Clinical trial NCT02604212: A Multi-dose Study of ARC-520 in Patients With Hepatitis B 'e' Antigen (HBeAg) Positive, Chronic Hepatitis B Virus Infection
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hepatitis B
Lead sponsor: Arrowhead Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2015-11-13
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with HBeAG positive, chronic HBV infection will receive either ARC-520 or placebo in combination with entecavir or tenofovir, and be evaluated for safety and efficacy.

Detailed description: This is a multicenter, randomized, double-blind, placebo-controlled, multi-dose study of ARC-520 in combination with entecavir or tenofovir administered to patients with HBeAg positive and immune active chronic HBV infection Eligible patients who have signed an Ethics Committee - approved informed consent, will be enrolled and will receive ARC-520 or placebo in combination with entecavir or tenofovir. The study will enroll up to a total of 90 eligible chronic HBV infected patients. 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 electrocardiograms (ECGs), liver fibrosis testing, concomitant medication assessment, blood sample collection for hematology, coagulation, chemistry, lactate, Pharmacokinetic (PK) measures (in a subset of patients), exploratory Pharmacodynamic (PD) measures, urinalysis, HBV serology, 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 33 weeks from screening to the Day 169 follow-up visit. For patients enrolling into a planned extension study, the total duration of this study is approximately 25 weeks from screening to Day 113 end of study visit.

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.
* No new abnormal finding of clinical relevance at the screening evaluation.
* Diagnosis of HBeAg positive, immune active, chronic HBV infection.
* \> 2months of continuous treatment with daily, oral entecavir or tenofovir.
* Willingness to continue taking entecavir or tenofovir throughout the study.
* 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 infection within 4 weeks of screening.
* Antiviral therapy other than entecavir or tenofovir within 3 months of screening.
* Prior treatment with interferon in the last 3 years.
* Use within the last 6 months or anticipated requirement for anticoagulants, 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, or hormonal contraceptives.
* Depot injection or implant of any drug within 3 months prior to treatment administration, except injectable/implantable birth control.
* Diagnosis of diabetes mellitus.
* History of autoimmune disease especially autoimmune hepatitis.
* Human immunodeficiency virus (HIV) infection.
* Sero-positive for Hepatitis C Virus (HCV), and/or a history of delta virus hepatitis.
* Hypertension defined as blood pressure \> 150/100 mmHg.
* History of cardiac rhythm disturbances.
* Family history or 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 a major surgery within 3 months of screening.
* History of alcohol and/or drug abuse \< 12 months from screening.
* Regular uses of alcohol within 6 months prior to screening (ie, more than 14 units of alcohol per week).
* Evidence of severe systemic acute inflammation, sepsis, or hemolysis.
* Diagnosed with a significant psychiatric disorder.
* Use of recreational drugs, such as marijuana, within 3 months prior to screening.
* Use of drugs such as cocaine, phencyclidine (PCP), and methamphetamines, within 1 year prior to screening.
* History of allergy to bee sting.
* Use of investigational agents or devices within 30 days prior to planned study dosing or current participation in an investigational study.
* Clinically significant history or presence of any gastrointestinal pathology, unresolved gastrointestinal symptoms, liver or kidney disease.
* Presence of cholangitis, cholecystitis, cholestasis, or duct obstruction.
* Clinically significant history or presence of poorly controlled/uncontrolled systemic disease.
* History of fever within 2 weeks of screening.
* Immunized with a live attenuated vaccine within 7 days prior to dosing or planned vaccination (excluding flu vaccine by injection).
* Presence of any medical or psychiatric condition or social situation that impacts compliance or results in additional safety risk.
* Participated in excessive exercise/physical activity within 7 days of screening or planned during the trial.
* History of coagulopathy/stroke within past 6 months, and/or concurrent anticoagulant medication(s).

Primary outcomes:
measure: Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113
timeFrame: Baseline, Day 113
Secondary outcomes:
measure: Change From Baseline in Log qHBsAg Over Time
timeFrame: Baseline, Days 15, 29, 43, 57, 71, 85, 99
measure: Change From Baseline at Day 15 in Log qHBsAg, by Category
timeFrame: Baseline, Day 15
measure: Change From Baseline at Day 29 in Log qHBsAg, by Category
timeFrame: Baseline, Day 29
measure: Change From Baseline at Day 43 in Log qHBsAg, by Category
timeFrame: Baseline, Day 43
measure: Change From Baseline at Day 57 in Log qHBsAg, by Category
timeFrame: Baseline, Day 57
measure: Change From Baseline at Day 71 in Log qHBsAg, by Category
timeFrame: Baseline, Day 71
measure: Change From Baseline at Day 85 in Log qHBsAg, by Category
timeFrame: Baseline, Day 85
measure: Change From Baseline at Day 99 in Log qHBsAg, by Category
timeFrame: Baseline, Day 99
measure: Change From Baseline at Day 113 in Log qHBsAg, by Category
timeFrame: Baseline, Day 113
measure: Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations Due to AEs
timeFrame: Through Day 169 (± 3 days)
measure: Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
measure: Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
measure: Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
measure: Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
measure: Pharmacokinetics of ARC-520: Clearance (CL)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
measure: Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
measure: Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
measure: Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2)
timeFrame: Through 48 hours post-dosing on Day 1 and Day 85
Other outcomes:
Locations:
city: Hong Kong
country: China
facility: Queen Mary Hospital
city: Hong Kong
country: China
facility: Prince of Wales Hospital
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe Universitaet
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg - Chirurgisch-Traumatologisches Zentrum
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Leipzig
country: Germany
facility: Eugastro Gmbh
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig
city: Muenchen
country: Germany
facility: Klinikum Der Ludwig-Maximilian-Universitaet Muenchen
city: Tuebingen
country: Germany
facility: University Hospital of Tuebingen
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm, Klinik fur Innere Medizin I
city: Wuerzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg, Medizinische Klinik Und Poliklinik II
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University College of Medicine
city: Yangsan-si Gyeongnam
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
Study officials:
References: