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A Study of Orally Administered JNJ-56136379 to Evaluate Safety, Tolerability and Pharmacokinetics After Single Ascending Doses and One Multiple Dose Regimen in Healthy Participants (Part I), and After Multiple Dose Regimens in Participants With Chronic Hepatitis B (Part II)

Primary Purpose

Healthy, Hepatitis, Chronic

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

JNJ-56136379

Placebo

About this trial

This is an interventional other trial for Healthy focused on measuring Healthy, Hepatitis, Chronic, JNJ-56136379, Placebo

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

For Part II, a female participant must be either of a) Non-childbearing potential defined as: 1) Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level (greater than (>)40 international unit per milliliter (IU/L) or milli-international units per milliliter (mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient, or 2) Permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy, or b) Childbearing potential and practicing sexual abstinence or a highly effective method of contraception from screening onwards and agree to continue to use the same method of contraception throughout study treatment and for at least 90 days after the last dose of study drug (or longer, if dictated by local regulation)
Female participants should have a negative serum pregnancy test at screening
Healthy Participants: Participants must have a body mass index (BMI; weight in kg divided by the square of height in meters) of 18.0 to 30.0 kilogram per square meter (kg/m2), extremes included
Chronic Hepatitis B Participants: Participants must have lack of advanced liver disease, ie, either: Metavir F0-F2 (or comparable histologic scoring system) as determined on a liver biopsy within one year of the screening visit; a result based on specific radiologic liver disease staging modalities (eg, Fibroscan, AFRI, magnetic resonance imaging [MRI]-Elastography) compatible with Metavir F0-F2 within 6 months of the screening visit
Chronic Hepatitis B Participants: Participants must have HBV DNA of greater than or equal [>=] 2,000 international unit per milliliter (IU/mL) at screening
Chronic Hepatitis B Participants: Participants must be aged between 18 years to 65 years, have a body mass index (BMI; weight in kg divided by the square of height in meters) of 18.0 to 35.0 kilogram per square meter (kg/m^2), extremes included

Exclusion Criteria:

Healthy Participants: Participants with a past history of cardiac arrhythmias (example, extrasystolic, tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT Syndrome)
Healthy Participants: Female participants who are breastfeeding at screening
Healthy Participants: Participants with current human immunodeficiency virus type 1 (HIV-1) or HIV-2 infection (confirmed by antibodies) at screening
Chronic Hepatitis B Participants: Participants with current HCV infection (confirmed by HCV antibody or HCV RNA) or hepatitis delta virus (HDV) infection (confirmed by HDV antibody) at screening
Chronic Hepatitis B Participants: Participants with positivity of anti-HBs antibodies
Chronic Hepatitis B Participants: Participants with a past history of cardiac arrhythmias (eg, extrasystolic, tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT Syndrome)
Chronic Hepatitis B Participants: Female participants who are breastfeeding at screening

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Part 1: Single Dose Escalation

Part 1: Multiple dose session

Part 2: Multiple dose escalation

Arm Description

The single dose escalation phase of the study will consist of 6 dosing sessions (Sessions I to VI) evaluated in 2 panels (Panels 1 and 2). The dose of JNJ-56136379 will be consecutively escalated over 5 levels, alternating between the 2 panels. Panel 1 will receive 3 single doses (SD1, SD3 and SD3fed) in Sessions I, III and V, respectively. Panel 2 will receive 3 single doses (SD2, SD4 and SD5) in Sessions II, IV and VI, respectively. There will be a washout period of at least 14 days between consecutive JNJ-56136379/placebo dosing in each individual participant.

After completion of the fifth single dose session another panel of healthy participant (panel 3) receive multiple doses of JNJ-56136379 at one dose level (MDx) or placebo for 12 or 19 consecutive days (Session VII) in fed or fasted conditions.

Multiple dose levels will be given in Panel 4 in Session VIII (European sites), Sessions IX and X (European and/or Asian sites) Session XI (Asian sites) for 28 consecutive days in fed conditions. Optional Sessions A-B-C (Panel 4) used for further dose evaluations at European and/or Asian sites. Per session, participants will receive JNJ 56136379 or placebo. Dose progression to the next multiple dose level may be adapted based on the emerging safety and PK outcome of the previous dosing levels.

Outcomes

Primary Outcome Measures

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An 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.

Part 2: Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Abnormal Physical Examinations

Physical examinations (including body weight measurement and skin examination) will be performed.

Part 2: Number of Participants With Abnormal Physical Examinations

Physical examinations (including body weight measurement and skin examination) will be performed.

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Abnormal Vital Signs

Vital signs (Supine Blood Pressure [SBP], Diastolic Blood Pressure [DBP] pulse rate: supine and standing) will be performed.

Part 2: Number of Participants With Abnormal Vital Signs

Vital signs (SBP, DBP pulse rate: supine and standing) will be performed.

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Clinically Significant Laboratory Findings

The laboratory abnormalities will be determined according to the criteria specified in the World Health Organization (WHO) Toxicity Grading Scale and in accordance with the normal ranges of the clinical laboratory.

Part 2: Number of Participants With Clinically Significant Laboratory Findings

Part 1: Maximum Observed Plasma Concentration (Cmax) After Single Dose Administration

Cmax is the Maximum observed plasma concentration.

Part 1: Maximum Observed Plasma Concentration (Cmax) After Multiple Dose Administration

Cmax is the Maximum observed plasma concentration.

Part 2: Maximum Observed Plasma Concentration (Cmax)

Cmax is the Maximum observed plasma concentration.

Part 1: Area Under the Curve From Time 0 to the Time of the Last Measurable Concentration (AUClast) After Single Dose Administration

AUClast is the area under the curve from time 0 to the time of the last measurable Concentration.

Part 2: Area Under the Curve From Time 0 to the Time of the Last Measurable Concentration (AUClast)

AUClast is the area under the curve from time 0 to the time of the last measurable Concentration.

Part 1: Area Under the Curve From Time 0 to Infinity (AUC infinity) After Single Dose Administration

AUC infinity is the area under the curve from time 0 to infinity.

Part 2: Area Under the Curve From Time 0 to Infinity (AUC infinity)

AUC infinity is the area under the curve from time 0 to infinity.

Secondary Outcome Measures

Part 2: Change From Baseline in Mean Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA)

HBV DNA will be quantified using an in vitro nucleic acid amplification test for the quantification of HBV DNA.

Part 2: Maximum Decrease in HBV DNA (Baseline-subtracted Mean)

HBV DNA will be quantified using an in vitro nucleic acid amplification test for the quantification of HBV DNA.

Part 2: Changes in Hepatitis B Surface Antigen (HBsAg) Levels

Quantitative HBsAg and levels will be determined from samples using standard serologic assays.

Part II: Percentage of Participants with Treatment Emerging Mutations

Treatment induced emerging mutations will be assessed by comparing the HBV genome sequence obtained at baseline with sequences obtained post-baseline.

Part II: Change From Baseline in HBV DNA (Antiviral Activity) in Chronic Hepatitis B (CHB) Participants with Sequence Variations in the HBV Genome

Sequence variations in the HBV genome will be assessed by sequencing of the viral genome. Antiviral activity will be assessed by measuring change from baseline in HBV DNA concentration using in vitro nucleic acid amplification test for the quantification of HBV DNA and compared between participants with and without HBV sequence variations.

Full Information

NCT ID

NCT02662712

First Posted

December 2, 2015

Last Updated

July 2, 2019

Sponsor

Janssen Sciences Ireland UC

1. Study Identification

Unique Protocol Identification Number

NCT02662712

Brief Title

A Study of Orally Administered JNJ-56136379 to Evaluate Safety, Tolerability and Pharmacokinetics After Single Ascending Doses and One Multiple Dose Regimen in Healthy Participants (Part I), and After Multiple Dose Regimens in Participants With Chronic Hepatitis B (Part II)

Official Title

A Phase 1, Double-blind, Randomized, Placebo-controlled, First-in-human Study of Orally Administered JNJ-56136379 to Evaluate Safety, Tolerability and Pharmacokinetics After Single Ascending Doses and One Multiple Dose Regimen in Healthy Subjects (Part I), and After Multiple Dose Regimens in Subjects With Chronic Hepatitis B (Part II)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

December 17, 2015 (Actual)

Primary Completion Date

June 29, 2018 (Actual)

Study Completion Date

June 29, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Sciences Ireland UC

4. Oversight

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

The purpose of this study is to evaluate pharmacokinetics and safety data including serious and other adverse events, physical examinations, vital signs, 12-lead electrocardiograms (ECGs) and clinical laboratory results (including biochemistry, hematology, and urine).

Detailed Description

Part 1: This is a first-in-human (FIH), double-blind (neither the researchers nor the participants know what treatment the participant is receiving), randomized (study medication assigned to participants by chance), placebo-controlled (an inactive substance; a pretend treatment [with no drug in it] that is compared in a clinical trial with a drug to test if the drug has a real effect) study. Part 1 includes healthy adult participants, divided into 3 panels (Panel 1, 2 and 3) and in Part 2 adult Chronic Hepatitis B Participants will be included, in Sessions VIII to XI and Optional Sessions A-B-C (Panel 4). The study will consists of screening phase (part 1: [less than or equal to <=28 days before the first intake of study drug; part 2: [<=56 to greater than or equal to {>=} 20 days before the first intake of study drug), Treatment Phase (multiple dose phase in part 1: Day -1 up to 12 or 19 days; part 2: up to 4 weeks) and Follow up Phase (part 1: 30-35 days after last study drug intake or after dropout; part 2: up to week 8 after actual end of study drug treatment). Participants' safety will be evaluated throughout the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Healthy, Hepatitis, Chronic

Keywords

Healthy, Hepatitis, Chronic, JNJ-56136379, Placebo

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

87 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Single Dose Escalation

Arm Type

Experimental

Arm Description

Arm Title

Part 1: Multiple dose session

Arm Type

Experimental

Arm Description

Arm Title

Part 2: Multiple dose escalation

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

JNJ-56136379

Intervention Description

JNJ-56136379 oral tablets will be given in Part 1 (single dose escalation and multiple dose session) and Part 2 (multiple dose escalation).

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Matching placebo to JNJ-56136379 will be given in Part 1 (single dose escalation and multiple dose session) and Part 2 (multiple dose escalation).

Primary Outcome Measure Information:

Title

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

Description

Time Frame

Until the last study-related activity (30-35 days after last dosing)

Title

Part 2: Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events

Description

Time Frame

Up to Week 12

Title

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Abnormal Physical Examinations

Description

Physical examinations (including body weight measurement and skin examination) will be performed.

Time Frame

30-35 days after last study drug intake or after dropout

Title

Part 2: Number of Participants With Abnormal Physical Examinations

Description

Physical examinations (including body weight measurement and skin examination) will be performed.

Time Frame

Up to Week 8

Title

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Abnormal Vital Signs

Description

Vital signs (Supine Blood Pressure [SBP], Diastolic Blood Pressure [DBP] pulse rate: supine and standing) will be performed.

Time Frame

30-35 days after last study drug intake or after dropout

Title

Part 2: Number of Participants With Abnormal Vital Signs

Description

Vital signs (SBP, DBP pulse rate: supine and standing) will be performed.

Time Frame

Up to Week 8

Title

Part 1 Single Ascending Dose and Multiple Dose : Number of Participants With Clinically Significant Laboratory Findings

Description

Time Frame

30-35 days after last study drug intake or after dropout

Title

Part 2: Number of Participants With Clinically Significant Laboratory Findings

Description

Time Frame

Up to Week 8

Title

Part 1: Maximum Observed Plasma Concentration (Cmax) After Single Dose Administration

Description

Cmax is the Maximum observed plasma concentration.

Time Frame

Pre-dose, 0.5 hour (hr), 1, 1.5, 2, 3, 4, 6, 8, 12 and 16 hr post-dose on Day 1

Title

Part 1: Maximum Observed Plasma Concentration (Cmax) After Multiple Dose Administration

Description

Cmax is the Maximum observed plasma concentration.

Time Frame

Pre-dose, 0.5 hr, 1, 1.5, 2, 3, 4, 6, 8, 12 and 16 hr Day 1; post-dose on Day 12

Title

Part 2: Maximum Observed Plasma Concentration (Cmax)

Description

Cmax is the Maximum observed plasma concentration.

Time Frame

Pre-dose, 8, 12 hr post-dose on Day 1; post-dose on Day 28

Title

Part 1: Area Under the Curve From Time 0 to the Time of the Last Measurable Concentration (AUClast) After Single Dose Administration

Description

AUClast is the area under the curve from time 0 to the time of the last measurable Concentration.

Time Frame

Pre-dose, 0.5 hour (hr), 1, 1.5, 2, 3, 4, 6, 8, 12 and 16 hr post-dose on Day 1

Title

Part 2: Area Under the Curve From Time 0 to the Time of the Last Measurable Concentration (AUClast)

Description

AUClast is the area under the curve from time 0 to the time of the last measurable Concentration.

Time Frame

Pre-dose, 8, 12 hr post-dose on Day 1; post-dose on Day 28

Title

Part 1: Area Under the Curve From Time 0 to Infinity (AUC infinity) After Single Dose Administration

Description

AUC infinity is the area under the curve from time 0 to infinity.

Time Frame

Pre-dose, 0.5 hour (hr), 1, 1.5, 2, 3, 4, 6, 8, 12 and 16 hr post-dose on Day 1

Title

Part 2: Area Under the Curve From Time 0 to Infinity (AUC infinity)

Description

AUC infinity is the area under the curve from time 0 to infinity.

Time Frame

Pre-dose, 8, 12 hr post-dose on Day 1; post-dose on Day 28

Secondary Outcome Measure Information:

Title

Part 2: Change From Baseline in Mean Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA)

Description

HBV DNA will be quantified using an in vitro nucleic acid amplification test for the quantification of HBV DNA.

Time Frame

Up to week 12

Title

Part 2: Maximum Decrease in HBV DNA (Baseline-subtracted Mean)

Description

HBV DNA will be quantified using an in vitro nucleic acid amplification test for the quantification of HBV DNA.

Time Frame

Up to week 12

Title

Part 2: Changes in Hepatitis B Surface Antigen (HBsAg) Levels

Description

Quantitative HBsAg and levels will be determined from samples using standard serologic assays.

Time Frame

Up to week 12

Title

Part II: Percentage of Participants with Treatment Emerging Mutations

Description

Treatment induced emerging mutations will be assessed by comparing the HBV genome sequence obtained at baseline with sequences obtained post-baseline.

Time Frame

Up to week 12

Title

Part II: Change From Baseline in HBV DNA (Antiviral Activity) in Chronic Hepatitis B (CHB) Participants with Sequence Variations in the HBV Genome

Description

Time Frame

Up to week 12

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: For Part II, a female participant must be either of a) Non-childbearing potential defined as: 1) Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level (greater than (>)40 international unit per milliliter (IU/L) or milli-international units per milliliter (mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient, or 2) Permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy, or b) Childbearing potential and practicing sexual abstinence or a highly effective method of contraception from screening onwards and agree to continue to use the same method of contraception throughout study treatment and for at least 90 days after the last dose of study drug (or longer, if dictated by local regulation) Female participants should have a negative serum pregnancy test at screening Healthy Participants: Participants must have a body mass index (BMI; weight in kg divided by the square of height in meters) of 18.0 to 30.0 kilogram per square meter (kg/m2), extremes included Chronic Hepatitis B Participants: Participants must have lack of advanced liver disease, ie, either: Metavir F0-F2 (or comparable histologic scoring system) as determined on a liver biopsy within one year of the screening visit; a result based on specific radiologic liver disease staging modalities (eg, Fibroscan, AFRI, magnetic resonance imaging [MRI]-Elastography) compatible with Metavir F0-F2 within 6 months of the screening visit Chronic Hepatitis B Participants: Participants must have HBV DNA of greater than or equal [>=] 2,000 international unit per milliliter (IU/mL) at screening Chronic Hepatitis B Participants: Participants must be aged between 18 years to 65 years, have a body mass index (BMI; weight in kg divided by the square of height in meters) of 18.0 to 35.0 kilogram per square meter (kg/m^2), extremes included Exclusion Criteria: Healthy Participants: Participants with a past history of cardiac arrhythmias (example, extrasystolic, tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT Syndrome) Healthy Participants: Female participants who are breastfeeding at screening Healthy Participants: Participants with current human immunodeficiency virus type 1 (HIV-1) or HIV-2 infection (confirmed by antibodies) at screening Chronic Hepatitis B Participants: Participants with current HCV infection (confirmed by HCV antibody or HCV RNA) or hepatitis delta virus (HDV) infection (confirmed by HDV antibody) at screening Chronic Hepatitis B Participants: Participants with positivity of anti-HBs antibodies Chronic Hepatitis B Participants: Participants with a past history of cardiac arrhythmias (eg, extrasystolic, tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT Syndrome) Chronic Hepatitis B Participants: Female participants who are breastfeeding at screening

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janssen Sciences Ireland UC Clinical Trial

Organizational Affiliation

Janssen Sciences Ireland UC

Official's Role

Study Director

Facility Information:

City

Brussel

Country

Belgium

City

Edegem

Country

Belgium

City

Mechelen

Country

Belgium

City

Merksem

Country

Belgium

City

Sofia

Country

Bulgaria

City

Clichy

Country

France

City

La Tronche

Country

France

City

Lyon

Country

France

City

Paris

Country

France

City

Tbilisi

Country

Georgia

City

Essen

Country

Germany

City

Hannover

Country

Germany

City

Wiesbaden

Country

Germany

City

Kuala Lumpur

Country

Malaysia

City

Chisinau

Country

Moldova, Republic of

City

Bucuresti

Country

Romania

City

Timisoara

Country

Romania

City

Barcelona

Country

Spain

City

Madrid

Country

Spain

City

Santander

Country

Spain

City

Sevilla

Country

Spain

City

Valencia

Country

Spain

City

Kaohsiung

Country

Taiwan

City

Keelung

Country

Taiwan

City

Taichung

Country

Taiwan

City

Taipei City

Country

Taiwan

City

Taoyuan

Country

Taiwan

12. IPD Sharing Statement

Citations:

PubMed Identifier

32343960

Citation

Zoulim F, Lenz O, Vandenbossche JJ, Talloen W, Verbinnen T, Moscalu I, Streinu-Cercel A, Bourgeois S, Buti M, Crespo J, Manuel Pascasio J, Sarrazin C, Vanwolleghem T, Shukla U, Fry J, Yogaratnam JZ. JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection. Gastroenterology. 2020 Aug;159(2):521-533.e9. doi: 10.1053/j.gastro.2020.04.036. Epub 2020 Apr 25.

Results Reference

derived

PubMed Identifier

31267367

Citation

Vandenbossche J, Jessner W, van den Boer M, Biewenga J, Berke JM, Talloen W, De Zwart L, Snoeys J, Yogaratnam J. Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects. Adv Ther. 2019 Sep;36(9):2450-2462. doi: 10.1007/s12325-019-01017-1. Epub 2019 Jul 2. Erratum In: Adv Ther. 2020 Mar 4;:

Results Reference

derived

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