield
country: United States
facility: The Office of Franco Felizarta, MD
state: California
city: Orlando
country: United States
facility: Orlando Immunology Center
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: New Orleans
country: United States
facility: Tulane Medical Center (TMC)
state: Louisiana
city: Hillsborough
country: United States
facility: I.D. Care, Inc.
state: New Jersey
city: New York
country: United States
facility: NYU Hepatology Associates
state: New York
city: Pittsburgh
country: United States
facility: UPMC Center For Liver Diseases
state: Pennsylvania
city: Antwerpen
country: Belgium
facility: SGS Clinical Pharmacology Unit (located in ZNA Stuivenberg)
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver ID Research and Care Centre Society
state: British Columbia
city: Vancouver
country: Canada
facility: GI Research Institute (G.I.R.I.)
state: British Columbia
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Toronto
country: Canada
facility: Toronto General Hospital
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Beiijing Friendship Hospital, Capital Medical University
city: Changchun
country: China
facility: The First Hospital of Jilin University
city: Guangzhou
country: China
facility: Nanfang Hospital
city: Clichy
country: France
facility: Hôpital Beaujon
city: Lyon
country: France
facility: Hopital de La Croix Rousse
city: Paris
country: France
facility: Hopital Saint-Antoine
city: Villejuif
country: France
facility: Hopital Paul Brousse
city: Berlin
country: Germany
facility: Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Frankfurt
country: Germany
facility: Universitätsklinikum Johann Wolfgang Goethe- Universität Frankfurt Medizinische Klinik 1
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg, Haus Lifi - Studien und Projekte GmbH
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital, University of Hong Kong
city: Shatin
country: Hong Kong
facility: The Chinese University of Hong Kong
city: Milano
country: Italy
facility: Irccs Ospedale Maggiore Di Milano
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Hiroshima-shi
country: Japan
facility: Hiroshima University Hospital
city: Musashino
country: Japan
facility: Musashino Red Cross Hospital
city: Nagasaki
country: Japan
facility: National Hospital Organization Nagasaki Medical Center
city: Nagoya
country: Japan
facility: Nagoya City University Hospital
city: Suita-shi
country: Japan
facility: Osaka University Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Alor Setar
country: Malaysia
facility: Hospital Sultanah Bahiyah
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Chorzow
country: Poland
facility: Szpital Specjalistyczny w Chorzowie
city: Kielce
country: Poland
facility: Wojewodzki Szpital Zespolony
city: Myslowice
country: Poland
facility: ID Clinic
city: Wroclaw
country: Poland
facility: SP ZOZ Wroclawskie Centrum Zdrowia
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Clinical Hospital #1
city: Novosibirsk
country: Russian Federation
facility: Medical Center SibNovoMed LLC
city: Samara
country: Russian Federation
facility: Medical Company Hepatolog Ltd
city: Stavropol
country: Russian Federation
facility: Stavropol State Medical University
city: Barcelona
country: Spain
facility: Hosp. Clinic I Provincial de Barcelona
city: Barcelona
country: Spain
facility: Hosp. Univ. Vall D Hebron
city: Madrid
country: Spain
facility: Hosp. Univ. Ramon Y Cajal
city: Santander
country: Spain
facility: Hosp. Univ. Marques de Valdecilla
city: Sevilla
country: Spain
facility: Hosp. Virgen Del Rocio
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Tao-Yuan
country: Taiwan
facility: Chang Gung Memorial Hospital Linkou Branch
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Chiang Mai
country: Thailand
facility: Chiang Mai University Hospital
city: Songkla
country: Thailand
facility: Prince Of Songkla University
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpasa Medical Faculty
city: İstanbul
country: Turkey
facility: Saglık Bilimleri University Şişli Trainig and Research Hospital,Department of Gastroenterology
city: Izmir
country: Turkey
facility: Ege University Medical of Faculty, Department of Gastroenterology
city: Trabzon
country: Turkey
facility: Karadeniz Teknik University Medical Faculty
city: Kharkiv
country: Ukraine
facility: Kharkiv National Medical University, Regional Clinical Infectious Hospital
city: Kharkiv
country: Ukraine
facility: SE 'National institute therapy named L.T. Maloi NAMS of Ukraine'
city: Odessa
country: Ukraine
facility: Odessa Regional Clinical Hospital
city: Vinnytsya
country: Ukraine
facility: Vinnytsia City Clinical Hospital #1, Department of Infectious Diseases #1
city: Crumpsall
country: United Kingdom
facility: North Manchester General Hospital
city: London
country: United Kingdom
facility: Grahame Hayton Unit
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
Study officials:
affiliation: Janssen Sciences Ireland UC
name: Janssen Sciences Ireland UC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Berke JM, Dehertogh P, Vergauwen K, Mostmans W, Vandyck K, Raboisson P, Pauwels F. Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379. Antimicrob Agents Chemother. 2020 Apr 21;64(5):e02439-19. doi: 10.1128/AAC.02439-19. Print 2020 Apr 21.