Study of Therapeutic Vaccination With Intensified Schedule Plus Pegasys Dual Therapy on Chronic Hepatitis B Infection

Study Overview
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Brief Summary
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A randomized, Open label, Single center, Prospective study to compare efficacy and safety of Therapeutic Vaccination with Intensified schedule plus Pegylated Interferon dual Therapy on Seroclearance of Hepatitis B virus Surface Antigen in Patients with Complete Virological Response Induced by Entecavir

Detailed Description
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A randomized, Open label, Single center, Prospective study to compare efficacy and safety of Therapeutic Vaccination with Intensified schedule plus Pegylated Interferon dual Therapy on Seroclearance of Hepatitis B virus Surface Antigen in Patients with Complete Virological Response Induced by Entecavir (E + VIP)

Official Title
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Phase4, to Compare Efficacy and Safety of Therapeutic Vaccination With Intensified Schedule Plus Pegylated Interferon Dual Therapy on Seroclearance of HBS Antigen in Patients With Complete Virological Response Induced by Entecavir

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Biological: Peginterferon alfa-2a
* Biological: HBV vaccination
* Drug: Entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 20 and 75 year-old HBsAg-positive for > 6 months apart (medical history can be alternative) Currently being treated with entecavir 0.5 mg/day for more than 18 months Undetectable HBV DNA in serum (<20IU/mL) and HBeAg-negative or positive for > 1year HBsAg titer < 3,000 IU/mL ALT<300 IU/L Signed written informed consent after being instructed about the objective and procedure of the clinical study Exclusion Criteria: Patients with decompensated liver cirrhosis, any one of the following ① Serum bilirubin > 3 mg/dL ② Prothrombin time > 6 seconds prolonged or INR >2.3 ③ Serum albumin < 2.8 g/dL ④ History of ascites, variceal hemorrhage, or hepatic encephalopathy ⑤ Child-Pugh score ≥7 (Child-Pugh class B or C) Patients who have evidence of renal insufficiency defined as serum creatinine>1.5 mg/dL Patients with psychological problem including depression Patients who have previous/current significant co-morbidities including congestive heart failure, chronic kidney disease, hematologic disease and malignancy including hepatocellular carcinoma(patients with malignancy cured 5 years before screening can be enrolled) Patients with seropositivity for anti-HCV, anti-HDV or anti-HIV Patients who have excessive alcohol consumption (> 30 g/day) Patients who have evidence of autoimmune hepatitis, hemochromatosis or Wilson's disease Pregnant or breast feeding females or plan for pregnancy or no contraception Patients with disease may deteriorate with interferon therapy(eg, autoimmune thyroiditis) Patients who have an psoriasis Patients who have history of antiviral-resistant HBV after previous treatment with oral antiviral agents Previous diagnosis with immunodeficiency or concomitant treatment of immune suppressive agent or previous organ transplantation Recipients Patients who have a history of hypersensitivity to study drug Uncontrollable seizure, convulsion and/or central nervous system disorders Patients with severe bone marrow disorder or with history of hypersensitivity to biologic agent such as vaccine. Neutrophil count < 1,500/mm3 or platelet count < 75,000/mm3 or hemoglobin < 10 g/dl Patients with Pulmonary disease (in case of history of pulmonary disease with complete recovery, enrollment is on investigator's discretion) Patients who have a fever ≥ 38 °C at the baseline Patients who have a risk of febrile response or systemic reaction Patients who the investigator deems inappropriate to participate in this study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Concomitant:Pegasys, Euvax B, Baracrude<br>Peginterferon alfa-2a: once weekly 180 μg subcutaneous injection for 48 weeks HBV vaccination (Euvax B Inj): 1.0 mL (20 μg) intramuscular injection at 4, 8, 12 and 28 weeks Continue Entecavir(0.5mg) for 100 weeks(once daily) | Biological: Peginterferon alfa-2a<br>* once weekly 180 μg subcutaneous injection for 48 weeks<br>* Other names: Pegasys;Biological: HBV vaccination<br>* 1.0 mL (20 μg) intramuscular injection at 4, 8, 12 and 28 weeks<br>* Other names: Euvax B Inj;Drug: Entecavir<br>* Continue Entecavir(0.5mg) for 100 weeks<br>* Other names: Baracrude;|
| Experimental: Sequential:Pegasys, Euvax B, Baracrude<br>Peginterferon alfa-2a: once weekly 180 μg or weight base dose subcutaneous injection for 48 weeks HBV vaccination (Euvax B Inj): 1.0 mL (20 μg) intramuscular injection at 52, 56, 60 and 76 weeks Continue Entecavir(0.5mg) for 100 weeks(once daily) | Biological: Peginterferon alfa-2a<br>* once weekly 180 μg subcutaneous injection for 48 weeks<br>* Other names: Pegasys;Biological: HBV vaccination<br>* 1.0 mL (20 μg) intramuscular injection at 4, 8, 12 and 28 weeks<br>* Other names: Euvax B Inj;Drug: Entecavir<br>* Continue Entecavir(0.5mg) for 100 weeks<br>* Other names: Baracrude;|
| Active Comparator: Control Group<br>Continue Entecavir(0.5mg) for 100 weeks(once daily) After EOS(100W), injection(once weekly) a Peginterferon alfa-2a for 48 weeks | Biological: Peginterferon alfa-2a<br>* once weekly 180 μg subcutaneous injection for 48 weeks<br>* Other names: Pegasys;Drug: Entecavir<br>* Continue Entecavir(0.5mg) for 100 weeks<br>* Other names: Baracrude;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of HBsAg-seroclearance | The rate of HBsAg-seroclearance at the time point of at weeks 100 in the sequential treatment group (24 weeks after termination of treatment) versus control group(ETV monotherapy) at weeks 100. | The rate of HBsAg-seroclearance at the time point of at weeks 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of HBsAg-seroconversion | The rate of HBsAg-seroconversion at weeks 100 in the sequential treatment group versus control group(ETV monotherapy) at weeks 100. | The rate of HBsAg-seroconversion at weeks 100 | 
| The change of HBsAg level from baseline | The change of HBsAg level from baseline at weeks 100 in the sequential treatment group versus control group(ETV monotherapy) at weeks 100. | The change of HBsAg level from baseline at weeks 100 | 
| The change of HBsAg-seroclearance | The change of HBsAg-seroclearance in the concomitant treatment group versus control group(ETV monotherapy) for exploratory assessment. | The change of HBsAg-seroclearance at weeks 4, weeks 12, weeks 24, weeks 36, weeks 48, weeks 60, weeks 72, weeks 96, weeks 100, weeks 148 | 
| The change of HBsAg-seroconversion | The change of HBsAg-seroconversion in the concomitant treatment group versus control group(ETV monotherapy) for exploratory assessment. | The change of HBsAg-seroconversion at weeks 4, weeks 12, weeks 24, weeks 36, weeks 48, weeks 60, weeks 72, weeks 96, weeks 100, weeks 148 | 
| The change of HBsAg level | The change of HBsAg level in the concomitant treatment group versus control group(ETV monotherapy) for exploratory assessment. | The change of HBsAg level at weeks 4, weeks 12, weeks 24, weeks 36, weeks 48, weeks 60, weeks 72, weeks 96, weeks 100, weeks 148 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic hepatitis B, Pegasys, Euvax B, Baracrude