Chronic Hepatitis BPhase 4ARESNCT00877760
Augmenting Response to Entecavir With Peginterferon a-2a for the Treatment of HBeAg-positive Chronic Hepatitis B
A Phase 4 study testing pegylated interferon a-2a and Entecavir in people with Chronic Hepatitis B, run by Foundation for Liver Research at 13 sites in 5 countries.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Hepatitis B
- What is being tested?
- pegylated interferon a-2a and Entecavir
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 184 participants
- Where
- 13 sitesin 5 countries
- Study dates
- Aug 2009to Jul 2013
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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)
Show all 17Show fewer
- 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
Trial locations and contacts
13 sites in 5 countries.
13 sites in 5 countries
China3 sites
Ruijin Hospital
Shanghai
Shanghai Public Health Center
Shanghai
Zhong Shan hospital, Fu Dan University
Shanghai
Poland3 sites
CMUMU
Bydgoszcz
Medical University, Dept of Infections Diseases
Wroclaw
WAMED
Zawiercie
Turkey (Türkiye)3 sites
University of Ankara, Medical School
Ankara
Yuksek Ihsitas Hospital, Dept. Gastroenterology
Ankara
Cerrahpasa Medical Faculty
Istanbul
Netherlands2 sites
Amsterdam Medical Center (AMC)
Amsterdam
Erasmus Medical Center
Rotterdam
Romania2 sites
Fundeni Clinical Institute
Bucharest
Nat. Institute of inf. Disease
Bucharest
About this study
Official title: Augmenting Response to Entecavir Using a Temporary Peginterferon Alpha-2a add-on Strategy for the Treatment of HBeAg-positive Chronic Hepatitis B
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
- Conditions
- Chronic Hepatitis B
- Being tested
- pegylated interferon a-2a, Entecavir
- Keywords
- Hepatitis B Entecavir pegylated interferon a-2a
- Medical subject headings
- Hepatitis B, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
pegylated interferon a-2aDrug
Also called Pegasys
180 μg, once per week s.c. for 24 weeks
EntecavirDrug
Also called Baraclude
0.5 mg once daily per os, either 72 weeks or 96 weeks
| Study group | Role | What they receive |
|---|---|---|
| ETV + pegIFN | Experimental | 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. Receives: Drug: pegylated interferon a-2a; Drug: Entecavir |
| ETV | Active comparator | 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. Receives: Drug: Entecavir |
What is being measured
The primary outcome is the main question the study is designed to answer.
The combined presence of HBV DNA level < 200 IU/mL and HBeAg loss
Measured: week 48
Secondary outcomes (5)
ALT normalization
Measured: up to week 96
Undetectable HBV DNA <60 IU/mL
Measured: up to week 96
HBsAg and HBeAg loss from serum
Measured: up to week 96
The emergence of HBV polymerase mutations associated with reduced susceptibility to entecavir
Measured: up to week 96
Sustained response defined as the combined presence of HBV DNA level < 200 IU/mL and HBeAg loss
Measured: week 96
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Apr 2009 (estimated)
- Study startAug 2009
- Primary completionJul 2013
- Study completionJul 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Chronic Hepatitis BStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 184 participants (actual)
Sponsor and investigators
- Lead sponsor
- Foundation for Liver Research
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Harry Janssen, Prof. dr., Principal investigator, Foundation for Liver Research (SLO) and Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00877760
- Sponsor's protocol ID
- HBV 09-01
- Acronym
- ARES
- Status last verified
- Mar 2014
- First submitted
- 7 Apr 2009
- Last updated
- 28 Mar 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 35941076Brakenhoff SM, de Knegt RJ, Oliveira J, van der Eijk AA, van Vuuren AJ, Hansen BE, Janssen HLA, de Man RA, Boonstra A, Sonneveld MJ. Levels of Antibodies to Hepatitis B Core Antigen Are Associated With Liver Inflammation and Response to Peginterferon in Patients With Chronic Hepatitis B. J Infect Dis. 2022 Dec 28;227(1):113-122. doi: 10.1093/infdis/jiac210.
PubMed 35599306Liem 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.
PubMed 30689258Brouwer 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.
PubMed 25348661
Study at a glance
From the registry record, last updated by the sponsor on 28 Mar 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Augmenting Response to Entecavir Using a Temporary Peginterferon Alpha-2a add-on Strategy for the Treatment of HBeAg-positive Chronic Hepatitis B
- ClinicalTrials.gov ID
- NCT00877760
- Acronym / sponsor ID
- ARES / HBV 09-01
- Conditions
- Chronic Hepatitis B
- Keywords
- Hepatitis B Entecavir pegylated interferon a-2a
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 184 participants (actual)
- Lead sponsor
- Foundation for Liver ResearchUniversity, hospital or other
- Study start
- Aug 2009
- Primary completion
- Jul 2013 (actual)
- Study completion
- Jul 2013 (actual)
- First posted
- 8 Apr 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ETV + pegIFN | Experimental | Drug: pegylated interferon a-2a, Drug: EntecavirPatients 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. |
| ETV | Active comparator | Drug: EntecavirPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (17 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| pegylated interferon a-2aAlso: Pegasys180 μg, once per week s.c. for 24 weeks | Drug | ETV + pegIFN |
| EntecavirAlso: Baraclude0.5 mg once daily per os, either 72 weeks or 96 weeks | Drug | ETV, ETV + pegIFN |
Primary outcome
The combined presence of HBV DNA level < 200 IU/mL and HBeAg loss
Time frame: week 48
5 secondary outcomes
ALT normalization
Time frame: up to week 96
Undetectable HBV DNA <60 IU/mL
Time frame: up to week 96
HBsAg and HBeAg loss from serum
Time frame: up to week 96
The emergence of HBV polymerase mutations associated with reduced susceptibility to entecavir
Time frame: up to week 96
Sustained response defined as the combined presence of HBV DNA level < 200 IU/mL and HBeAg loss
Time frame: week 96
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Mar 2014.
- Derived from this study: PubMed 35941076Brakenhoff 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.
- Derived from this study: PubMed 35599306Brakenhoff SM, de Knegt RJ, Oliveira J, van der Eijk AA, van Vuuren AJ, Hansen BE, Janssen HLA, de Man RA, Boonstra A, Sonneveld MJ. Levels of Antibodies to Hepatitis B Core Antigen Are Associated With Liver Inflammation and Response to Peginterferon in Patients With Chronic Hepatitis B. J Infect Dis. 2022 Dec 28;227(1):113-122. doi: 10.1093/infdis/jiac210.
- Derived from this study: PubMed 30689258Liem 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.
- Derived from this study: PubMed 25348661Brouwer 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Harry Janssen, Prof. dr. principal investigator
Foundation for Liver Research (SLO) and Erasmus Medical Center
13 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing pegylated interferon a-2a and Entecavir in people with Chronic Hepatitis B, run by Foundation for Liver Research at 13 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in China, Poland, Turkey (Türkiye), Netherlands, Romania. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The combined presence of HBV DNA level < 200 IU/mL and HBeAg loss (time frame: week 48). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00877760, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2014.