Study of ARC-520 With or Without Other Drugs Used in the Treatment of Chronic Chronic Hepatitis B Virus (HBV)

Study Overview
=================
Brief Summary
-----------------
Patients with chronic HBV infection will receive either ARC-520 alone or ARC-520 in combination with other treatments such as entecavir (ENT) or tenofovir (TDF) and/or pegylated interferon (PEG IFN) alpha 2a therapy, and be evaluated for safety and efficacy.

Detailed Description
-----------------
This is a multicenter, open-label study of ARC-520 based treatment regimens administered to patients with HBeAg positive or HBeAg negative immune active chronic Hepatitis B Virus (HBV) infection of various genotypes, or patients with Hepatitis D Virus (HDV). Eligible patients naive to previous treatment, and who have signed an Ethics Committee - approved informed consent, will be enrolled and will receive ARC-520 alone or ARC-520 plus additional treatments such as entecavir (ETV) or tenofovir (TDF) and/or pegylated interferon alpha 2a (PEG IFN) therapy. The study may initially involve up to a total of 96 eligible chronic HBV and HDV infected patients. Patients in all cohorts will receive a total of 13 doses of ARC-520 at 2mg/kg or 4 mg/kg. 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), 12-lead ECGs, liver fibrosis testing, concomitant medication assessment, blood sample collection for hematology, coagulation, chemistry, exploratory Pharmacodynamic (PD) measures, urinalysis, HBV serology, cytokines, 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. For each patient, the duration of the study is approximately 96 weeks, from enrolment to last visit. Prior to enrolment there is a 60 day screening period. Addition of new cohorts and additional treatment regimens are anticipated for this study.

Official Title
-----------------
A Multicenter, Open-Label Study to Evaluate ARC-520 Administered Alone and in Combination With Other Therapeutics in Patients With Chronic Hepatitis B Virus (HBV) Infection (MONARCH)

Conditions
-----------------
Hepatitis B, Hepatitis D

Intervention / Treatment
-----------------
* Drug: ARC-520
* Drug: entecavir
* Biological: pegylated interferon alpha 2a
* Drug: tenofovir disoproxil
* Drug: antihistamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, 18 to 75 years of age Written informed consent No clinically significant abnormalities at screening/pre-dose 12-lead ECG assessment Diagnosis of HBeAg negative or positive chronic HBV infection. Must be HBsAg (+) during screening. Must be treatment naïve: never on PEG IFN alpha 2a and/or ETV or TDF; and Have not used nucleoside/nucleotide analogs (NUCs) within the last 2 years prior to dosing on Day 1 Must use 2 effective methods of contraception (double barrier contraception or hormonal contraceptive along with a barrier contraceptive) (both male and female partners) Exclusion Criteria: Pregnant or lactating Acute signs of hepatitis/other severe infections within 4 weeks of screening Use within the last 14 days or anticipated requirement for anticoagulants, systemic corticosteroids, immunomodulators, or immunosuppressants Use of prescription medication within 14 days prior to treatment administration except: topical products without systemic absorption, statins (except rosuvastatin), hypertension medications, over-the-counter (OTC) and prescription pain medication or hormonal contraceptives History of poorly controlled autoimmune disease or any history of autoimmune hepatitis History of heterozygous or homozygous familial hypercholesterolemia. Human immunodeficiency virus (HIV) infection Is sero-positive for Hepatitis C Virus (HCV), or has a history of delta virus hepatitis (except for cohort in which delta virus infection is acceptable) Has hypertension: blood pressure > 170/100 mmHg; well-controlled blood pressure on hypertensive medication allowed 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, or in situ cervical cancer Has had major surgery within 1 month of screening Regular use of alcohol within 6 months prior to screening (ie, more than 14 units of alcohol per week) Use of recreational drugs such as cocaine, phencyclidine (PCP), and methamphetamines, within 1 year prior to the screening History of allergy to bee sting Clinically significant history of any alcoholic liver disease, cirrhosis, Wilson's disease, hemochromatosis, or alpha-1 antitrypsin deficiency Presence of cholangitis, cholecystitis, cholestasis, or duct obstruction Clinically significant history or presence of poorly controlled/uncontrolled systemic disease Presence of any medical or psychiatric condition or social situation that impacts compliance or results in additional safety risk History of coagulopathy/stroke within past 6 months, and/or concurrent anticoagulant medication(s)

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Treatment-naïve, hepatitis B e antigen (HBeAg)-positive participants with chronic hepatitis B (CHB) of any genotype administered ARC-520 (2 mg/kg intravenous [IV]) every 4 weeks for 48 weeks (13 doses). | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|
| Experimental: Cohort 2<br>Treatment-naïve, HBeAg-positive, Genotype B participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered peginterferon (PEG IFN) alpha 2a for 48 weeks starting Day 87. | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Drug: entecavir<br>* 0.5 mg once daily; oral<br>* Other names: Baraclude;Biological: pegylated interferon alpha 2a<br>* 180 mcg; subcutaneous injection once weekly<br>* Other names: Pegasys;Drug: tenofovir disoproxil<br>* 300 mg once daily; oral<br>* Other names: Viread;Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|
| Experimental: Cohort 3<br>Treatment-naïve, HBeAg-negative, Genotype B participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Drug: entecavir<br>* 0.5 mg once daily; oral<br>* Other names: Baraclude;Biological: pegylated interferon alpha 2a<br>* 180 mcg; subcutaneous injection once weekly<br>* Other names: Pegasys;Drug: tenofovir disoproxil<br>* 300 mg once daily; oral<br>* Other names: Viread;Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|
| Experimental: Cohort 4<br>Treatment-naïve, HBeAg-positive, Genotype C participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Drug: entecavir<br>* 0.5 mg once daily; oral<br>* Other names: Baraclude;Biological: pegylated interferon alpha 2a<br>* 180 mcg; subcutaneous injection once weekly<br>* Other names: Pegasys;Drug: tenofovir disoproxil<br>* 300 mg once daily; oral<br>* Other names: Viread;Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|
| Experimental: Cohort 5<br>Treatment-naïve, HBeAg-negative, Genotype C participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Drug: entecavir<br>* 0.5 mg once daily; oral<br>* Other names: Baraclude;Biological: pegylated interferon alpha 2a<br>* 180 mcg; subcutaneous injection once weekly<br>* Other names: Pegasys;Drug: tenofovir disoproxil<br>* 300 mg once daily; oral<br>* Other names: Viread;Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|
| Experimental: Cohort 6<br>Treatment-naïve, HBeAg-negative, Genotype D participants with CHB administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) concomitantly with daily orally administered ETV or TDF for approximately 60 weeks starting Day 1 and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 87. | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Drug: entecavir<br>* 0.5 mg once daily; oral<br>* Other names: Baraclude;Biological: pegylated interferon alpha 2a<br>* 180 mcg; subcutaneous injection once weekly<br>* Other names: Pegasys;Drug: tenofovir disoproxil<br>* 300 mg once daily; oral<br>* Other names: Viread;Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|
| Experimental: Cohort 7<br>Treatment-naïve, HBeAg-negative or HBeAg-positive participants with hepatitis delta virus (HDV) administered ARC-520 (2 mg/kg increasing to 4 mg/kg or 4 mg/kg IV) every 4 weeks for 48 weeks (13 doses) and weekly subcutaneously administered PEG IFN alpha 2a for 48 weeks starting Day 15. | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Biological: pegylated interferon alpha 2a<br>* 180 mcg; subcutaneous injection once weekly<br>* Other names: Pegasys;Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|
| Experimental: Cohort 8<br>Treatment-naïve, HBeAg-positive participants with CHB of any genotype administered ARC-520 (4 mg/kg IV) every 4 weeks for 48 weeks (13 doses). | Drug: ARC-520<br>* ARC-520 will be administered intravenously concomitantly with 0.9% normal saline using an infusion rate of 0.4 mL/min (24 mL/hour) for study treatment and 200 mL/hr for saline.<br>Drug: antihistamine<br>* All 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. Acceptable antihistamines are: diphenhydramine 50 mg p.o., chlorpheniramine 8 mg p.o., hydroxyzine 50 mg p.o., or cetirizine 10 mg p.o.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a 1-log Reduction in Hepatitis B Surface Antigen (HBsAg) at Week 60 Compared to Baseline | The percentage of participants with chronic HBV achieving a 1-log reduction in HBsAg compared to baseline (mean of pre-dose values) at Week 60 after completion of 48 weeks of ARC-520 Injection. | Baseline, Week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment | The Principal Investigator (or medically qualified designee) will use clinical judgment to determine the relationship. An adverse event (AE) was considered possibly related when there is a reasonable possibility that the incident, experience, or outcome may have been caused by the product under investigation. An AE was considered probably related when there are facts, evidence, or arguments to suggest that the event is related to the product under investigation. Only AEs that occurred post-dose were considered treatment-emergent. Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs. | From first dose of study drug up to 36 weeks of treatment, plus up to 48 weeks of follow-up | 
| Percentage of Participants With HBsAg Loss (Based on Qualitative Assay) Over Time | The qualitative HBsAg assay gives a binary result, positive or negative. | Weeks 52, 60, 72 and 96 | 
| Percentage of Participants Achieving a 1-log Reduction in HBsAg and Achieving an HBsAg Level < 100 IU/L Over Time |  | Weeks 52, 60, 72 and 96 | 
| Time to HBsAg Loss |  | Baseline through Week 96 | 
| Time to Anti-HBs (Antibody to Hepatitis B Surface Antigen) Seroconversion |  | Baseline through Week 96 | 
| Percentage of Participants With Anti-HBs Seroconversion Over Time |  | Weeks 52, 60, 72 and 96 | 
| Percentage of Participants With HBeAg Loss and Anti-Hepatitis B e Antigen (Anti-HBe) Seroconversion (if HBeAg-Positive at Study Entry) Over Time |  | Weeks 52, 60, 72 and 96 | 
| Percentage of Participants With Resistance to ARC-520 Injection by Week 52 | Resistance is defined as > 1.0 log IU/mL quantitative HBsAg (qHBsAg) increase from nadir, confirmed by repeat test. | Week 52 | 
| Percentage of Participants With Resistance to the Combination Therapy From Baseline to Week 60 | Resistance is defined as > 1.0 log IU/mL increase in HBV DNA from nadir, confirmed by repeat test. | Baseline, Week 60 | 
| Percentage of Participants With HDV With Undetectable HDV Ribonucleic Acid (RNA) After 48 Weeks of Concomitant ARC-520 Injection and PEG IFN Alpha 2a Therapy Over Time (Cohort 7 Only) |  | Weeks 52, 60, 72 and 96 | 
| Log Change From Baseline in Quantitative HBV Deoxyribonucleic Acid (DNA) Serum Levels Over Time |  | Baseline, Weeks 52, 60, 72 and 96 |