An Efficacy, Safety, and Pharmacokinetics Study of JNJ-56136379 in Participants With Chronic Hepatitis B Virus Infection

Sponsor

Janssen Sciences Ireland UC (Industry)

Overall Status

Completed

CT.gov ID

NCT03361956

Collaborator

(none)

232

Enrollment

Locations

Arms

Actual Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis B	Drug: JNJ-56136379 Drug: Placebo Drug: NA (ETV or TDF)	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

232 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 13, 2018

Actual Primary Completion Date :

Sep 5, 2019

Actual Study Completion Date :

Aug 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: Arm 1 (JNJ-56136379 or NA) (open label) Participants with hepatitis B virus (HBV) currently not being treated and receiving JNJ-56136379 tablet (at a lower dose) orally for 24 weeks, will stop further dosing with JNJ-56136379 and start treatment with nucleos(t)ide analog (NA) (entecavir [ETV] or tenofovir disoproxil fumarate [TDF]), and enter the 24 week post treatment follow-up phase.	Drug: JNJ-56136379 Participants will receive JNJ-56136379 tablet orally. Other Names: JNJ-6379 Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Placebo Comparator: Part A: Arm 2 (Placebo+NA [ETV] or [TDF]) Participants with HBV currently not being treated will receive matching placebo along with NA (ETV or TDF) tablets orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: Placebo Participants will receive matching placebo tablet orally. Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Experimental: Part A: Arm 3 (JNJ-56136379 + NA [ETV or TDF]) Participants with HBV currently not being treated will receive JNJ-56136379 along with NA (ETV or TDF) tablet orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: JNJ-56136379 Participants will receive JNJ-56136379 tablet orally. Other Names: JNJ-6379 Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Placebo Comparator: Part A: Arm 4 (Placebo + NA [ETV or TDF]) Virologically suppressed participants will receive matching placebo along with NA (ETV or TDF) tablets orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: Placebo Participants will receive matching placebo tablet orally. Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Experimental: Part A: Arm 5 (JNJ-56136379 + NA [ETV or TDF]) Virologically suppressed participants will receive JNJ-56136379 along with NA (ETV or TDF) tablets orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: JNJ-56136379 Participants will receive JNJ-56136379 tablet orally. Other Names: JNJ-6379 Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Experimental: Part B: Arm 6 (JNJ-56136379 + NA [ETV or TDF]) (open label) Participants with HBV currently not being treated will receive JNJ-56136379 tablet at a high dose, orally for 24 weeks. The eligible participants may enter the extension phase and will receive JNJ-56136379 along with NA (ETV or TDF) from Week 24 to Week 48.	Drug: JNJ-56136379 Participants will receive JNJ-56136379 tablet orally. Other Names: JNJ-6379 Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Placebo Comparator: Part B: Arm 7 (placebo + NA [ETV or TDF]) Participants with HBV currently not being treated will receive matching placebo along with NA (ETV or TDF) tablets orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: Placebo Participants will receive matching placebo tablet orally. Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Experimental: Part B: Arm 8 (JNJ-56136379 + NA [ETV or TDF]) Participants with HBV currently not being treated will receive JNJ-56136379 tablet at a high dose along with NA (ETV or TDF) tablets orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: JNJ-56136379 Participants will receive JNJ-56136379 tablet orally. Other Names: JNJ-6379 Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Placebo Comparator: Part B: Arm 9 (placebo + NA [ETV or TDF]) Virologically suppressed participants will receive matching placebo along with NA (ETV or TDF) tablets orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: Placebo Participants will receive matching placebo tablet orally. Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.
Experimental: Part B: Arm 10 (JNJ-56136379 + NA [ETV or TDF]) Virologically suppressed participants will receive JNJ-56136379 tablet at a high dose along with NA (ETV or TDF) tablets orally for 24 weeks. The eligible participants may enter the extension phase and will continue study drugs up to 48 weeks.	Drug: JNJ-56136379 Participants will receive JNJ-56136379 tablet orally. Other Names: JNJ-6379 Drug: NA (ETV or TDF) Participants will receive NA (ETV or TDF) tablet orally as per approved label.

Outcome Measures

Primary Outcome Measures

Main Study: Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels at Week 24 [Baseline and Week 24]
Change from baseline in Hepatitis B surface antigen (HBsAg) levels at Week 24 will be assessed.

Secondary Outcome Measures

Main Study: Number of Participants With Adverse Events (AEs) [Up to Follow Up (maximum up to Week 96)]
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Main Study: Number of Participants With Serious Adverse Events (SAEs) [Up to Follow Up (maximum up to Week 96)]
A serious adverse event (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.
Main Study: Number of Participants with Abnormalities in Vital Signs, Physical Examinations, Electrocardiogram (ECG), Clinically Significant Laboratory Findings [Up to Follow Up (maximum up to Week 96)]
Number of participants with abnormalities in vital signs, physical examinations, ECG, clinically significant laboratory findings will be assessed.
Main Study: Change from Baseline in Hepatitis B Surface Antigen (HBsAg) Levels [Baseline up to follow up (maximum up to Week 96)]
Change from baseline in Hepatitis B surface antigen (HBsAg) levels will be assessed.
Main Study: Percentage of Participants With HBsAg Levels Less Than (<) 1,000 or <100 IU/mL [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Percentage of participants with HBsAg levels less than (<) 1,000 or <100 International Units Per Milliliter (IU/mL) will be assessed.
Main Study: Percentage of Participants With Greater Than (>) 0.5 or >1 log10 IU/mL Reduction in HBsAg From Baseline [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Percentage of participants with >0.5 or >1 log10 IU/mL reduction in HBsAg from baseline will be assessed.
Main Study: Change From Baseline in Hepatitis B Virus (HBV) Deoxyribonucleic acid (DNA) Levels [Baseline up to follow up (maximum up to Week 96)]
Change from baseline in Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels will be assessed.
Main Study: Percentage of Participants With Undetectable HBV DNA Levels [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Percentage of participants with undetectable HBV DNA levels will be evaluated.
Main Study: Change From Baseline in Hepatitis B E Antigen (HBeAg) Levels [Baseline up to follow up (maximum up to Week 96)]
Change from baseline in Hepatitis B E antigen (HBeAg) levels will be assessed.
Main Study: Percentage of Participants by HBeAg Levels [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Percentage of participants by HBeAg levels will be evaluated.
Main Study: Percentage of Participants With HBsAg or HBeAg Seroclearance [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Percentage of participants with seroclearance (defined as HBsAg or HBeAg negativity, respectively) will be assessed.
Main Study: Percentage of Participants With HBsAg or HBeAg Seroconversion [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Percentage of participants with seroconversion (defined as HBsAg or HBeAg negativity and anti-HBs or anti-HBe antibody positivity, respectively) will be assessed.
Main Study: Percentage of Participants With Normalized Alanine Aminotransferase (ALT) Levels [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Percentage of participants with normalized alanine aminotransferase (ALT) levels will be assessed whose ALT levers above upper limit of normal at baseline.
Main Study: Percentage of Participants With Virological Breakthrough [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, and 24]
Percentage of participants with viral breakthrough defined as confirmed on treatment HBV DNA increase by greater than (>) 1 log10 from nadir level or confirmed on treatment level >200 International Units Per Milliliter (IU/mL) in participants who had HBV DNA level below the lower limit of quantification (LLOQ) of the HBV DNA assay.
Main Study: Plasma Concentrations of NA (Entecavir [ETV] or Tenofovir Disoproxil Fumarate [TDF]) [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26 and 28]
Plasma concentrations of NA (entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) administered as monotherapy or co-administered with JNJ-56136379, will be determined.
Main Study: Plasma Concentrations of JnJ-56136379 [Baseline, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 26 and 28]
Plasma concentrations of JNJ-56136379 administered as monotherapy or when co-administered with NA (ETV or TDF), will be determined.
Main Study: Percentage of Participants With Treatment-Associated Mutations [Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 36 and 48]
Viral genome sequence analysis will be performed to evaluate emergence of mutations associated with JNJ-56136379 and/or ETV or TDF treatment.

Other Outcome Measures

Substudy: Change from Baseline in Intrahepatic Hepatitis B Virus (HBV) Covalently Closed Circular Deoxyribo Nucleic Acid (cccDNA) Levels at Week 24 and 48 [Baseline, Week 24 and Week 48]
Change from baseline in intrahepatic HBV cccDNA levels at Week 24 and 48 will be assessed.
Substudy: Change from Baseline in HBV cccDNA Transcriptional Activity at Week 24 and 48 [Baseline, Week 24 and Week 48]
Change from baseline in HBV cccDNA transcriptional activity at Week 24 and 48 will be assessed. cccDNA and intracellular viral RNA levels will be used to estimate transcriptional activity of cccDNA.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Office of Franco Felizarta, MD	Bakersfield	California	United States	93301
2	Orlando Immunology Center	Orlando	Florida	United States	32803
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	Tulane Medical Center (TMC)	New Orleans	Louisiana	United States	70112
5	I.D. Care, Inc.	Hillsborough	New Jersey	United States	08844
6	NYU Hepatology Associates	New York	New York	United States	10016
7	UPMC Center For Liver Diseases	Pittsburgh	Pennsylvania	United States	15213
8	SGS Clinical Pharmacology Unit (located in ZNA Stuivenberg)	Antwerpen		Belgium	2060
9	Cliniques Universitaires Saint-Luc	Bruxelles		Belgium	1200
10	UZ Antwerpen	Edegem		Belgium	2650
11	University of Calgary	Calgary	Alberta	Canada	T2N 1N4
12	Vancouver ID Research and Care Centre Society	Vancouver	British Columbia	Canada	V6Z 2C7
13	GI Research Institute (G.I.R.I.)	Vancouver	British Columbia	Canada	V6Z 2K5
14	McGill University Health Centre	Montreal	Quebec	Canada	H3H 2R9
15	Toronto General Hospital	Toronto		Canada	ON M5G 2C4
16	Peking University People's Hospital	Beijing		China	100034
17	Beiijing Friendship Hospital, Capital Medical University	Beijing		China	100050
18	The First Hospital of Jilin University	Changchun		China	130021
19	Nanfang Hospital	Guangzhou		China	510515
20	Hôpital Beaujon	Clichy		France	92110
21	Hopital de La Croix Rousse	Lyon		France	69004
22	Hopital Saint-Antoine	Paris		France	75012
23	Hopital Paul Brousse	Villejuif		France	94800
24	Zentrum für Infektiologie Berlin Prenzlauer Berg GmbH	Berlin		Germany	10439
25	Universitatsklinikum Essen	Essen		Germany	45122
26	Universitätsklinikum Johann Wolfgang Goethe- Universität Frankfurt Medizinische Klinik 1	Frankfurt		Germany	60590
27	Asklepios Klinik St. Georg, Haus Lifi - Studien und Projekte GmbH	Hamburg		Germany	20099
28	Queen Mary Hospital, University of Hong Kong	Hong Kong		Hong Kong
29	The Chinese University of Hong Kong	Shatin		Hong Kong
30	Irccs Ospedale Maggiore Di Milano	Milano		Italy	20122
31	ASST Grande Ospedale Metropolitano Niguarda	Milano		Italy	20162
32	Azienda Ospedaliero Universitaria Pisana	Pisa		Italy	56124
33	Hiroshima University Hospital	Hiroshima		Japan	734-8551
34	Musashino Red Cross Hospital	Musashino		Japan	180-8610
35	National Hospital Organization Nagasaki Medical Center	Nagasaki		Japan	856-8562
36	Nagoya City University Hospital	Nagoya		Japan	467-8602
37	Osaka University Hospital	Suita		Japan	565-0871
38	Pusan National University Hospital	Busan		Korea, Republic of	49241
39	Seoul National University Hospital	Seoul		Korea, Republic of	03080
40	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
41	Asan Medical Center	Seoul		Korea, Republic of	05505
42	Hospital Sultanah Bahiyah	Alor Setar		Malaysia	05460
43	University Malaya Medical Centre	Kuala Lumpur		Malaysia	59100
44	Szpital Specjalistyczny w Chorzowie	Chorzow		Poland	41-500
45	Wojewodzki Szpital Zespolony	Kielce		Poland	25-317
46	ID Clinic	Myslowice		Poland	41-400
47	SP ZOZ Wroclawskie Centrum Zdrowia	Wroclaw		Poland	50-136
48	Sverdlovsk Regional Clinical Hospital #1	Ekaterinburg		Russian Federation	620102
49	Medical Center SibNovoMed LLC	Novosibirsk		Russian Federation	630005
50	Medical Company Hepatolog Ltd	Samara		Russian Federation	443063
51	Stavropol State Medical University	Stavropol		Russian Federation	355017
52	Hosp. Clinic I Provincial de Barcelona	Barcelona		Spain	8028
53	Hosp. Univ. Vall D Hebron	Barcelona		Spain	8035
54	Hosp. Univ. Ramon Y Cajal	Madrid		Spain	28034
55	Hosp. Univ. Marques de Valdecilla	Santander		Spain	39008
56	Hosp. Virgen Del Rocio	Sevilla		Spain	41013
57	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan	80756
58	Taichung Veterans General Hospital	Taichung		Taiwan	40705
59	National Cheng Kung University Hospital	Tainan		Taiwan	70403
60	Chang Gung Memorial Hospital Linkou Branch	Tao-Yuan		Taiwan	333
61	King Chulalongkorn Memorial Hospital	Bangkok		Thailand	10500
62	Siriraj Hospital	Bangkok		Thailand	10700
63	Chiang Mai University Hospital	Chiang Mai		Thailand	50200
64	Prince Of Songkla University	Songkla		Thailand	90110
65	Istanbul University Cerrahpasa Medical Faculty	Istanbul		Turkey	34098
66	Saglık Bilimleri University Şişli Trainig and Research Hospital,Department of Gastroenterology	İstanbul		Turkey	34371
67	Ege University Medical of Faculty, Department of Gastroenterology	Izmir		Turkey	35100
68	Karadeniz Teknik University Medical Faculty	Trabzon		Turkey	61080
69	Kharkiv National Medical University, Regional Clinical Infectious Hospital	Kharkiv		Ukraine	61000
70	SE 'National institute therapy named L.T. Maloi NAMS of Ukraine'	Kharkiv		Ukraine	61039
71	Odessa Regional Clinical Hospital	Odessa		Ukraine	65025
72	Vinnytsia City Clinical Hospital #1, Department of Infectious Diseases #1	Vinnytsya		Ukraine	21021
73	North Manchester General Hospital	Crumpsall		United Kingdom	M8 5RB
74	Grahame Hayton Unit	London		United Kingdom	E1 1BB
75	Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne		United Kingdom	NE7 7DN
76	Nottingham University Hospitals NHS Trust	Nottingham		United Kingdom	NG7 2UH