Normal healthy volunteer (NHV) participants will enroll sequentially into a total of 6 escalating dose levels (6 subjects per dose level), randomized to receive a single dose of ARC-521 Injection or placebo. The maximum study duration for NHVs is approximately 21 weeks. Hepatitis B e Antigen (HBeAg)-negative participants with (CHB) will enroll sequentially into 3 dose levels (8 patients per dose level) to receive multiple doses of open label ARC-521 Injection. For each CHB participant the maximum study duration is approximately 37 weeks.
Phase 1a/1b multicenter dose-escalation study of ARC-521 Injection in normal healthy volunteers and patients with CHB. Eligible participants who have signed an Ethics Committee (EC)/Institutional Review Board (IRB) approved informed consent form and have met all of the protocol eligibility criteria. Patients will undergo the following evaluations at regular intervals during the study: medical history, physical examinations, vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature), weight, adverse events assessment (AEs), concomitant medications/therapies assessment, electrocardiograms (ECGs), telemetry \[NHVs only\], measures of hepatic fibrosis \[CHBs only\], blood sample collection for hematology, coagulation, chemistry, Pharmacokinetics (PK) \[NHVs only\], metabolic analysis \[NHVs only\], exploratory Pharmacodynamic (PD) measures, urinalysis, hepatitis B virus (HBV) serology, immunogenicity, Follicle Stimulating Hormone (FSH) testing (post-menopausal females) and pregnancy testing for females of childbearing potential. Clinically significant changes including AEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the patient is lost to follow-up. Prior to enrollment there is a 60 day screening period.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
0.9% normal saline
Approximately two hours prior to ARC-521 or placebo administration, participants will be pre-treated with an oral antihistamine, selected by the investigator from the list of approved antihistamines that is available in that country. Approved antihistamines are: diphenhydramine 50 mg by mouth (PO), chlorpheniramine 8 mg PO, or hydroxyzine 50 mg PO.
Research Site 1
Grafton, Auckland, New Zealand
Number of Participants With Treatment-Emergent Adverse Events (TEAEs): Healthy Volunteers
An adverse event (AE) is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. A serious AE is any AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is a medically important event or reaction.Events were categorized as mild, moderate or severe. TEAEs were defined as all AEs starting or worsening after commencement of treatment with investigational product. A treatment-related TEAE was one whose relationship to treatment was noted as unlikely, possibly, or probably related.
Time frame: From first dose of study drug through Day 29 (± 1 day)
Number of Participants With TEAEs: CHB Participants
An AE is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. A serious AE is any AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is a medically important event or reaction.Events were categorized as mild, moderate or severe. TEAEs were defined as all AEs starting or worsening after commencement of treatment with investigational product. A treatment-related TEAE was one whose relationship to treatment was noted as unlikely, possibly, or probably related.
Time frame: From first dose of study drug through Day 142 (± 3 days)
Pharmacokinetics of ARC-521 Injection: Area Under the Plasma-Concentration-Time Curve From Time 0-24 Hours (AUC0-24), Healthy Volunteers
Time frame: Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast), Healthy Volunteers
Time frame: Through 48 hours post-dose on Day 1
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Approximately two hours prior to ARC-521 or placebo administration, participants will be pre-treated with acetaminophen (500 - 1000 mg PO, per local strength availability).
Participants take entecavir OR tenofovir daily throughout the study.
Participants take entecavir OR tenofovir daily throughout the study.
Pharmacokinetics of ARC-521 Injection: Area Under the Plasma-Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf), Healthy Volunteers
Time frame: Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Maximum Observed Plasma Concentration (Cmax), Healthy Volunteers
Time frame: Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Clearance (CL), Healthy Volunteers
Time frame: Through 48 hrs post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Apparent Volume of Distribution (V), Healthy Volunteers
Time frame: Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Terminal Elimination Rate Constant (Kel), Healthy Volunteers
Time frame: Through 48 hours post-dose on Day 1
Pharmacokinetics of ARC-521 Injection: Terminal Elimination Half-Life (t1/2), Healthy Volunteers
Time frame: Through 48 hours post-dose on Day 1
Change Over Time in Viral Antigens and DNA in CHB Participants as a Measure of Activity of ARC-521 Injection
Time frame: Baseline to Day 142
Change Over Time in Cytokine Levels After Single and Multiple Doses of ARC-521 Injection
Time frame: Through 24 hours post-dose (Day 1 for NHVs, and Days 1, 29 & 57 for CHB participants)
Change Over Time in Complement Levels After Single and Multiple Doses of ARC-521 Injection
Time frame: Through 24 hours post-dose (Day 1 for NHVs, and Days 1, 29 & 57 for CHB participants)