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Augmenting Response to Entecavir With Peginterferon a-2a for the Treatment of HBeAg-positive Chronic Hepatitis B (ARES)

Primary Purpose

Chronic Hepatitis B

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
pegylated interferon a-2a
Entecavir
Sponsored by
Foundation for Liver Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Hepatitis B focused on measuring Hepatitis B Entecavir pegylated interferon a-2a

Eligibility Criteria

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

Inclusion Criteria:

  • Chronic hepatitis B (HBsAg positive > 6 months)
  • HBeAg positive, anti-HBe negative at screening
  • ALT > 1.3 x ULN within 60 days prior to screening and during screening
  • Liver biopsy performed within 2 years prior to screening or during screening
  • Age > 18 years
  • Written informed consent
  • Adequate contraception for males and females during treatment and follow up; negative pregnancy test (for women of childbearing potential)

Exclusion Criteria:

  • Antiviral therapy against HBV within the previous 6 months
  • Treatment with any investigational drug within 30 days of screening
  • Previous treatment with lamivudine or telbivudine for more than six months
  • Severe hepatitis activity as documented by ALT>10 x ULN
  • History of decompensated cirrhosis (defined as jaundice in the presence of cirrhosis, ascites, bleeding gastric or esophageal varices or encephalopathy)
  • Pre-existent neutropenia (neutrophils < 1,500/mm3) or thrombocytopenia (platelets < 90,000/mm3)
  • Co-infection with hepatitis C virus or human immunodeficiency virus (HIV)
  • Other acquired or inherited causes of liver disease (i.e. alcoholic liver disease, obesity induced liver disease, drug related liver disease, auto-immune hepatitis, hemochromatosis, Wilson's disease or alpha-1 antitrypsin deficiency)
  • Alpha fetoprotein > 50 ng/ml
  • Hyper- or hypothyroidism (subjects requiring medication to maintain TSH levels in the normal range are eligible if all other inclusion/exclusion criteria are met)
  • Immune suppressive treatment within the previous 6 months
  • Contra-indications for alpha-interferon therapy like suspected hypersensitivity to interferon or PEG-interferon or any known pre-existing medical condition that could interfere with the patient's participation in and completion of the study.
  • Pregnancy, lactation
  • Other significant medical illness that might interfere with this study: significant pulmonary dysfunction in the previous 6 months, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g. HIV positivity, auto-immune diseases, organ transplants other than cornea and hair transplant)
  • Any medical condition requiring, or likely to require chronic systemic administration of steroids, during the course of the study
  • Substance abuse, such as alcohol (> 80 g/day), I.V. drugs and inhaled drugs in the past 2 years.
  • Any other condition which in the opinion of the principal investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study

Sites / Locations

  • Ruijin Hospital
  • Shanghai Public Health Center
  • Zhong Shan hospital, Fu Dan University
  • Amsterdam Medical Center (AMC)
  • Erasmus Medical Center
  • CMUMU
  • Medical University, Dept of Infections Diseases
  • WAMED
  • Fundeni Clinical Institute
  • Nat. Institute of inf. Disease
  • University of Ankara, Medical School
  • Yuksek Ihsitas Hospital, Dept. Gastroenterology
  • Cerrahpasa Medical Faculty

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

ETV + pegIFN

ETV

Arm Description

Patients receive Entecavir in a dosage of 0.5 mg once daily per os from day 0, up to week 48. From week 24 to week 48, they also receive pegylated-interferon a-2a in a dose of 180 μg per week s.c. At week 48, response will be assessed. Responders will continue to take Entecavir until week 72, and quit subsequently. Non-responders at week 48 will continue on Entecavir up to week 96.

Patients receive Entecavir in a dosage of 0.5 mg once daily per os from day 0, up to week 48. At week 48, response will be assessed. Responders will continue to take Entecavir until week 72, and quit subsequently. Non-responders at week 48 will continue on Entecavir up to week 96.

Outcomes

Primary Outcome Measures

The combined presence of HBV DNA level < 200 IU/mL and HBeAg loss

Secondary Outcome Measures

ALT normalization
Undetectable HBV DNA <60 IU/mL
HBsAg and HBeAg loss from serum
The emergence of HBV polymerase mutations associated with reduced susceptibility to entecavir
Sustained response defined as the combined presence of HBV DNA level < 200 IU/mL and HBeAg loss

Full Information

First Posted
April 7, 2009
Last Updated
March 27, 2014
Sponsor
Foundation for Liver Research
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1. Study Identification

Unique Protocol Identification Number
NCT00877760
Brief Title
Augmenting Response to Entecavir With Peginterferon a-2a for the Treatment of HBeAg-positive Chronic Hepatitis B
Acronym
ARES
Official Title
Augmenting Response to Entecavir Using a Temporary Peginterferon Alpha-2a add-on Strategy for the Treatment of HBeAg-positive Chronic Hepatitis B
Study Type
Interventional

2. Study Status

Record Verification Date
March 2014
Overall Recruitment Status
Completed
Study Start Date
August 2009 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
July 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Foundation for Liver Research

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to investigate whether it is possible to augment the response of patients with HBeAg-positive chronic hepatitis B to entecavir by using a temporary peginterferon alpha-2a add-on strategy

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Hepatitis B
Keywords
Hepatitis B Entecavir pegylated interferon a-2a

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
184 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ETV + pegIFN
Arm Type
Experimental
Arm Description
Patients receive Entecavir in a dosage of 0.5 mg once daily per os from day 0, up to week 48. From week 24 to week 48, they also receive pegylated-interferon a-2a in a dose of 180 μg per week s.c. At week 48, response will be assessed. Responders will continue to take Entecavir until week 72, and quit subsequently. Non-responders at week 48 will continue on Entecavir up to week 96.
Arm Title
ETV
Arm Type
Active Comparator
Arm Description
Patients receive Entecavir in a dosage of 0.5 mg once daily per os from day 0, up to week 48. At week 48, response will be assessed. Responders will continue to take Entecavir until week 72, and quit subsequently. Non-responders at week 48 will continue on Entecavir up to week 96.
Intervention Type
Drug
Intervention Name(s)
pegylated interferon a-2a
Other Intervention Name(s)
Pegasys
Intervention Description
180 μg, once per week s.c. for 24 weeks
Intervention Type
Drug
Intervention Name(s)
Entecavir
Other Intervention Name(s)
Baraclude
Intervention Description
0.5 mg once daily per os, either 72 weeks or 96 weeks
Primary Outcome Measure Information:
Title
The combined presence of HBV DNA level < 200 IU/mL and HBeAg loss
Time Frame
week 48
Secondary Outcome Measure Information:
Title
ALT normalization
Time Frame
up to week 96
Title
Undetectable HBV DNA <60 IU/mL
Time Frame
up to week 96
Title
HBsAg and HBeAg loss from serum
Time Frame
up to week 96
Title
The emergence of HBV polymerase mutations associated with reduced susceptibility to entecavir
Time Frame
up to week 96
Title
Sustained response defined as the combined presence of HBV DNA level < 200 IU/mL and HBeAg loss
Time Frame
week 96

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Chronic hepatitis B (HBsAg positive > 6 months) HBeAg positive, anti-HBe negative at screening ALT > 1.3 x ULN within 60 days prior to screening and during screening Liver biopsy performed within 2 years prior to screening or during screening Age > 18 years Written informed consent Adequate contraception for males and females during treatment and follow up; negative pregnancy test (for women of childbearing potential) Exclusion Criteria: Antiviral therapy against HBV within the previous 6 months Treatment with any investigational drug within 30 days of screening Previous treatment with lamivudine or telbivudine for more than six months Severe hepatitis activity as documented by ALT>10 x ULN History of decompensated cirrhosis (defined as jaundice in the presence of cirrhosis, ascites, bleeding gastric or esophageal varices or encephalopathy) Pre-existent neutropenia (neutrophils < 1,500/mm3) or thrombocytopenia (platelets < 90,000/mm3) Co-infection with hepatitis C virus or human immunodeficiency virus (HIV) Other acquired or inherited causes of liver disease (i.e. alcoholic liver disease, obesity induced liver disease, drug related liver disease, auto-immune hepatitis, hemochromatosis, Wilson's disease or alpha-1 antitrypsin deficiency) Alpha fetoprotein > 50 ng/ml Hyper- or hypothyroidism (subjects requiring medication to maintain TSH levels in the normal range are eligible if all other inclusion/exclusion criteria are met) Immune suppressive treatment within the previous 6 months Contra-indications for alpha-interferon therapy like suspected hypersensitivity to interferon or PEG-interferon or any known pre-existing medical condition that could interfere with the patient's participation in and completion of the study. Pregnancy, lactation Other significant medical illness that might interfere with this study: significant pulmonary dysfunction in the previous 6 months, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g. HIV positivity, auto-immune diseases, organ transplants other than cornea and hair transplant) Any medical condition requiring, or likely to require chronic systemic administration of steroids, during the course of the study Substance abuse, such as alcohol (> 80 g/day), I.V. drugs and inhaled drugs in the past 2 years. Any other condition which in the opinion of the principal investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Harry Janssen, Prof. dr.
Organizational Affiliation
Foundation for Liver Research (SLO) and Erasmus Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ruijin Hospital
City
Shanghai
Country
China
Facility Name
Shanghai Public Health Center
City
Shanghai
Country
China
Facility Name
Zhong Shan hospital, Fu Dan University
City
Shanghai
Country
China
Facility Name
Amsterdam Medical Center (AMC)
City
Amsterdam
Country
Netherlands
Facility Name
Erasmus Medical Center
City
Rotterdam
Country
Netherlands
Facility Name
CMUMU
City
Bydgoszcz
Country
Poland
Facility Name
Medical University, Dept of Infections Diseases
City
Wroclaw
Country
Poland
Facility Name
WAMED
City
Zawiercie
Country
Poland
Facility Name
Fundeni Clinical Institute
City
Bucharest
Country
Romania
Facility Name
Nat. Institute of inf. Disease
City
Bucharest
Country
Romania
Facility Name
University of Ankara, Medical School
City
Ankara
Country
Turkey
Facility Name
Yuksek Ihsitas Hospital, Dept. Gastroenterology
City
Ankara
Country
Turkey
Facility Name
Cerrahpasa Medical Faculty
City
Istanbul
Country
Turkey

12. IPD Sharing Statement

Citations:
PubMed Identifier
35941076
Citation
Brakenhoff SM, de Knegt RJ, van Campenhout MJH, van der Eijk AA, Brouwer WP, van Bommel F, Boonstra A, Hansen BE, Berg T, Janssen HLA, de Man RA, Sonneveld MJ. End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients. J Microbiol Immunol Infect. 2023 Feb;56(1):31-39. doi: 10.1016/j.jmii.2022.06.002. Epub 2022 Jul 2.
Results Reference
derived
PubMed Identifier
30689258
Citation
Liem KS, van Campenhout MJH, Xie Q, Brouwer WP, Chi H, Qi X, Chen L, Tabak F, Hansen BE, Janssen HLA. Low hepatitis B surface antigen and HBV DNA levels predict response to the addition of pegylated interferon to entecavir in hepatitis B e antigen positive chronic hepatitis B. Aliment Pharmacol Ther. 2019 Feb;49(4):448-456. doi: 10.1111/apt.15098.
Results Reference
derived
PubMed Identifier
25348661
Citation
Brouwer WP, Xie Q, Sonneveld MJ, Zhang N, Zhang Q, Tabak F, Streinu-Cercel A, Wang JY, Idilman R, Reesink HW, Diculescu M, Simon K, Voiculescu M, Akdogan M, Mazur W, Reijnders JG, Verhey E, Hansen BE, Janssen HL; ARES Study Group. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study). Hepatology. 2015 May;61(5):1512-22. doi: 10.1002/hep.27586. Epub 2015 Feb 27.
Results Reference
derived

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Augmenting Response to Entecavir With Peginterferon a-2a for the Treatment of HBeAg-positive Chronic Hepatitis B

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