Clinical trial NCT02577029: Study of ARC-520 With or Without Other Drugs Used in the Treatment of Chronic Chronic Hepatitis B Virus (HBV)
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hepatitis B
Hepatitis D
Lead sponsor: Arrowhead Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2015-10-15
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Percentage of Participants Achieving a 1-log Reduction in Hepatitis B Surface Antigen (HBsAg) at Week 60 Compared to Baseline
timeFrame: Baseline, Week 60
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Considered Possibly or Probably Related to Treatment
timeFrame: From first dose of study drug up to 36 weeks of treatment, plus up to 48 weeks of follow-up
measure: Percentage of Participants With HBsAg Loss (Based on Qualitative Assay) Over Time
timeFrame: Weeks 52, 60, 72 and 96
measure: Percentage of Participants Achieving a 1-log Reduction in HBsAg and Achieving an HBsAg Level < 100 IU/L Over Time
timeFrame: Weeks 52, 60, 72 and 96
measure: Time to HBsAg Loss
timeFrame: Baseline through Week 96
measure: Time to Anti-HBs (Antibody to Hepatitis B Surface Antigen) Seroconversion
timeFrame: Baseline through Week 96
measure: Percentage of Participants With Anti-HBs Seroconversion Over Time
timeFrame: Weeks 52, 60, 72 and 96
measure: Percentage of Participants With HBeAg Loss and Anti-Hepatitis B e Antigen (Anti-HBe) Seroconversion (if HBeAg-Positive at Study Entry) Over Time
timeFrame: Weeks 52, 60, 72 and 96
measure: Percentage of Participants With Resistance to ARC-520 Injection by Week 52
timeFrame: Week 52
measure: Percentage of Participants With Resistance to the Combination Therapy From Baseline to Week 60
timeFrame: Baseline, Week 60
measure: 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)
timeFrame: Weeks 52, 60, 72 and 96
measure: Log Change From Baseline in Quantitative HBV Deoxyribonucleic Acid (DNA) Serum Levels Over Time
timeFrame: Baseline, Weeks 52, 60, 72 and 96
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Concord
country: Australia
facility: Concord Repatriation General Hospital, Gastroenterology & Liver Services
state: New South Wales
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital Sydney
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Health Clayton Campus
state: Victoria
city: Fitzroy
country: Australia
facility: St. Vincent's Hospital Melbourne
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research Ltd.
state: Western Australia
city: Pleven
country: Bulgaria
facility: MHAT St. Pantaleimon OOD, Department of Gastroenterology
city: Sofia
country: Bulgaria
facility: UMHAT St. Ivan Rilski EAD, Clinic of Gastroenterology
city: Sofia
country: Bulgaria
facility: Diagnostic and Consultative Center - Focus 5 - Outpatient Medical Center, EOOD
city: Varna
country: Bulgaria
facility: Diagnostic and Consultative Center Mladost-M Varna
city: Hong Kong
country: China
facility: Queen Mary Hospital, Department of Medicine
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Chisinau
country: Moldova, Republic of
facility: IMSP Spitalul Clinic de Boli Infectioase, Toma Ciorba
city: Papatoetoe
country: New Zealand
facility: Middlemore Clinical Trials, Middlemore Hospital
state: Aukland
city: Dunedin
country: New Zealand
facility: Dunedin Hospital, Gastroenterology Research Unit
state: Otago-Southland
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies
city: Douliou
country: Taiwan
facility: National Taiwan University Hospital, Yun-Lin Branch
state: Yunlin County
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Hospital of Tropical Diseases
city: Bangkok
country: Thailand
facility: Phramongkutklao Hospital, Division of Digestive and Liver Disease
city: Chiang Mai
country: Thailand
facility: Maharaj Nakhon Chiang Mai Hospital, Gastroenterology Division
city: Khon Kaen
country: Thailand
facility: Khon Kaen University
city: Pathumthani
country: Thailand
facility: Thammasat University Hospital, Gastroenterology Unit
Study officials:
References: