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

Phase 2

Terminated

Conditions: Hepatitis D
Hepatitis B

Interventions: Drug: ARC-520
Drug: antihistamine
Drug: entecavir
Biological: pegylated interferon alpha 2a
Drug: tenofovir disoproxil

Registration Number: NCT02577029

Lead Sponsor: Arrowhead Pharmaceuticals

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 79

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1	antihistamine	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).
Cohort 2	ARC-520	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.
Cohort 2	antihistamine	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.
Cohort 2	tenofovir disoproxil	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.
Cohort 2	entecavir	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.
Cohort 2	pegylated interferon alpha 2a	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.
Cohort 3	pegylated interferon alpha 2a	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.
Cohort 5	pegylated interferon alpha 2a	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.
Cohort 3	ARC-520	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.
Cohort 3	antihistamine	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.
Cohort 6	pegylated interferon alpha 2a	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.
Cohort 6	antihistamine	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.
Cohort 7	ARC-520	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.
Cohort 4	pegylated interferon alpha 2a	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.
Cohort 4	antihistamine	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.
Cohort 8	antihistamine	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).
Cohort 5	antihistamine	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.
Cohort 7	pegylated interferon alpha 2a	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.
Cohort 7	antihistamine	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.
Cohort 1	ARC-520	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).
Cohort 4	ARC-520	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.
Cohort 5	ARC-520	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.
Cohort 6	ARC-520	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.
Cohort 8	ARC-520	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).
Cohort 3	entecavir	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.
Cohort 3	tenofovir disoproxil	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.
Cohort 4	entecavir	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.
Cohort 4	tenofovir disoproxil	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.
Cohort 5	entecavir	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.
Cohort 5	tenofovir disoproxil	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.
Cohort 6	entecavir	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.
Cohort 6	tenofovir disoproxil	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving a 1-log Reduction in Hepatitis B Surface Antigen (HBsAg) at Week 60 Compared to Baseline	Baseline, Week 60	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.

Secondary Outcome Measures

Name	Time	Method
Time to Anti-HBs (Antibody to Hepatitis B Surface Antigen) Seroconversion	Baseline through Week 96
Percentage of Participants With Resistance to ARC-520 Injection by Week 52	Week 52	Resistance is defined as \> 1.0 log IU/mL quantitative HBsAg (qHBsAg) increase from nadir, confirmed by repeat test.
Percentage of Participants With Resistance to the Combination Therapy From Baseline to Week 60	Baseline, Week 60	Resistance is defined as \> 1.0 log IU/mL increase in HBV DNA from nadir, confirmed by repeat test.
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
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment	From first dose of study drug up to 36 weeks of treatment, plus up to 48 weeks of follow-up	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.
Percentage of Participants With HBsAg Loss (Based on Qualitative Assay) Over Time	Weeks 52, 60, 72 and 96	The qualitative HBsAg assay gives a binary result, positive or negative.
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
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
Time to HBsAg Loss	Baseline through Week 96

Trial Locations

Locations (33): St. Vincent's Hospital Sydney
🇦🇺
Darlinghurst, New South Wales, Australia
Westmead Hospital
🇦🇺
Westmead, New South Wales, Australia
Concord Repatriation General Hospital, Gastroenterology & Liver Services
🇦🇺
Concord, New South Wales, Australia
Seoul National University Hospital
🇰🇷
Seoul, Korea, Republic of
Kyungpook National University Hospital
🇰🇷
Daegu, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷
Seoul, Korea, Republic of
Pusan National University Hospital
🇰🇷
Busan, Korea, Republic of
Gangnam Severance Hospital, Yonsei University Health System
🇰🇷
Seoul, Korea, Republic of
Inje University Busan Paik Hospital
🇰🇷
Busan, Korea, Republic of
Middlemore Clinical Trials, Middlemore Hospital
🇳🇿
Papatoetoe, Aukland, New Zealand
Dunedin Hospital, Gastroenterology Research Unit
🇳🇿
Dunedin, Otago-Southland, New Zealand
Auckland Clinical Studies
🇳🇿
Auckland, New Zealand
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳
Kaohsiung, Taiwan
Changhua Christian Hospital
🇨🇳
Changhua, Taiwan
Khon Kaen University
🇹🇭
Khon Kaen, Thailand
Thammasat University Hospital, Gastroenterology Unit
🇹🇭
Pathumthani, Thailand
UMHAT St. Ivan Rilski EAD, Clinic of Gastroenterology
🇧🇬
Sofia, Bulgaria
MHAT St. Pantaleimon OOD, Department of Gastroenterology
🇧🇬
Pleven, Bulgaria
Monash Health Clayton Campus
🇦🇺
Clayton, Victoria, Australia
Royal Melbourne Hospital
🇦🇺
Parkville, Victoria, Australia
Diagnostic and Consultative Center - Focus 5 - Outpatient Medical Center, EOOD
🇧🇬
Sofia, Bulgaria
Diagnostic and Consultative Center Mladost-M Varna
🇧🇬
Varna, Bulgaria
IMSP Spitalul Clinic de Boli Infectioase, Toma Ciorba
🇲🇩
Chisinau, Moldova, Republic of
National Taiwan University Hospital, Yun-Lin Branch
🇨🇳
Douliou, Yunlin County, Taiwan
King Chulalongkorn Memorial Hospital
🇹🇭
Bangkok, Thailand
Hospital of Tropical Diseases
🇹🇭
Bangkok, Thailand
Phramongkutklao Hospital, Division of Digestive and Liver Disease
🇹🇭
Bangkok, Thailand
Maharaj Nakhon Chiang Mai Hospital, Gastroenterology Division
🇹🇭
Chiang Mai, Thailand
Queen Mary Hospital, Department of Medicine
🇨🇳
Hong Kong, China
Linear Clinical Research Ltd.
🇦🇺
Nedlands, Western Australia, Australia
Royal Prince Alfred Hospital
🇦🇺
Camperdown, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺
Adelaide, South Australia, Australia
St. Vincent's Hospital Melbourne
🇦🇺
Fitzroy, Victoria, Australia