REEF-1: A Study of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus Infection

Sponsor
Janssen Sciences Ireland UC (Industry)
Overall Status
Completed
CT.gov ID
NCT03982186
Collaborator
(none)
471
108
6
32.8
4.4
0.1

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
471 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Aug 1, 2019
Actual Primary Completion Date :
Mar 29, 2021
Actual Study Completion Date :
Apr 26, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm 1: JNJ-73763989 (medium dose) + JNJ-56136379 + NA

Participants will receive medium dose of JNJ-73763989 along with JNJ-56136379 and nucleos(t)ide analog (NA) treatment (either entecavir [ETV], tenofovir disoproxil fumarate [TDF], or tenofovir alafenamide [TAF]) up to 48 weeks.

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.

Drug: JNJ-56136379
JNJ-56136379 tablets will be administered orally.

Drug: Nucleos(t)ide Analog (NA)
NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.

Experimental: Arm 2: JNJ-73763989 (high dose) + Placebo + NA

Participants will receive high dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.

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.

Drug: Placebo for JNJ-56136379
Placebo for JNJ-56136379 tablets will be administered orally.

Drug: Nucleos(t)ide Analog (NA)
NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.

Experimental: Arm 3: JNJ-73763989 (medium dose) + Placebo + NA

Participants will receive medium dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.

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.

Drug: Placebo for JNJ-56136379
Placebo for JNJ-56136379 tablets will be administered orally.

Drug: Nucleos(t)ide Analog (NA)
NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.

Experimental: Arm 4: JNJ-73763989 (low dose) + Placebo + NA

Participants will receive low dose of JNJ-73763989 along with placebo for JNJ-56136379 and NA (either ETV, TDF, or TAF) up to 48 weeks.

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.

Drug: Placebo for JNJ-56136379
Placebo for JNJ-56136379 tablets will be administered orally.

Drug: Nucleos(t)ide Analog (NA)
NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.

Experimental: Arm 5: Placebo + JNJ-56136379 + NA

Participants will receive placebo for JNJ-73763989 and a fixed dose of JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.

Drug: Placebo for JNJ-73763989
Placebo for JNJ-73763989 will be administered as subcutaneous injection.

Drug: JNJ-56136379
JNJ-56136379 tablets will be administered orally.

Drug: Nucleos(t)ide Analog (NA)
NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.

Placebo Comparator: Arm 6 (Control): Placebo + Placebo + NA

Participants will receive placebo for JNJ-73763989 and placebo for JNJ-56136379 along with NA (either ETV, TDF, or TAF) up to 48 weeks.

Drug: Placebo for JNJ-73763989
Placebo for JNJ-73763989 will be administered as subcutaneous injection.

Drug: Placebo for JNJ-56136379
Placebo for JNJ-56136379 tablets will be administered orally.

Drug: Nucleos(t)ide Analog (NA)
NA treatment that is either of ETV, TDF or TAF tablets will be administered orally.

Outcome Measures

Primary Outcome Measures

  1. Percentage of Participants Meeting the Nucleos(t)ide Analog (NA) Treatment Completion Criteria at Week 48 [Week 48]

    Percentage of participants meeting the NA treatment completion criteria at week 48 will be reported.

Secondary Outcome Measures

  1. Number of Participants with Adverse Events (AE) and Serious Adverse Events (SAE) as a Measure of Safety and Tolerability [Up to follow-up (maximum up to 150 weeks)]

    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.

  2. Number of Participants with Abnormalities in Clinical Laboratory Tests, 12-Lead Electrocardiogram (ECG), and Vital Signs [Up to follow-up (maximum up to 150 weeks)]

    Number of participants with abnormalities in clinical laboratory tests, 12-lead ECG, and vital signs will be reported.

  3. Percentage of Participants with HBsAg Seroclearance After Completion of all Study Intervention [Week 72 and Week 96]

    Percentage of participants with hepatitis B surface antigen (HBsAg) seroclearance after completion of all study intervention will be reported.

  4. Percentage of Participants with HBV DNA less than (<) Lower Limit of Quantification (LLOQ) After Completion of all Study Intervention [Week 72 and Week 96]

    Percentage participants with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) <LLOQ after completion of all study intervention will be reported.

  5. Percentage of Participants Meeting the NA Treatment Completion Criteria During Follow-up [Up to 96 weeks]

    Percentage of participants meeting the NA treatment completion criteria during follow-up will be reported.

  6. Percentage of Participants with HBsAg Seroclearance After Completion of NA Treatment at any Time During Follow-up [Up to 150 weeks]

    Percentage of participants with HBsAg seroclearance after completion of NA treatment at any time during follow-up will be reported.

  7. Percentage of Participants Requiring NA Re-treatment During Follow-up [Up to 150 weeks]

    Percentage of participants requiring NA re-treatment during follow-up will be reported.

  8. Percentage of Participants with Relapse [Up to 150 weeks]

    Percentage of participants with relapse will be reported.

  9. Percentage of Participants with (Sustained) Reduction, Suppression, and/or Seroclearance Considering Single and Multiple Markers [Up to Week 96]

    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.

  10. Percentage of Participants with HBsAg Seroconversion [Up to 150 weeks]

    Percentage of participants with HBsAg seroconversion will be reported.

  11. Percentage of Participants with HBeAg Seroconversion [Up to 150 weeks]

    Percentage of participants with HBeAg seroconversion will be reported.

  12. Change From Baseline in HBsAg Levels [Baseline up to follow up (up to Week 150)]

    Change from baseline in HBsAg levels will be determined.

  13. Change From Baseline in HBeAg Levels [Baseline up to follow up (up to Week 150)]

    Change from baseline in HBeAg levels will be determined.

  14. Change from Baseline in HBV DNA Levels [Baseline up to follow up (up to Week 150)]

    Change from baseline in HBV DNA levels will be determined.

  15. Time to Achieve HBsAg Seroclearance [Up to Week 96]

    Time to achieve HBsAg seroclearance will be determined.

  16. Time to Achieve HBeAg Seroclearance [Up to Week 96]

    Time to achieve HBeAg seroclearance will be determined.

  17. Percentage of Participants with <100 IU/mL or >1 log10 IU/mL Reduction in HBsAg From Baseline [Baseline up to Week 150]

    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.

  18. Percentage of HBeAg-positive Participants with HBeAg Levels [Baseline up to Week 150]

    Percentage of HBeAg-positive participants with HBeAg levels will be reported.

  19. Percentage of Participants with ALT Decrease and Normalization [Up to follow-up (maximum up to 150 weeks)]

    Percentage of participants with alanine aminotransferase (ALT) decrease and normalization will be reported.

  20. Percentage of Participants with Virologic Breakthrough [Up to Week 48]

    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 <LLOQ of the HBV DNA assay will be reported.

  21. Percentage of Participants with Undetectable HBV DNA Levels After Re-start of NA Treatment During Follow-up [Up to 150 weeks]

    Percentage of participants who reach HBV DNA undetectability after re-start of NA treatment during follow-up will be reported.

  22. Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of JNJ-73763989 [Days 1, 29, 85, 169 and 337]

    The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state.

  23. Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of JNJ-56136379 [Days 1, 29, 85, 169 and 337]

    The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state.

  24. Area Under the Plasma Concentration-time Curve over the Dosing Interval (tau) at Steady-state (AUCtau,ss) of NA [Days 1, 29, 85, 169 and 337]

    The AUC (tau,ss) is the area under the plasma concentration time curve observed during a dosing interval (tau) at steady state.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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)

Contacts and Locations

Locations

Site City State Country Postal Code
1 The Office of Franco Felizarta, MD Bakersfield California United States 93301
2 Ruane Clinical Research Group Inc Los Angeles California United States 90036
3 Southern California GI and Liver Center San Clemente California United States 92673
4 Johns Hopkins Office of Capital Region Research - Sibley Memorial Hospital Washington District of Columbia United States 20016
5 Johns Hopkins University Baltimore Maryland United States 21287
6 Washington University School of Medicine Saint Louis Missouri United States 63110
7 I.D. Care, Inc. Hillsborough New Jersey United States 08844
8 NYU Hepatology Associates New York New York United States 10016
9 Cliniques Universitaires Saint-Luc Brussel Belgium 1200
10 UZ Antwerpen Edegem Belgium 2650
11 UZA-SGS Edegem Belgium 2650
12 Universitair Ziekenhuis Gent Gent Belgium 9000
13 UZ Leuven Leuven Belgium 3000
14 Fundação De Medicina Tropical Doutor Heitor Vieira Dourado Manaus Brazil 69040-000
15 Hospital das Clinicas da Universidade Federal da Bahia Salvador Brazil 40110-060
16 Hospital Das Clinicas Da Faculdade De Medicina Da Universidade De Sao Paulo Sao Paulo Brazil 05403-000
17 University of Calgary Calgary Alberta Canada T2N 4Z6
18 University of Alberta - Faculty of Medicine & Dentistry Edmonton Alberta Canada T6G 2G3
19 GI Research Institute (G.I.R.I.) Vancouver British Columbia Canada V6Z 2K5
20 Vancouver ID Research and Care Centre Society Vancouver British Columbia Canada V6Z2C7
21 Toronto General Hospital Toronto Canada ON M5G 2C4
22 Nanfang Hospital Guangzhou China 510515
23 FN Hradec Kralove Hradec Kralove Czechia 500 05
24 RESEARCH SITE s.r.o. Plzen Czechia 32600
25 KLIN MED s.r.o Praha 2 Czechia 120 00
26 IKEM Praha Czechia 140 21
27 Hôpital Beaujon Clichy France 92110
28 CHU de Grenoble - Hôpital Albert Michallon Grenoble France 38043
29 Hopital de La Croix Rousse Lyon France 69004
30 Hopital Saint Joseph Marseille France 13008
31 CHU de Nantes hôtel-Dieu Nantes France 44093
32 Hopital Saint-Antoine Paris France 75012
33 Chu Rennes - Hopital Pontchaillou Rennes France 35033
34 Hopital Paul Brousse Villejuif France 94800
35 EPIMED GmbH Berlin Germany 10787
36 Universitatsklinikum Essen Essen Germany 45147
37 Universitätsklinikum Johann Wolfgang Goethe- Universität Frankfurt Medizinische Klinik 1 Frankfurt Germany 60590
38 ICH Study Center GmbH & Co. KG Hamburg Germany 20146
39 University Medical Center Hamburg Germany D-20246
40 Medizinische Hochschule Hannover Hannover Germany 30625
41 Universitatsklinikum Leipzig Leipzig Germany 04103
42 Universitätsmedizin der Johannes Gutenberg-Universität Mainz Mainz Germany 55121
43 The University of Hong Kong Hong Kong Hong Kong
44 The Chinese University of Hong Kong Shatin Hong Kong
45 Azienda Ospedaliera Universitaria Policlinico G. Martino Messina Italy 98124
46 Irccs Ospedale Maggiore Di Milano Milano Italy 20122
47 Azienda Ospedaliero-Universitaria di Modena, Ospedale di Baggiovara Modena Italy 41126
48 Azienda Ospedaliero Universitaria Pisana Pisa Italy 56124
49 Universita degli Studi di Roma 'La Sapienza' - Umberto I Policlinico di Roma Rome Italy 00161
50 Tokyo Medical and Dental University Hospital Bunkyo-Ku Japan 113-8519
51 Chiba University Hospital Chiba Japan 260-8677
52 Fukui-ken Saiseikai Hospital Fukui City Japan 918-8503
53 Fukuyama City Hospital Fukuyama Japan 721-8511
54 Hiroshima University Hospital Hiroshima-shi Japan 734-8551
55 Kagawa Prefectural Central Hospital Kagawa Japan 760-8557
56 Nara Medical University Hospital Kashihara Japan 634-8522
57 Musashino Red Cross Hospital Musashino Japan 180-8610
58 National Hospital Organization Nagasaki Medical Center Nagasaki Japan 856-8562
59 Nagoya City University Hospital Nagoya Japan 467-8602
60 The Hospital of Hyogo College of Medicine Nishinomiya Japan 663-8501
61 Hokkaido University Hospital Sapporo-shi Japan 060-8648
62 Osaka University Hospital Suita-shi Japan 565-0871
63 Toranomon Hospital Tokyo Japan 105-8470
64 Fujita Health University Hospital Toyoake Japan 470-1192
65 Seoul National University Hospital Seoul Korea, Republic of 03080
66 Severance Hospital, Yonsei University Health System Seoul Korea, Republic of 03722
67 Asan Medical Center Seoul Korea, Republic of 05505
68 Samsung Medical Center Seoul Korea, Republic of 06351
69 Hospital Sultanah Bahiyah Alor Setar Malaysia 05460
70 Hospital Selayang Batu Caves Malaysia 68100
71 Hospital University Sains Malaysia Kota Bharu Malaysia 16150
72 University Malaya Medical Centre Kuala Lumpur Malaysia 59120
73 Wojewodzki Szpital Obserwacyjno-Zakazny im. Tadeusza Browicza w Bydgoszczy Bydgoszcz Poland 85-030
74 Neutrum Lekarze M.Hlebowicz i Partnerzy spolka partnerska Gdansk Poland 80-462
75 ID Clinic Myslowice Poland 41-400
76 Wojewodzki Szpital Zakazny w Warszawie Warszawa Poland 01-201
77 SP ZOZ Wroclawskie Centrum Zdrowia Wroclaw Poland 50-136
78 Ural State Medical University Chelyabinsk Russian Federation 454092
79 Sverdlovsk Regional Clinical Hospital #1 Ekaterinburg Russian Federation 620102
80 Krasnoyarsk Regional Center For AIDS And Infectious Diseases Treatment And Prophylaxis Krasnoyarsk Russian Federation 660049
81 Clinic of the Modern Medicine Moscow Russian Federation 121170
82 Medical Center SibNovoMed LLC Novosibirsk Russian Federation 630005
83 St. Petersburg City Center for AIDS and Infectious Diseases Treatment and Prophylaxis Saint Petersburg Russian Federation 190103
84 Republican Clinical Infectious Hospital Saint Petersburg Russian Federation 196645
85 Clinical Infectious Diseases Hospital n. a. S.P. Botkin Saint-Petersburg Russian Federation 195067
86 Medical Company Hepatolog Ltd Samara Russian Federation 443063
87 Smolensk Regional Clinical Hospital Smolensk Russian Federation 214018
88 Stavropol State Medical University Stavropol Russian Federation 355017
89 Hosp. Clinic I Provincial de Barcelona Barcelona Spain 8028
90 Hosp. Univ. Vall D Hebron Barcelona Spain 8035
91 Hosp. Univ. 12 de Octubre Madrid Spain 28041
92 Hospital Puerta De Hierro Madrid Spain 28222
93 Hosp. Univ. Marques de Valdecilla Santander Spain 39008
94 Hosp. Gral. Univ. Valencia Valencia Spain 46014
95 King Chulalongkorn Memorial Hospital Bangkok Thailand 10500
96 Siriraj Hospital Bangkok Thailand 10700
97 Chiang Mai University Hospital Chiang Mai Thailand 50200
98 Prince Of Songkla University Songkla Thailand 90110
99 Ankara University Medical Faculty Ankara Turkey 06620
100 Hacettepe University Hospital Ankara Turkey 6230
101 Ankara Sehir Hastanesi Ankara Turkey 6800
102 Istanbul University Cerrahpasa Medical Faculty Istanbul Turkey 34098
103 Ege University Medical of Faculty, Department of Gastroenterology Izmir Turkey 35100
104 Karadeniz Teknik University Medical Faculty Trabzon Turkey 61080
105 NHS Greater Glasgow and Clyde - Gartnavel General Hospital Glasgow United Kingdom G12 0YN
106 Grahame Hayton Unit London United Kingdom E1 1BB
107 Kings College Hospital London United Kingdom SE5 9RF
108 St George's, University of London and St George's University Hospitals NHS Foundation Trust London United Kingdom SW17 0RE

Sponsors and Collaborators

  • Janssen Sciences Ireland UC

Investigators

  • Study Director: Janssen Sciences Ireland UC Clinical Trial, Janssen Sciences Ireland UC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Janssen Sciences Ireland UC
ClinicalTrials.gov Identifier:
NCT03982186
Other Study ID Numbers:
  • CR108608
  • 2019-000622-22
  • 73763989HPB2001
First Posted:
Jun 11, 2019
Last Update Posted:
Jun 8, 2022
Last Verified:
Jun 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
Yes
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jun 8, 2022