Clinical trial NCT03439488: 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
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Hepatitis B
Keywords: First in Human
Healthy Volunteers
Hepatitis B Virus
JNJ-64530440
Lead sponsor: Alios Biopharma Inc.
Sponsor class: INDUSTRY
First posted: 2018-02-20
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

Brief 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).


Eligibility criteria: 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

Primary outcomes:
measure: Parts 1, 2, and 3: Number of Participants With Adverse Events (AEs) as a Measure of Safety and Tolerability
timeFrame: Approximately up to 8 weeks
measure: Parts 1, 2, and 3: Number of Participants With Clinically Significant Changes in Physical Examination (Body Weight Measurement and Skin Examination)
timeFrame: Approximately up to 8 weeks
measure: Parts 1, 2, and 3: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: Approximately up to 8 weeks
measure: Parts 1, 2, and 3: Number of Participants With ECG Abnormalities
timeFrame: Approximately up to 8 weeks
measure: Parts 1, 2, and 3: Number of Participants With Holter Monitoring Abnormalities
timeFrame: Up to 24 hours post-dose on Day 1
measure: Parts 1, 2, and 3: Number of Participants With Clinical Laboratory Abnormalities
timeFrame: Approximately up to 8 weeks
measure: Part 1: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 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)
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC [0-last])
timeFrame: 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)
measure: Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity])
timeFrame: 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)
measure: Part 3: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 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])
measure: Part 3: Observed Plasma Concentration From Time 0 to tau Hours Postdose (C[0-tau])
timeFrame: 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])
measure: Part 3: Area Under the Curve From Time Zero to End of Dosing Interval (AUC[0-tau])
timeFrame: 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 outcomes:
measure: Part 1: Ratio of Cmax Values Between Test and Reference Ratio (Cmax, test/reference) for Different Dosage Forms
timeFrame: 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)
measure: Part 1: Ratio of AUC(0-last) Values Between Test and Reference (Ratio AUC[0-last],test/reference) for Different Dosage Forms
timeFrame: 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)
measure: Part 1: Ratio of AUC(0-infinity) Values Between Test and Reference (Ratio AUC[0-infinity], test/reference) for Different Dosage Forms
timeFrame: 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)
measure: Part 1: Ratio of Cmax Values Between Fed and Fasted (Ratio Cmax, test/reference) Conditions
timeFrame: 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)
measure: Part 1: Ratio of AUC(0-last) Values Between Fed and Fasted (Ratio AUC[0- last],test/reference)
timeFrame: 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)
measure: Part 1: Ratio of AUC(0-infinity) Values Between Fed and Fasted (Ratio AUC[0-infinity], test/reference)
timeFrame: 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)
measure: Part 3: Mean Change from Baseline in HBV DNA Levels
timeFrame: Baseline up to Day 56
measure: Part 3: Percentage of Participants with HBV DNA Levels and Undetectable HBV DNA
timeFrame: Baseline up to Day 56
measure: Part 3: Change From Baseline in Hepatitis B Surface Antigen (HBsAg) Levels
timeFrame: Baseline up to Day 56
measure: Part 3: Change From Baseline in Hepatitis B e Antigen (HBeAg) Levels
timeFrame: Baseline up to Day 56
measure: Part 3: Relationship Between Plasma Concentration and Antiviral Activity
timeFrame: Up to Day 56
measure: Part 3: Relationship Between Plasma Concentration and Select AEs or Laboratory Changes
timeFrame: Up to Day 56
measure: Part 3: Change From Baseline in HBV DNA (Antiviral Activity) in Chronic Hepatitis B (CHB) Participants with Sequence Variations in the HBV Genome
timeFrame: Baseline up to Day 56
measure: Part 3: Number of Participants with Emergence of Treatment Associated Mutations in the HBV Genome
timeFrame: Baseline up to Day 29
measure: Parts 1, 2, and 3: Relationship Between JNJ-440 Plasma Concentrations and Time-Matched Change from Baseline QTcF
timeFrame: Approximately up to 18 weeks
Other outcomes:
Locations:
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: Chisnau
country: Moldova, Republic of
facility: Republican Clinical Hospital
city: Auckland
country: New Zealand
facility: Auckland Clinical Services
city: Bangkok
country: Thailand
facility: Research Unit of Hepatitis and Liver Cancer, Department.Biochemistry, Faculty of Medicine King Chulalongkorn Memorial Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital Department of Gastroenterology, Faculty of Medicine, Khon Kaen University
city: Kapitanavka
country: Ukraine
facility: Limited Liability Company "ARENSIA EXPLORATORY MEDICINE"
Study officials:
affiliation: Alios Biopharma Inc.
name: Jeysen Yogaratnam
role: STUDY_DIRECTOR
References:
citation: Gane EJ, Schwabe C, Berliba E, Tangkijvanich P, Jucov A, Ghicavii N, Verbinnen T, Lenz O, Talloen W, Kakuda TN, Westland C, Patel M, Yogaratnam JZ, Dragone L, Van Remoortere P. Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection. J Antimicrob Chemother. 2022 Mar 31;77(4):1102-1110. doi: 10.1093/jac/dkab491.
citation: Kakuda TN, Yogaratnam JZ, Westland C, Gane EJ, Schwabe C, Vuong J, Patel M, Snoeys J, Talloen W, Lenz O, Fry J, Chanda S, van Remoortere P. Pharmacokinetics, safety and tolerability of single- and multiple-ascending doses of JNJ-64530440, a novel hepatitis B virus capsid assembly modulator, in healthy volunteers. Antivir Ther. 2021 Jan-Feb;26(1-2):13-24. doi: 10.1177/13596535211044331. Epub 2021 Sep 23.