Phase 2 Trial of Therapeutic Hepatitis B Vaccine (Mimogen-based) for Chronic Hepatitis B

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) treatment in chronic hepatitis B patients and to explore the most effective dosage and provide the rational for optimal dosing schedule.

Detailed Description
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First stage(0-76 weeks): Eligible subjects are enrolled and assigned to 3 groups randomly in a 1:1:1 ratio： εPA-44 600μg group：Subcutaneous inject εPA-44 600μg at week 0, 4, 8, 12, 20, 28；Polyene Phosphatidylcholine Capsules will be taken orally beginning in week 28. εPA-44 900μg group：Subcutaneous inject εPA-44 900μg at week 0, 4, 8, 12, 20, 28；Polyene Phosphatidylcholine Capsules will be taken orally beginning in week 28. Placebo control group：Subcutaneous inject empty liposome at week 0, 4, 8, 12, 20, 28；Polyene Phosphatidylcholine Capsules will be taken orally beginning in week 28. The study cycle consists of screening and enrollment period (week -6-0), treatment period (week 0-28) and follow-up period (week 28-76). Second stage(76-144 weeks): In this follow-up stage the trial is open designed, and all the subjects completed the first stage study(0-76 weeks): Subjects with no virological response and no serological response in the first stage , and refuse to continue the this follow-up study, will be provided domestic Adefovir Dipivoxil for one year freely; Subjects with virological response but no serological response/with serological response but no virological response/neither virological nor serological response in the first stage, and be willing to continue the this follow-up study, will be treated by εPA-44 900 μg； Subjects with both virological and serological response, will be followed-up to 144 weeks with no Adefovir Dipivoxil or εPA-44 900 μg treatment. The definition of response is defined as below: Virological response: HBV DNA<2.93×10∧3IU/ml at 76 weeks; Serological response: serological conversion of HBeAg at 76 weeks.

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

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Biological: εPA-44
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-65 years, male or female Conforms to diagnosis standard of chronic hepatitis B according to2005 Guideline for Prevention and Treatment of Hepatitis B, (with positive HBsAg for more than 6 months), and HBV-DNA more than 100000 copies/ml;HBeAg (+),HBsAb(-); Alanine aminotransferase（ALT） within 2 to 10 times of ULN (upper limit of normal) HLA-A2 positive Compensatory liver disease having following hematological and biochemical indicators:WBC≥3.5E+9/L; ANC≥1.5E+9/L; PLT≥80E+9/L; Hb≥110g/L; TBil≤1.5ULN; ALB ≥ lower limit of normal value; BUN (Urea)≤upper limit of normal value; Cr≤upper limit of normal value; prothrombin time(PT) elongation≤3 sec; Activated partial thromboplastin time（APTT） within normal value; Fasting blood glucose≤7.0mmol/L TSH within normal value AFP ≤20ng/ml Uses effective contraception for subject with child-bearing potential (including females and female partners of males) Understands and signs ICF approved by EC Willing to comply with the study procedures and complete the study Exclusion Criteria: Antibody of HAV IgM, HCV, HDV IgM or HEV IgM is positive Antibody of CMV IgM, EBV IgM or HIV is positive Antinuclear antibody titer>1:160 Hepatocarcinoma, suspected hepatocarcinoma or hepatic cirrhosis Has any of the following illnesses or has a severe disease inappropriate for participation in the study based on the investigator's judgment, such as: 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: bronchiectasis, 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 or metal illness history,etc. Has used anti-HBV drug (Interferon, Lamivudine, Adefovir Dipivoxil, Entecavir and Telbivudine) and immunomodulator (Thymic peptide,etc ) 6 months prior to the administration of study medication Has participated in any other drug clinical investigations within the past 3 months Has allergy habitus or has suspected allergy to study drug Female who is in pregnancy, in lactation or planning to become pregnant during the course of the study Has a 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 Has a history of organ transplant (except external corneal transplantation and hair transplantation) Any other factors inappropriate for enrollment 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: εPA-44 900μg<br>Inject εPA-44 900μg at week 0, 4, 8, 12, 20, 28. | Biological: εPA-44<br>* subcutaneously injection of εPA-44 at week 0, 4, 8, 12, 20, 28.<br>* Other names: Therapeutic HBV vaccine;|
| Experimental: εPA-44 600μg+Placebo 300μg<br>Inject εPA-44 600μg+Placebo 300μg at week 0, 4, 8, 12, 20, 28. | Biological: εPA-44<br>* subcutaneously injection of εPA-44 at week 0, 4, 8, 12, 20, 28.<br>* Other names: Therapeutic HBV vaccine;Other: Placebo<br>* subcutaneously injection of Placebo at week 0, 4, 8, 12, 20, 28.<br>|
| Placebo Comparator: Placebo 900μg<br>Inject Placebo 900μg at week 0, 4, 8, 12, 20, 28. | Other: Placebo<br>* subcutaneously injection of Placebo at week 0, 4, 8, 12, 20, 28.<br>|

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 Endpoint . | Primary endpoint data were summarised under End of Study,using the last available post-baseline observation(Last Observation Carried Forward,LOCF) | Endpoint(LOCF), up to 76 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBeAg Seroconversion at Weeks 12, 28, 32, 40, 52, 64, 76 | HBeAg seroconversion=HBeAg loss and presence of hepatitis B e antibody (HBeAb). HBeAg is a hepatitis B viral protein and is an indicator of active viral replication | serology response at week 12, 28, 32, 40, 52, 64, 76 | 
| The Proportion of Patients With Serum HBV DNA Load Decrease Equal or Greater Than 1 Log Scale; |  | week 12, 28, 32, 40, 52, 64, 76 | 
| Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 12,28,32,40,52,64,76 |  | week 12, 28, 32, 40, 52, 64, 76 | 
| The Proportion of Patients With Both Negative HBeAg and HBeAb; |  | at week 12, 28, 32, 40, 52, 64, 76. | 
| The Proportion of Patients With Positive Anti-HBe |  | at week 12, 28, 32, 40, 52, 64, 76. | 
| Change From Baseline by Visit for HBeAg Titer | Measuring the change in value of each visit viewpoints HBeAg titers decreased compared with baseline values | at week 12, 28, 32, 40, 52, 64, 76. | 
| The Proportion of Patients With Serum HBV DNA Load Decrease Equal or Greater Than 2 Log Scale; |  | week 12, 28, 32, 40, 52, 64, 76 | 
| The Proportion of Patients With Serum HBV DNA Level < 29300 IU / ml; |  | week 12, 28, 32, 40, 52, 64, 76 | 
| Change From Baseline by Visit for Serum HBV DNA | Measuring the change in value of each visit viewpoints HBV DNA titers decreased compared with baseline values | week 12, 28, 32, 40, 52, 64, 76 | 

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