A Study of Orally Administered JNJ-440 to Evaluate the Safety, Tolerability, and Pharmacokinetics After Single Ascending Doses Including Food Effect Evaluation; After Multi-Day Dosing in Healthy Participants; and After Multiple (Ascending) Doses in Participants With Chronic Hepatitis B

Chronic Hepatitis B Clinical Trial

Official title:

A Multipart Phase 1, Double-Blind, Randomized, Placebo-Controlled, First-in-Human, Study of Orally Administered JNJ-440 to Evaluate the Safety, Tolerability, and Pharmacokinetics After Single Ascending Doses Including Food Effect Evaluation (Part 1); After Multi-Day Dosing (Part 2) in Healthy Subjects; and After Multiple (Ascending) Doses in Subjects With Chronic Hepatitis B (Part 3)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03439488
• Other study ID #: JNJ-440-1301
• Secondary ID: JNJ-440-13012017
• Status: Completed
• Phase: Phase 1
• Start date: March 26, 2018
• Est. completion date: October 10, 2019

Study information

• Verified date: December 2019
• Source: Alios Biopharma Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and tolerability of JNJ-440 in healthy and Chronic Hepatitis B (CHB) participants after single and multiple doses; and to evaluate the pharmacokinetic (PK) of JNJ-440 in healthy participants and in CHB participants following single and multiple dose regimens, administered alone (healthy participants and CHB participants).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 130
• Est. completion date: October 10, 2019
• Est. primary completion date: October 10, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

Inclusion Criteria for Healthy Participants:

• Female participants (except for postmenopausal women) must have a negative pregnancy test at screening and on Day -1

• Participants must have a body mass index (BMI; weight in kilogram [kg] divided by the square of height in meters) of 18.0 to 30.0 kilogram per meter square (kg/m^2), extremes included

• Participants must agree not to donate blood during the study and for at least 1 month after the completion of study drug administration

Inclusion Criteria for Participants with Chronic Hepatitis B (CHB):

• Participant must have CHB infection documented by: (a) Serum hepatitis B surface antigen (HBsAg) positive at screening and at least 6 months prior to screening; (b) Serum antibody immunoglobulin M (IgM) anti-HBc antibody negative at screening

• Participants must currently not be receiving any CHB treatment at screening, that is, have never received treatment with hepatitis B virus (HBV) antiviral medicines, nucleos(t)ide analog (NAs), interferon (IFN) products, or investigational anti-HBV agents, OR Have not been on treatment with HBV antiviral medicines, NAs, or IFN products within 6 months prior to baseline (first intake of study drugs)

Exclusion Criteria:

Exclusion Criteria for Healthy Participants:

• Participants with a past history of cardiac arrhythmias (example, extrasystoli, tachycardia at rest), history of risk factors for Torsade 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 electrocardiogram [ECG] abnormalities), moderate to severe valvular disease or uncontrolled hypertension at screening. Any evidence of heart block or bundle branch block is also exclusionary

• Participants with any history of confirmed clinically significant skin disease such as, but not limited to, dermatitis, eczema, drug rash, psoriasis, food allergy, and urticarial

• Participants with a history of confirmed clinically significant drug allergy such as, but not limited to, sulfonamides and penicillins, or drug allergy witnessed in previous studies with experimental drugs

Exclusion Criteria for Participants with CHB:

• Participant with positivity of anti-HBs antibodies

• Participants with current hepatitis D virus (HDV) infection (confirmed by HDV antibody) at screening

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• JNJ-440
JNJ-440 will be administered as oral tablets in Parts 1, 2 and 3. JNJ-440 may be provided as oral solution in a cohort in Part 1.
• Placebo
Matching placebo as oral tablets will be administered in Parts 1, 2 and 3.

Locations

Country	Name	City	State
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Moldova, Republic of	Republican Clinical Hospital	Chisnau
New Zealand	Auckland Clinical Services	Auckland
Thailand	Research Unit of Hepatitis and Liver Cancer, Department.Biochemistry, Faculty of Medicine King Chulalongkorn Memorial Hospital	Bangkok
Thailand	Srinagarind Hospital Department of Gastroenterology, Faculty of Medicine, Khon Kaen University	Khon Kaen
Ukraine	Limited Liability Company "ARENSIA EXPLORATORY MEDICINE"	Kapitanavka

Sponsors (1)

Lead Sponsor	Collaborator
Alios Biopharma Inc.

Countries where clinical trial is conducted

Korea, Republic of,  Moldova, Republic of,  New Zealand,  Thailand,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Parts 1, 2, and 3: Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability	Number of participants with AE (any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship) will be reported.	Approximately up to 8 weeks
Primary	Parts 1, 2, and 3: Number of Participants With Clinically Significant Changes in Physical Examination (Body Weight Measurement and Skin Examination)	A symptom directed physical examination (including body weight measurement and skin examination) will be performed to further assess number of participants with clinically significant changes.	Approximately up to 8 weeks
Primary	Parts 1, 2, and 3: Number of Participants With Clinically Significant Changes in Vital Signs	Number of participants with clinically significant changes in the vital signs will be reported.	Approximately up to 8 weeks
Primary	Parts 1, 2, and 3: Number of Participants With ECG Abnormalities	Number of participants with electrocardiogram (ECG) abnormalities will be reported.	Approximately up to 8 weeks
Primary	Parts 1, 2, and 3: Number of Participants With Holter Monitoring Abnormalities	Number of participants with Holter monitoring abnormalities will be reported.	Up to 24 hours post-dose on Day 1
Primary	Parts 1, 2, and 3: Number of Participants With Clinical Laboratory Abnormalities	Number of participants with clinical laboratory abnormalities will be reported.	Approximately up to 8 weeks
Primary	Part 1: Maximum Observed Plasma Concentration (Cmax)	The Cmax is the maximum observed plasma concentration.	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Primary	Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC [0-last])	The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Primary	Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity])	The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Primary	Part 3: Maximum Observed Plasma Concentration (Cmax)	The Cmax is the maximum observed plasma concentration.	Day 1 (predose, and at 0.5, 1, 2, 4, 8, and 12 hours post dose), morning predose on Days 2, 15 and 21, and Day 28 (predose, and at 0.5, 1, 2, 4, 8, and 12 hours postdose; 24 hours postdose [once daily {QD} dosing only])
Primary	Part 3: Observed Plasma Concentration From Time 0 to tau Hours Postdose (C[0-tau])	C(0-tau) is defined as the observed plasma concentration from time 0 to tau hours postdose (tau = dosing interval).	Day 1 (predose, and at 0.5, 1, 2, 4, 8, and 12 hours post dose), morning predose on Days 2, 15 and 21, and Day 28 (predose, and at 0.5, 1, 2, 4, 8, and 12 hours postdose; 24 hours postdose [QD dosing only])
Primary	Part 3: Area Under the Curve From Time Zero to End of Dosing Interval (AUC[0-tau])	The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption.	Day 1 (predose, and at 0.5, 1, 2, 4, 8, and 12 hours post dose), morning predose on Days 2, 15 and 21, and Day 28 (predose, and at 0.5, 1, 2, 4, 8, and 12 hours postdose; 24 hours postdose [QD dosing only])
Secondary	Part 1: Ratio of Cmax Values Between Test and Reference Ratio (Cmax, test/reference) for Different Dosage Forms	Ratio Cmax, test/reference is the ratio of individual Cmax values between test and reference treatment. Test = JNJ-440 in oral solution (Cohort 9) or tablet (Cohort 10), and reference = JNJ-440 in fasted conditions (Cohort 2 or Cohort 4-7 [depending on dose], respectively).	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Secondary	Part 1: Ratio of AUC(0-last) Values Between Test and Reference (Ratio AUC[0-last],test/reference) for Different Dosage Forms	Ratio AUC(0-last),test/ref is the ratio of individual AUC(0-last) values between test and reference treatment. Test = JNJ-440 in oral solution (Cohort 9) or tablet (Cohort 10), and reference = JNJ-440 in fasted conditions (Cohort 2 or Cohort 4-7 [depending on dose], respectively).	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Secondary	Part 1: Ratio of AUC(0-infinity) Values Between Test and Reference (Ratio AUC[0-infinity], test/reference) for Different Dosage Forms	Ratio AUC(0-infinity),test/ref is the ratio of individual AUC(0-infinity) values between test and reference treatment. Test = JNJ-440 in oral solution (Cohort 9) or tablet (Cohort 10), and ref = JNJ-440 in fasted conditions (Cohort 2 or Cohort 4-7 [depending on dose], respectively).	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Secondary	Part 1: Ratio of Cmax Values Between Fed and Fasted (Ratio Cmax, test/reference) Conditions	Ratio Cmax, test/reference is the ratio of individual Cmax values between test and reference treatment. Test = JNJ-440 in fed conditions (Cohort 8), and reference = JNJ-440 in fasted conditions (Cohort 3).	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Secondary	Part 1: Ratio of AUC(0-last) Values Between Fed and Fasted (Ratio AUC[0- last],test/reference)	Ratio AUC(0-last),test/ref is the ratio of individual AUC(0-last) values between test and reference treatment. Test = JNJ-440 in fed conditions (Cohort 8), and ref = JNJ-440 in fasted conditions (Cohort 3).	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Secondary	Part 1: Ratio of AUC(0-infinity) Values Between Fed and Fasted (Ratio AUC[0-infinity], test/reference)	Ratio AUC(0-infinity),test/ref is the ratio of individual AUC(0- infinity) values between test and reference treatment. Test = JNJ-440 in fed conditions (Cohort 8), and ref = JNJ-440 in fasted conditions (Cohort 3).	Day 1 (predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose)
Secondary	Part 3: Mean Change from Baseline in HBV DNA Levels	Changes of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels as assessed by mean change from baseline in HBV DNA will be evaluated.	Baseline up to Day 56
Secondary	Part 3: Percentage of Participants with HBV DNA Levels and Undetectable HBV DNA	Percentage of participants with HBV DNA levels such as less than (<) 100 international units per milliliter (IU/mL) and undetectable HBV DNA will be evaluated.	Baseline up to Day 56
Secondary	Part 3: Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels	The difference of HBsAg levels from baseline will be evaluated.	Baseline up to Day 56
Secondary	Part 3: Change From Baseline in Hepatitis B e Antigen (HBeAg) Levels	The difference of HBeAg levels from baseline will be evaluated.	Baseline up to Day 56
Secondary	Part 3: Relationship Between Plasma Concentration and Antiviral Activity	The potential association between antiviral activity (like HBV DNA or HBsAg or HBeAg) and plasma concentration of JNJ-440 will be assessed.	Up to Day 56
Secondary	Part 3: Relationship Between Plasma Concentration and Select AEs or Laboratory Changes	The potential association between select AEs or laboratory changes and plasma concentration of JNJ-440 may be assessed. Based on the clinically relevant AEs or laboratory changes during the study, this analysis may be performed.	Up to Day 56
Secondary	Part 3: 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 and compared between participants with and without HBV sequence variations.	Baseline up to Day 56
Secondary	Part 3: Number of Participants with Emergence of Treatment Associated Mutations in the HBV Genome	Treatment induced emerging mutations will be assessed by comparing the HBV genome sequence obtained at baseline with sequences obtained post-baseline.	Baseline up to Day 29
Secondary	Parts 1, 2, and 3: Relationship Between JNJ-440 Plasma Concentrations and Time-Matched Change from Baseline QTcF	The relationship between plasma levels of JNJ-440 and Q-T interval corrected for heart rate according to Fridericia's formula (QTcF) exposure response relationship will be assessed.	Approximately up to 18 weeks