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A Multi-dose Study of ARC-520 in Patients With Hepatitis B 'e' Antigen (HBeAg) Negative, Chronic Hepatitis B Virus (HBV) Infection

Primary Purpose

Hepatitis B

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ARC-520 Injection
placebo
entecavir
tenofovir
antihistamine
Sponsored by
Arrowhead Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis B

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 negative, immune active, chronic HBV infection
  • > 2 months 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).

Sites / Locations

  • Queen Mary Hospital
  • Prince of Wales Hospital
  • Klinikum der Johann Wolfgang Goethe Universitaet
  • Asklepios Klinik St. Georg - Chirurgisch-Traumatologisches Zentrum
  • Medizinische Hochschule Hannover
  • Eugastro Gmbh
  • Universitaetsklinikum Leipzig
  • Klinikum Der Ludwig-Maximilian-Universitaet Muenchen
  • University Hospital of Tuebingen
  • Universitaetsklinikum Ulm, Klinik fur Innere Medizin I
  • Universitaetsklinikum Wuerzburg, Medizinische Klinik Und Poliklinik II
  • Pusan National University Hospital
  • Gachon University Gil Medical Center
  • Seoul National University Hospital
  • Severance Hospital, Yonsei University College of Medicine
  • Pusan National University Yangsan Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Placebo Comparator

Experimental

Experimental

Arm Label

PBO Low Dose

PBO High Dose

ARC-520 Injection 1 mg/kg

ARC-520 Injection 2 mg/kg

Arm Description

0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period

0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period

Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period

Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period

Outcomes

Primary Outcome Measures

Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.

Secondary Outcome Measures

Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
An AE is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. An SAE is any AE that: 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. A treatment emergent AE (TEAE) was defined as an AE that was not present prior to the first study medication administration and started at/after the time of initiation of administration of study medication, or an AE which was present prior to initiation of study medication administration, which increased in severity after study medication administration.
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24)
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast)
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf)
Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax)
Pharmacokinetics of ARC-520: Clearance (CL)
Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V)
Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel)
Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2)

Full Information

First Posted
November 11, 2015
Last Updated
January 11, 2019
Sponsor
Arrowhead Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02604199
Brief Title
A Multi-dose Study of ARC-520 in Patients With Hepatitis B 'e' Antigen (HBeAg) Negative, Chronic Hepatitis B Virus (HBV) 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 Negative, Chronic Hepatitis B Virus (HBV) Infection
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Terminated
Why Stopped
Company decision to discontinue trial
Study Start Date
September 2015 (Actual)
Primary Completion Date
January 2017 (Actual)
Study Completion Date
January 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Arrowhead Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Patients with 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 Hepatitis B 'e' Antigen (HBeAg) negative 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 60 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis B

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PBO Low Dose
Arm Type
Placebo Comparator
Arm Description
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Arm Title
PBO High Dose
Arm Type
Placebo Comparator
Arm Description
0.9% normal saline, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Arm Title
ARC-520 Injection 1 mg/kg
Arm Type
Experimental
Arm Description
Intravenous ARC-520 at 1.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Arm Title
ARC-520 Injection 2 mg/kg
Arm Type
Experimental
Arm Description
Intravenous ARC-520 at 2.0 mg/kg, once every 4 weeks for 4 doses plus daily oral entecavir (0.5 or 1.0 mg/day) or tenofovir (300 mg) throughout the study period
Intervention Type
Drug
Intervention Name(s)
ARC-520 Injection
Intervention Description
ARC-520 Injection was administered concomitantly, IV with 0.9% normal saline using an infusion rate of 0.4 mL/min for study treatment and 3.6 mL/min for saline.
Intervention Type
Other
Intervention Name(s)
placebo
Intervention Description
Placebo was administered concomitantly, IV with 0.9% normal saline using an infusion rate of 0.4 mL/min for study treatment and 3.6 mL/min for saline.
Intervention Type
Drug
Intervention Name(s)
entecavir
Intervention Description
All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.
Intervention Type
Drug
Intervention Name(s)
tenofovir
Intervention Description
All participants will take entecavir or tenofovir throughout the study. Participants will be instructed to take their medication daily.
Intervention Type
Drug
Intervention Name(s)
antihistamine
Intervention Description
All participants will be pretreated with an oral antihistamine, administered 2 hours (±30 minutes) pre-dose. The antihistamine used should in general be an H1>H2 receptor blocker and would include diphenhydramine 50 mg, cetirizine 10 mg, chlorpheniramine 8 mg or hydroxyzine 50 mg. The Investigator is free to choose any of these antihistamines available locally and consistent with their country's Marketing Authorisation.
Primary Outcome Measure Information:
Title
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) at Day 113
Description
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
Time Frame
Baseline, Day 113
Secondary Outcome Measure Information:
Title
Change From Baseline in Quantitative Hepatitis B Surface Antigen (Log qHBsAg) Over Time
Description
Change From Baseline in log qHBsAg at Day 113 in response to multiple doses of ARC-520 versus placebo, using a a mixed effect model for repeated measures (MMRM). Includes parameter baseline as a continuous covariate, and treatment and visit as fixed factors, interaction of treatment and visit, and interaction of parameter baseline and visit.
Time Frame
Baseline, Day 15, 29, 43, 57, 71, 85, 99
Title
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths and Discontinuations Due to AEs
Description
An AE is any untoward medical occurrence which does not necessarily have a causal relationship with this treatment. An SAE is any AE that: 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. A treatment emergent AE (TEAE) was defined as an AE that was not present prior to the first study medication administration and started at/after the time of initiation of administration of study medication, or an AE which was present prior to initiation of study medication administration, which increased in severity after study medication administration.
Time Frame
Through Day 169
Title
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85
Title
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85
Title
Pharmacokinetics of ARC-520: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85
Title
Pharmacokinetics of ARC-520: Maximum Observed Plasma Concentration (Cmax)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85
Title
Pharmacokinetics of ARC-520: Clearance (CL)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85
Title
Pharmacokinetics of ARC-520: Apparent Volume of Distribution (V)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85
Title
Pharmacokinetics of ARC-520: Terminal Elimination Rate Constant (Kel)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85
Title
Pharmacokinetics of ARC-520: Terminal Elimination Half-Life (t1/2)
Time Frame
Through 48 hours post-dosing on Day 1 and Day 85

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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 negative, immune active, chronic HBV infection > 2 months 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).
Facility Information:
Facility Name
Queen Mary Hospital
City
Hong Kong
ZIP/Postal Code
999077
Country
China
Facility Name
Prince of Wales Hospital
City
Hong Kong
Country
China
Facility Name
Klinikum der Johann Wolfgang Goethe Universitaet
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
Asklepios Klinik St. Georg - Chirurgisch-Traumatologisches Zentrum
City
Hamburg
ZIP/Postal Code
20099
Country
Germany
Facility Name
Medizinische Hochschule Hannover
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Eugastro Gmbh
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Universitaetsklinikum Leipzig
City
Leipzig
ZIP/Postal Code
4103
Country
Germany
Facility Name
Klinikum Der Ludwig-Maximilian-Universitaet Muenchen
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
University Hospital of Tuebingen
City
Tuebingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Universitaetsklinikum Ulm, Klinik fur Innere Medizin I
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Universitaetsklinikum Wuerzburg, Medizinische Klinik Und Poliklinik II
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Pusan National University Hospital
City
Busan
ZIP/Postal Code
602-739
Country
Korea, Republic of
Facility Name
Gachon University Gil Medical Center
City
Incheon
ZIP/Postal Code
405-760
Country
Korea, Republic of
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
110-744
Country
Korea, Republic of
Facility Name
Severance Hospital, Yonsei University College of Medicine
City
Seoul
ZIP/Postal Code
120-752
Country
Korea, Republic of
Facility Name
Pusan National University Yangsan Hospital
City
Yangsan-si Gyeongnam
ZIP/Postal Code
626-770
Country
Korea, Republic of

12. IPD Sharing Statement

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A Multi-dose Study of ARC-520 in Patients With Hepatitis B 'e' Antigen (HBeAg) Negative, Chronic Hepatitis B Virus (HBV) Infection

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