A Study to Evaluate the Safety and Efficacy of Therapeutic Hepatitis B Vaccine

Study Overview
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Brief Summary
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A single center, open labeled phase I/IIa study to evaluate safety, tolerability and efficacy of a therapeutic hepatitis B vaccine in oral antiviral drug-treated chronic hepatitis B virus carriers

Detailed Description
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Objectives: To explore the appropriate dose of a therapeutic hepatitis B vaccine through the evaluation of safety, tolerability, and efficacy Subjects: Chronic hepatitis B carrier with normal ALT range Study hypothesis: The immune tolerance break and strong immune responses in the chronic hepatitis B carrier could be achieved with therapeutic hepatitis B vaccine containing novel adjuvant

Official Title
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A Single Center, Open Labeled Phase I/IIa Study to Evaluate Safety, Tolerability and Efficacy of a Therapeutic Hepatitis B Vaccine in Oral Antiviral Drug-treated Chronic Hepatitis B Virus Carriers

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Biological: CVI-HBV-002


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult between 19 to 60 years of age Chronic hepatitis B carriers (HBsAg positive over 6 months) HBeAg positive patient, or patient who had lost HBeAg during Antiviral drug treatment Antiviral drug treated patient reducing the HBV DNA level below 2000 IU/mL measured by COBAS TaqManM HBV Test (Duration of drug administration should be over 6 months and no limitation on the type of antiviral drug) Patient has low ALT than 1.1 fold of upper limit of normal ALT level at screening Patient is able to provide written informed consent by oneself or legal representative Exclusion Criteria: Patient has liver diseases except chronic hepatitis B (i.e. hematochromatosis, alcoholic liver disease, nonalcoholic fatty liver disease, alpha-1 antitrypsin deficiency etc.) Patient has one or more test results and symptoms at the screening ALT > upper limit of normal level X 1.1 Total bilirubin > upper limit of normal Prothrombin time > Over 3 second than normal Serum Albumin < 30 g/L (3 g/dL) Patient has history of ascites, yellow jaundice, variceal hemorrhage, hepatic encephalopathy, or liver failure Liver FibroScan > F3 (F0: no fibrosis, F1: portal fibrosis, F2: periportal fibrosis, F3: septal fibrosis, F4: cirrhosis) Patient has one or more test results at the screening Hemoglobin < 9.0 g/dL Absolute neutrophil count (ANC) < 1.5 x 109 /L (1500 /mm3) Platelet count < 100 x 109 /L (100 x 103 /mm3) Serum creatinine > 1.5 mg/dL Serum amylase > 2 x ULN and Lipase > 2 x ULN Patient has history of Interferon treatment Patient is pregnant or breastfeeding or intending to become pregnant during the study Patient has active microbial, viral, or fungal infections in need of systemic treatment Alpha-fetoprotein (AFP) > 50 ng/mL or Hepatocellular Carcinoma (HCC) patient Among the patients treated with immunosuppressive drug within 6 months before screening, suspected case of the declined immunity in the opinion of the investigator Patient had long term systemic treatment (more than 14 days consecutively) of high dose (over 20 mg of prednisolone or equivalent dose*) corticosteroid (Decision to participate of patient who had local treatment of corticosteroid is allowed in the opinion of the investigator) *equivalent to cortisone 125 mg, hydrocortisone 100 mg, prednisone 20 mg, methylprednisolone 16 mg, triamcinolone 16 mg, dexamethasone 3 mg, or betamethasone 2.4 mg Patient diagnosed with a malignant tumor within 5 years before screening or relapsed patient (Benign tumor patient is able to participate in this study at the discretion of the investigator) Patient has history of organ transplantation Patient has serious disease judged by investigator such as heart failure, renal failure, and pancreatitis Patient has history of serious heart disease (NYHA Functional Class III or IV heart failure, myocardial infarction within 6 months, treatment required ventricular tachyarrhythmias, or unstable angina etc.) Patient has seizure disorder required anticonvulsants treatment Uncontrollable diabetic patient (FBS>130mg/dl, HbA1c>7.5%) Uncontrollable hypertension patient (SBP≥140mmHg 또는 DBP≥90mmHg) HCV, HDV, or HIV patient Patient has a plan to participate in other clinical study, or took part in other clinical study within 1 month before enrollment Patient has hypersensitivity or anaphylactic reaction for components of investigational product or HBV vaccine Patient has continuous drinking (>21 units/week, 1 unit = 10g of pure alcohol) or dependence on alcohol Patient concerned about the decline in daily activity or not able to understand the objectives and methods due to the psychiatric problems Patient has potential to severe febrile or systemic reaction Subject unacceptable in this study under the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 60 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CVI-HBV-002 (20ug, 3 shots)<br>HBV surface antigen 20ug/dose Intramuscular injection at 0, 1, 2 month | Biological: CVI-HBV-002<br>* Investigational product: CVI-HBV-002 Dose: 20ug or 40ug Frequency: 3 or 6 times Vaccination schedule: 0, 1, 2 months or 0, 1, 2, 3, 4, 5 months Administration route: Intramuscular injection<br>|
| Experimental: CVI-HBV-002 (20ug, 6 shots)<br>HBV surface antigen 20ug/dose Intramuscular injection at 0, 1, 2, 3, 4, 5 month | Biological: CVI-HBV-002<br>* Investigational product: CVI-HBV-002 Dose: 20ug or 40ug Frequency: 3 or 6 times Vaccination schedule: 0, 1, 2 months or 0, 1, 2, 3, 4, 5 months Administration route: Intramuscular injection<br>|
| Experimental: CVI-HBV-002 (40ug, 3 shots)<br>HBV surface antigen 40ug/dose Intramuscular injection at 0, 1, 2 month | Biological: CVI-HBV-002<br>* Investigational product: CVI-HBV-002 Dose: 20ug or 40ug Frequency: 3 or 6 times Vaccination schedule: 0, 1, 2 months or 0, 1, 2, 3, 4, 5 months Administration route: Intramuscular injection<br>|
| Experimental: CVI-HBV-002 (40ug, 6 shots)<br>HBV surface antigen 40ug/dose Intramuscular injection at 0, 1, 2, 3, 4, 5 month | Biological: CVI-HBV-002<br>* Investigational product: CVI-HBV-002 Dose: 20ug or 40ug Frequency: 3 or 6 times Vaccination schedule: 0, 1, 2 months or 0, 1, 2, 3, 4, 5 months Administration route: Intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability (including incidence of adverse events or expected adverse reactions for vaccine treatment) measured for 7 days after each vaccination | Occurrence of severe local and/or systemic tolerability signs and symptoms measured for 7 days after each vaccination | 7 days after each vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HBeAg loss | HBeAg disappearance at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) comparing with that of baseline | at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) | 
| HBe seroconversion rate | HBeAg seroconversion rate at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) comparing with that of baseline | at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) | 
| HBsAg loss | HBsAg disappearance at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) comparing with that of baseline | at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) | 
| HBsAg seroconversion rate | HBsAg seroconversion rate at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) comparing with that of baseline | at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) | 
| HBV specific T cell immunity | HBV specific T cell response at the 3rd month (for 3 shot group) or 6th month (for 6 shot group) comparing with that of baseline | at the 3rd month (for 3 shot group) or 6th month (for 6 shot group) | 
| HBV DNA level | HBV DNA level at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) comparing with that of baseline | at the 3rd and 5th month (for 3 shot group) or 6th and 8th month (for 6 shot group) |