A Phase I, The Study to Evaluate the Safety, Immunogenicity and Efficacy of YS-HBV-002

Study Overview
=================
Brief Summary
-----------------
This is the first-in-human Phase I, double-blind, randomized, placebo-controlled, dose escalating study to evaluate the safety, immunogenicity and preliminary efficacy of the YSHBV-002 in the treatment of CHB in adults ≥18 years old. There will be 3 escalating doses of YS-HBV-002 to be administered intramuscularly: 0.5mL, 1.0mL, and 2.0mL.

Detailed Description
-----------------
This is the first-in-human Phase I, double-blind, randomized, placebo-controlled, dose escalating study to evaluate the safety, immunogenicity and preliminary efficacy of the YSHBV-002 in the treatment of CHB in adults ≥18 years old. There will be 3 escalating doses of YS-HBV-002 to be administered intramuscularly: 0.5mL, 1.0mL, and 2.0mL. Enrollment in the study will sequentially start from the low dose 0.5mL as Group A, then to the mid-dose 1.0mL as Group B and lastly to the high dose of 2.0mL as Group C. Each group will have 16 patients enrolled. The first 4 enrollees in Group A will be sentinel patients and will be allocated at a 1:1 ratio to receive 0.5mL of either YS-HBV-002 or placebo (Table 3). As there is no comparable equivalent to YS-HBV-002 available in the market, the placebo of normal saline solution to be injected intramuscularly will serve as the control in this trial. The next 12 enrollees in Group A will be the main patients and will be allocated at 5:1 to receive 0.5mL of either YS-HBV-002 or placebo. The vaccination regimen will be 1 IM injection every 3 days in the deltoid muscle, alternately for approximately 6 weeks. A total of 14 injections will be administered to each patient.

Official Title
-----------------
A Phase I, Double-blind, Randomized, Placebo-controlled, Dose Escalating Study to Evaluate the Safety, Immunogenicity and Efficacy of YS-HBV-002 in the Treatment of Chronic Hepatitis B (CHB) Infection in Adults ≥ 18 Years Old

Conditions
-----------------
Chronic Hepatitis b

Intervention / Treatment
-----------------
* Biological: YS-HBV-002


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years during screening Body Mass Index (BMI) of 18.5-30 kg/m2 Diagnosed or laboratory confirmed to have CHB Have CHB infection for at least 6 months HBsAg titer ≥ 1000 IU/mL HBV DNA ≥ 2000 IU/mL Serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) ≤ 2 × upper limit of normal (ULN) Able to provide informed consent Able and willing to comply with all study procedures throughout the study period of approximately 3 months For female subjects with childbearing potential: must agree to avoid pregnancy throughout the study period of approximately 3 months. Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must use an acceptable method of avoiding pregnancy during this period. Acceptable methods on avoiding pregnancy include: a sterile sexual partner, sexual abstinence (not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal patch, or implant), vaginal ring, intrauterine device (IUD), or the combination of a condom or diaphragm with a spermicide. Exclusion Criteria: Pregnant or breastfeeding or intending to become pregnant within the projected duration of the trial Transient elastography at screening revealing a FibroScan value of ≥ 9 kPa or a previous liver biopsy evidencing hepatic fibrosis at or within 24 months prior to vaccination Patients with hepatitis caused by other etiologies History of or manifestations of liver decompensation (e.g., Child-Pugh Class B or C, or ascites, gastrointestinal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, etc....) Currently participating in or has participated in a study with an IP within 30 days preceding Day 0 Fever (axillary temperature ≥ 37.8 ℃) Subjects with abnormal indicators of blood biochemistry and other routine blood tests deemed clinically significant by the investigator History of severe allergic reactions (such as acute anaphylaxis, urticaria, skin eczema, dyspnea, angioneurotic edema, or allergic abdominal pain) or allergy to any of the components of YS-HBV-002 Any history of anaphylaxis or angioedema after any vaccination Allergy to kanamycin and aminoglycosides Past or family history of convulsion, epilepsy, encephalopathy, or mental illness Diagnosed with congenital or acquired immune deficiency, HIV infection, lymphoma, leukemia, or other autoimmune diseases History of coagulation dysfunction (e.g., coagulation factor deficiency, coagulation disease) Bleeding disorder, or receipt of anticoagulants in the past 21 days preceding inclusion, contraindicating IM vaccination based on the investigator's judgement Vaccinated with live attenuated vaccine within 1 month, or other vaccine/non-COVID-19 vaccine within 14 days prior to vaccination Receiving immunotherapy or inhibitor therapy (consistently oral or infusion for more than 14 days) within 3 months prior to vaccination Received systemic immunosuppressants within 4 months prior to vaccination or anticipating the need for immunosuppressant at any time during participation in the study. Topical or inhaled treatment is allowed if not used within 14 days prior to vaccination Have received antiviral therapy for chronic hepatitis but have stopped for less than 30 days or plan to take antiviral therapy during the study Received blood products within 3 months before vaccine administration History of alcohol or drug abuse within the past 2 years Any condition that, in the opinion of the investigator, would pose a health risk to the patient if enrolled or could interfere with evaluation of the study vaccine or interpretation of study results.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose 0.5mL<br>Group A ：The first 4 enrollees in Group A will be sentinel patients and will be allocated at a 1:1 ratio to receive 0.5mL of either YS-HBV-002 or placebo(saline solution), The next 12 enrollees in Group A will be the main patients and will be allocated at 5:1 to receive 0.5mL of either YS-HBV-002 or placebo. | Biological: YS-HBV-002<br>* YS-HBV-002, A recombinant hepatitis B vaccine with PIKA adjuvant<br>|
| Experimental: Mid-dose 1.0mL<br>Group B ：The first 4 enrollees in Group B will be sentinel patients and will be allocated at a 1:1 ratio to receive 1.0mL of either YS-HBV-002 or placebo(saline solution), The next 12 enrollees in Group A will be the main patients and will be allocated at 5:1 to receive 1.0mL of either YS-HBV-002 or placebo. | Biological: YS-HBV-002<br>* YS-HBV-002, A recombinant hepatitis B vaccine with PIKA adjuvant<br>|
| Experimental: High dose 2.0mL<br>Group C ：The first 4 enrollees in Group C will be sentinel patients and will be allocated at a 1:1 ratio to receive 2.0mL of either YS-HBV-002 or placebo(saline solution), The next 12 enrollees in Group A will be the main patients and will be allocated at 5:1 to receive 2.0mL of either YS-HBV-002 or placebo. | Biological: YS-HBV-002<br>* YS-HBV-002, A recombinant hepatitis B vaccine with PIKA adjuvant<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AEs within 30 minutes after vaccination. | To assess the safety and tolerability | 30 minutes post each vaccination | 
| Incidence of solicited local reactions within 7 days after each vaccination. | To assess the safety and tolerability | 7 days post each vaccination | 
| Incidence of solicited systemic reactions from first vaccination to 7 days after the last vaccination (D1 to D46). | To assess the safety and tolerability | From Day1 to Day46 | 
| Incidence of unsolicited AEs, serious adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs), adverse events of special interest (AESIs), and AEs leading to withdrawals throughout the study period | To assess the safety and tolerability | From Day1 to Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients showing reduction in HBV DNA using PCR for each dose from baseline to the end of the study and at specified timepoints. | To evaluate the preliminary efficacy, immunogenicity and determine the appropriate dose | Day0， Day16， Day34， Day60， Day90 | 
| Change in mean log10 of HBV DNA from baseline to end of study and at each specified timepoint. | To evaluate the preliminary efficacy, immunogenicity and determine the appropriate dose | Day0， Day16， Day34， Day60， Day90 | 
| Change in serum levels of HBeAg, HBcAg, and HBsAg from baseline to end of study at each specified timepoint. | To evaluate the preliminary efficacy, immunogenicity and determine the appropriate dose | Day0， Day16， Day34， Day60， Day90 | 
| Change in serum levels of HBeAg, HBcAg, and HBsAg from baseline to end of study and at each specified timepoint. | To evaluate the preliminary efficacy, immunogenicity and determine the appropriate dose | Day0， Day16， Day34， Day60， Day90 | 
| Proportion of patients with loss (defined as lower limit of quantitation [LLOQ]) or decline in HBsAg, HBcAg, and HBeAg from baseline to the end of the study and at each specified timepoint. | To evaluate the preliminary efficacy, immunogenicity and determine the appropriate dose | Day0， Day16， Day34， Day60， Day90 | 
| GMTs of antibodies against HBsAg, HBcAg and HBeAg at baseline and at pre-defined post-vaccination timepoints. | To evaluate the preliminary efficacy, immunogenicity and determine the appropriate dose | Day0， Day16， Day34， Day60， Day90 | 
| Seroconversion rates of antibodies against HBsAg, HBcAg, and HBeAg. | To evaluate the preliminary efficacy, immunogenicity and determine the appropriate dose | Day0， Day16， Day34， Day60， Day90 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PIKA Adjuvant