A Clinical Study on Therapeutic Double-plasmid Hepatitis B Virus (HBV) DNA Vaccine in Patients With HBeAg-positive Chronic Hepatitis B

A Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Study on Specific-Population to Evaluate the Safety and Efficacy of Therapeutic Double-plasmid HBV DNA Vaccine in HBeAg-positive Patients With Chronic Hepatitis B

To preliminarily evaluate the efficiency and safety of therapeutic double- plasmid HBV DNA vaccine on HBeAg-positive, chronic hepatitis B patients, and provide evidence for the next dosing regimen.

The current study is a multicenter, randomized, double-blind, placebo- controlled clinical trial. The eligible subjects are assigned randomly into 2 arms, the Vaccine + Lamivudine group and the Placebo + Lamivudine group, respectively, by a ratio of 2:1. The efficacy variables include the change of HBV DNA load at Week 72, and at each visits the rate of subjects with HBV DNA titer reducing > 2 logarithms ,the change of HBeAg and HBsAg titer, the change of ALT, HBsAg/HBeAg serum conversion rate, the INF-gamma expression level in peripheral blood mononuclear cells (PBMC), the amount of HBV-specific CTL, the change of expression level of peripheral cytokines (IL-4,IL-10,IL-12 and INF-gamma) against the baseline level.

Inclusion Criteria:

The following conditions must be met for all enrolled subjects:

1. Aged 18-65 years with either sex;

2. HBV serology meet the following criteria:

   • HBsAg-positive lasting for at least 6 months at the time of screening;
   • HBeAg-positive at the time of screening;
   • Serum HBV DNA≥1.0×10E5 copies/ml at the time of screening

3. 80U/L<ALT<400U/L;

4. TBIL<40μmol/L;

5. No YMDD mutation of the HBV drug resistance gene

6. Subjects agree not to participate in any other clinical trial or take any other anti-HBV therapeutics during the study;

7. Subjects understand and sign the ICF which approved by EC, and are able to comply with the study procedures and complete the study.

Exclusion Criteria:

Subjects meeting the following conditions will not be enrolled in the study:

1. Was suspected with HCC by the following evidence:

   • B-Ultrasound or imaging which shows occupying lesions;
   • Continuingly elevating serum AFP level even if the B-Ultrasound is normal;
   • AFP >100ng/ml;

2. With acute hepatic decompensation caused by liver disease aggravation or with clinical symptoms of decompensated liver disease at baseline;

3. Serum Cr≥1.5mg/dl (≥130μmol/l) at the time of screening;

4. Serum amylase > two-fold of the upper limit of the normal reference value;

5. Hb (male<100g/ L, female<90g/L), WBC<3.5×10E9/L,PLT<60×10E9/L (except hypersplenism and cirrhosis);

6. Co-infection with HCV (anti-HCV positive), HIV and anti-HAV IgM positive, anti-HDV IgM positive, anti-HEV IgM positive, anti-CMV IgM positive and autoimmune hepatitis (e.g. antinuclear antibody titer>1:160 ) or other active liver disease caused by known or unknown factors;

7. Any other serious disease or active diseases other than hepatitis B that are considered by investigators to be potential factors that may interfere with the therapy, assessment or compliance with the protocol, including any uncontrolled diseases with clinical significance, e.g. kidney, heart, lung, blood vessel, neurogenic, digestive system and metabolic diseases (diabetes, hyperthyroidism, adrenal gland diseases), autoimmune dysfunctions, and tumors, etc;

8. History of alcohol or drug abuse that is considered by investigators that could affect subject's compliance with the protocol or could influence the result of the analysis;

9. Pregnant or breast-feeding female subjects, or those who plan to be pregnant during the course of the study or male subjects' companions who plan to be pregnant during the course of the study;

10. Having used immunosuppressive agents, immunomodulators (thymosin), cytotoxic drugs within 6 months or transaminase-decreasing drugs within one month prior to the initiation of this study;

11. Having used anti-HBV drugs (Lamivudine, interferon, adefovir, entecavir, or sebivo, etc.) within 6 months prior to the initiation of this study;

12. Had or planning to have liver transplantation;

13. Having received experimental drug treatment from any other study within 3 months prior to the screening;

14. Allergic to nucleoside drugs or nucleoside analogues;

15. Not agreeing to the study protocol or any other factors considered not eligible for this study by investigators.