Study of ARC-520 in Participants With Hepatitis B Virus e Antigen (HBeAg) Positive Chronic Hepatitis B Virus

Study Overview
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Brief Summary
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Participants with chronic HBV infection will receive multiple doses of ARC-520 in combination with entecavir or tenofovir and be evaluated for safety and efficacy.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Multi-dose Study to Determine the Depth of Hepatitis B Surface Antigen (HBsAg) Reduction Following Intravenous ARC-520 in Combination With Entecavir or Tenofovir in Patients With HBeAg Positive, Chronic Hepatitis B Virus (HBV) Infection

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: ARC-520
* Drug: Placebo
* Drug: Entecavir
* Drug: Tenofovir
* Drug: diphenhydramine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18 to 75 years of age Written informed consent Body mass index (BMI) between 17.5 and 30.0 kg/m2 No clinically significant abnormalities at screening/pre-dose 12-lead ECG assessment No abnormal finding of clinical relevance Diagnosis of HBeAg positive, immune active, chronic HBV infection > 2 months of continuous treatment with daily oral entecavir or tenofovir Must use 2 effective methods of contraception (double barrier contraception or hormonal contraceptive along with a barrier contraceptive) Exclusion Criteria: Pregnant or lactating Acute signs of hepatitis/other infection within 4 weeks of screening Hepatic transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) > 3 times the upper limits of normal Liver Elastography (i.e. FibroScan®) score > 9 Antiviral therapy other than entecavir or tenofovir within 3 months of screening Prior treatment with interferon in the last 3 years Use of anticoagulants, corticosteroids, immunomodulators, or immunosuppressants within 6 months of screening Use within 7 days prior to screening of dietary and/or herbal supplements that can interfere with liver metabolism Use of any drugs known to induce or inhibit hepatic drug metabolism within 30 days of study drug administration Use of prescription medication within 14 days prior to study drug administration Depot injection/implant of any drug except birth control within 3 months prior to study drug administration Known diagnosis of diabetes mellitus History of autoimmune disease Human immunodeficiency virus (HIV) infection Sero-positive for Hepatitis C Virus (HCV), and/or a history of delta virus hepatitis Hypertension; blood pressure > 150/100 mmHg History of cardiac rhythm disturbances Family history of congenital long QT syndrome, Brugada syndrome or unexplained sudden cardiac death Symptomatic heart failure, unstable angina, myocardial infarction, severe cardiovascular disease within 6 months prior to study entry History of malignancy, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, in situ cervical cancer Major surgery within 3 months of screening History of alcohol and/or drug abuse < 12 months from screening Regular use of alcohol within 6 months (ie, more than 14 units of alcohol per week) Evidence of systemic acute inflammation, sepsis, or hemolysis Diagnosed with a significant psychiatric disorder Use of drugs of abuse History of allergy to bee venom Positive reaction to the bee venom allergy immunoglobulin E (IgE) test Use of investigational agents or devices within 30 days Clinically significant inherited or acquired gastrointestinal pathology, unresolved gastrointestinal symptoms, liver or kidney disease Presence of cholangitis, cholecystitis, cholestasis, or duct obstruction Clinically significant history or presence of uncontrolled systemic disease Donated or had a loss of whole blood of 50 milliliters (mL) to 499 mL within 30 days or more than 499 mL between 31 and 56 days prior to study treatment History of fever within 2 weeks of screening Immunization/planned immunization with live attenuated vaccine except influenza vaccine Presence of any medical or psychiatric condition or social situation that impacts compliance or results in additional safety risk Excessive exercise/physical activity within 7 days of screening/enrolment or during study History of coagulopathy/stroke within past 6 months, and/or concurrent anticoagulant medication(s)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARC-520<br>Intravenous administration of 1.0 mg/kg ARC-520 once every 4 weeks for 3 total doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day), taken throughout the study. Pretreatment with diphenhydramine 50 mg 2 hours (±30 minutes) prior to administration of study drug. | Drug: ARC-520<br> <br> Drug: Entecavir<br>* 0.5 or 1.0 mg/day orally<br>* Other names: Baraclude;Drug: Tenofovir<br>* 300 mg/day orally<br>* Other names: Viread;Drug: diphenhydramine<br>* 50 mg orally as pretreatment antihistamine<br>|
| Placebo Comparator: Placebo<br>Intravenous administration of normal saline (0.9%) once every 4 weeks for 3 total doses, plus entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg/day), taken throughout the study. Pretreatment with diphenhydramine 50 mg 2 hours (±30 minutes) prior to administration of placebo. | Drug: Placebo<br> <br> Drug: Entecavir<br>* 0.5 or 1.0 mg/day orally<br>* Other names: Baraclude;Drug: Tenofovir<br>* 300 mg/day orally<br>* Other names: Viread;Drug: diphenhydramine<br>* 50 mg orally as pretreatment antihistamine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 85 |  | Baseline, Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with treatment. An SAE was defined as any untoward medical occurrence that, at any dose: 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. An AE was classified as a TEAE if the AE was not present prior to the first study medication administration and started at or after the time of initiation of administration of study medication, or if the AE presented prior to initiation of administration of study medication, continued and increased in intensity after administration of study medication. | From time of informed consent through Day 147 ± 3 days | 
| Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of ARC-520: Apparent Clearance (CL) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2) |  | Through 48 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of Entecavir or Tenofovir: AUC0-24 |  | Through 24 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of Entecavir or Tenofovir: AUClast |  | Through 24 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of Entecavir or Tenofovir: Cmax |  | Through 24 hours post-dosing on Days 1 and 57 | 
| Pharmacokinetics of Entecavir or Tenofovir: Time of Cmax (Tmax) |  | Through 24 hours post-dosing on Days 1 and 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis B Virus, Chronic Hepatitis B, HBV