Therapeutic Hepatitis B Vaccine (Mimogen-based) Joint Entecavir in Treating Chronic Hepatitis B Patients

Study Overview
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Brief Summary
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The purpose is to evaluate efficacy and safety of therapeutic hepatitis B virus (HBV) vaccine (mimogen-based)) Joint entecavir treatment in chronic hepatitis B patients.

Detailed Description
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Eligible subjects are enrolled and assigned into 2 groups randomly with a 1:1 ratio： Therapeutic HBV vaccine Joint Entecavir group：Inject εPA-44 900μg at week 0, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48 + Oral intake entecavir 0.5mg per day ； Empty liposome Joint Entecavir group：Inject empty liposome at week 0, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48 + Oral intake entecavir 0.5mg per day. The study cycle consists of screening and enrollment period (week -4～0), treatment and follow-up period (week 0-96).

Official Title
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A Randomized, Double-blind, Multicenter Phase II Clinical Trial to Evaluate the Efficacy and Safety of Therapeutic Hepatitis B Vaccine (Mimogen-based) Joint Entecavir in Treating HBeAg Positive Chronic Hepatitis B Patients

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Biological: Therapeutic HBV vaccine
* Drug: entecavir
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-65 years, male or female; Conforming to diagnosis standard of chronic hepatitis B according to  2005 Guideline for Prevention and Treatment of Hepatitis B  , (with positive HBsAg for more than 6 months), never have systemic treatment of anti-HBV viral ,and HBV-DNA ≥ 1.72×10^4 IU/ml； HBeAg (+), HBeAb (-)； ALT within 2 to 10 times of ULN (upper limits of normal); HLA-A2 positive; Compensatory liver disease having following hematological and biochemical parameters: WBC ≥ 3.5×10^9/L; ANC ≥ 1.5×10^9/L; PLT ≥ 80×10^9/L; Hb ≥ 100g/L; TBil ≤ 1.5 ULN; ALB not lower than low limit of normal value; BUN no more than high limit of normal value; Cr ≤ 1.5 ULN high limit of normal value; PT elongation ≤ 3 sec, APTT in normal value; Fasting blood glucose ≤ 7.0mmol/L; TSH in normal value; AFP test result no more than high limit of normal value; Take effective contraception for subject with child-bearing potential (including females and female partners of males); Understand and sign ICF approved by EC; Willing to comply with the study procedures and complete the study. Exclusion Criteria: Antibodies of HCV, HDV or HIV is positive; ANA titer > 1:100; Decompensated liver disease (such as gullet and pylorus varicose veins, hepatic encephalopathy); Have the following illness or with severe disease inappropriate to participate in the study in the view of the investigator, in cardiovascular system: instable or significant cardiovascular illness such as angina pectoris, heart attack of myocardial infarction, congestive heart failure, severe hypertension, significant arrhythmia or abnormal ECG etc; Respiratory system: bronchiectasia, bronchial asthma, chronic obstructive pulmonary disease, respiratory failure, etc; Endocrine, metabolism diseases: diabetes mellitus, uncontrolled thyroid diseases, etc; Others: autoimmune disorder, active tuberculosis, malignancies (e.g.: tumor), neuropathic, metal, acute or chronic pancreatitis illness history, etc. Have used anti-HBV drug ( Interferon, Lamivudine, Adefovir Dipivoxil, Entecavir and Telbivudine ) and immunomodulator ( Thymic peptide, etc ) to the administration of study medication; Have allergic diathesis or have suspected allergy to εPA-44; Female in pregnancy, lactation or those who plan to pregnancy during the course of the study; Have history of alcohol abuse (Alcohol consumption for more than 5 years, with daily consumption over 40g for males and over 20g for females) and known drug dependence; Have history of organ transplantation (except corneal transplantation and hair transplantation); Have participated in any other drug clinical investigations within 3 months; Any other factors inappropriate for enroll in the study or study completion in the view of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic HBV vaccine+Entecavir<br>Inject εPA-44 900μg at week 0, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48 and Oral intake entecavir 0.5mg per day. | Biological: Therapeutic HBV vaccine<br>* Inject εPA-44 900μg at week 0, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48.<br>* Other names: εPA-44;Drug: entecavir<br>* 0.5mg,per day,oral intake.<br>* Other names: Baraclude;|
| Placebo Comparator: placebo+Entecavir<br>Placebo comparator: Inject placebo 900μg at week 0, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48 and Oral intake entecavir 0.5mg per day. | Drug: entecavir<br>* 0.5mg,per day,oral intake.<br>* Other names: Baraclude;Other: placebo<br>* Inject placebo 900μg at week 0, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48.<br>* Other names: empty liposome;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBeAg Seroconversion at Week 48 | Primary endpoint data were summarised under End of Study,using the last available post-baseline observation(Last Observation Carried Forward,LOCF) | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serological Response | Serological response at every observation time: serological conversion rate of HBeAg, negative conversion rate of HBeAg, and change of HBeAg. | 96 weeks | 
| Virological Response | Virological response at every observation time: the proportion of patients with serum HBV DNA level reduction to undetectable level, decreased amount of serum HBV DNA compared with the baseline value, and HBV DNA load decrease 2 log scales or HBV DNA level <1.72×104 IU/ml. | 96 weeks | 
| Biochemistry Response | Biochemistry response at every observation time, mean the ALT level reduce to normal. | 96 weeks | 
| Histological Response | Histological response at week 72, mean histological score limited reduce 2 (reduced score 2-5), and no fiber deterioration compare with before treatment. | 72 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Hepatitis B, Therapeutic HBV Vaccine, HBeAg positive, HBV-specific Cytotoxic T Lymphocyte