A Study of Switching From Entecavir to Tenofovir Disoproxil Fumarate in Subjects With Chronic Hepatitis B

Study Overview
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Brief Summary
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Tenofovir Disoproxil Fumarate is a nucleos(t)ide analogue that inhibits Hepatitis B Virus (HBV) growth, and is marketed in Japan with an indication for inhibition of HBV growth in subjects with chronic hepatitis B associated with HBV growth and abnormal liver function. This study has been planned to evaluate the virological effects and safety of switching from ETV to TDF in chronic hepatitis B (hepatitis B e-antigen [HBeAg])-positive and HBV- deoxyribonucleic acid (DNA) undetectable subjects. This study is designed as a multi-center, one-arm, post-marketing clinical study to investigate the HBsAg reduction in subjects who have not achieved the long-term goal, the loss of hepatitis B surface antigen (HBsAg). The study will be conducted in HBeAg-positive and HBV-DNA undetectable subjects treated with ETV. After switching ETV to TDF, TDF will be administered for 96 weeks. Approximately 80 subjects will be screened to achieve 65 evaluable subjects.

Official Title
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A Multi-centre, One-arm Prospective Study to Evaluate Efficacy and Safety of Switching From Entecavir (ETV) to Tenofovir Disoproxil Fumarate (TDF) in Japanese Chronic Hepatitis B HBeAg-positive and HBV-DNA Undetectable Subjects

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: Tenofovir Disoproxil Fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be 20 to 69 years of age inclusive, at the time of signing the informed consent Male and female subjects. A female subject is eligible to participate if she is not pregnant and not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP), OR A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 days after the last dose of study treatment Capable of giving signed informed consent form (ICF) Subjects with chronic hepatitis B (CHB) (excluding hospitalized subjects) Subjects treated with ETV for at least 2 years prior to initiation of study treatment. The serum HBV-DNA level at screening is below the limit of quantitation (< 2.1 Log10 copies/milliliter [mL] or < 20 international unit [IU]/mL). Subjects with serum HBeAg positive at screening Meet either of the following serum HBsAg levels at screening: Serum HBsAg 80 < to < 800 IU/mL and fluctuation range is equal or more than -0.1 Log10 IU/mL per year Serum HBsAg >=800 IU/mL Meet all of the following criteria at screening: Creatinine clearance (CLcr) >=70 mL/minute. CLcr is calculated using the following Cockcroft-Gault formula. Male: CLcr = (body weight in kilogram [kg] multiplied by [140 minus age in years]) divided by (72 multiplied by serum creatinine [milligram {mg}/deciliter {dL}]) Female: CLcr = CLcr (male) multiplied by 0.85 Hemoglobin >= 8 gram/dL WBC >=1000 per cubic millimeter (mm^3) Exclusion Criteria: QTc > 450 millisecond (msec) or > 480 msec for subjects with bundle branch block Received any interferon or Hepatitis B vaccine therapy within 24 weeks prior to initiation of the study treatment. Received overdose of nonsteroidal anti-inflammatory drugs (NSAIDs) (excluding temporary or topical use) within 7 days prior to initiation of the study treatment. Received any of the following drugs within 8 weeks prior to initiation of the study treatment (excluding topical products such as ointment and/or cream etc). Drugs causing renal impairment (examples: aminoglycosides, amphotericin B, vancomycin, foscarnet, cisplatin, pentamidine, tacrolimus, cyclosporine, some contrast mediums [ionic high-osmolar contrast media, ionic low-osmolar contrast media] Competitors of renal excretion (except temporary use, example: probenecid) Immunosuppressants (examples: azathioprine, cycolphosphamide) or chemotherapeutics (example: etoposide) Glucocorticoid preparation Received TDF, Adefovir pivoxil (ADV) or Tenofovir Alafenamide Fumarate (TAF) within 2 years prior to initiation of the study treatment Participation in another clinical study within 6 months prior to screening, or planned participation in another clinical study simultaneously with this study. Co-infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) Subjects with serious complication other than compensated CHB (cancer, significant renal, cardiovascular, pulmonary, or neurological disease, uncontrollable diabetes, etc.) Received or have a plan for solid organ or bone marrow transplantation Has proximal tubulopathy. Subjects with decompensated CHB who meet the following: direct bilirubin > 1.5 times upper limit of normal (ULN), Prothrombin Time (PT) < 60%, platelets < 75,000/mm3 and serum albumin < 3.0 g/dL Autoimmune hepatitis (Antinuclear titer > 1:160), excluding CHB Subjects with or suspected of having hepatocellular carcinoma (HCC) (including both primary and metastatic) from diagnostic imaging at screening, or with serum alpha-fetoprotein (AFP) > 50 nanogram (ng)/mL at screening History of HCC (except subjects who underwent resection or received curative treatment by radiofrequency, and with AFP <=10 ng/mL at screening) Woman who is pregnant, possibly pregnant, lactating or planning a pregnancy during the study period. Psychiatry disorder or cognitive disorder that may affect the subject's ability to give informed consent or to follow specified study procedures. Subjects with a history of alcohol or drug abuse Subjects whom the investigator (or sub-investigator) considers ineligible for the study. Subjects with hypersensitivity to study treatments or their components, nucleoside and/or nucleotide analogues. Subjects with drug allergy that, in the investigator's (sub-investigator's) [or medical monitor's] opinion, labeled contraindication for participation in the study, or other allergy.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 69 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
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single arm study where on-going ETV treatment is switched to TDF treatment. There is no randomization in this study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All subjects treated with Tenofovir Disoproxil Fumarate<br>Subjects with on-going ETV treatment will be switched to Tenofovir Disoproxil Fumarate treatment. Subjects will start TDF on the day ETV is discontinued, without having overlapping treatment periods. All subjects will receive one tablet of TDF 300 mg once daily orally for 96 weeks. | Drug: Tenofovir Disoproxil Fumarate<br>* Tenofovir Disoproxil Fumarate is a nucleos(t)ide analogue that inhibits HBV growth. All subjects will receive one tablet of TDF 300 mg once daily orally for 96 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved 0.25 Logarithm to the Base 10 (Log10) Hepatitis B Surface Antigen (HBsAg) Reduction From the Baseline at Week 48 | Blood samples were collected to evaluate the HBsAg reduction from Baseline at Week 48. HBsAg reduction potential was obtained by evaluating log10 observation values minus log10 Baseline values. The HBsAg responder values were<=-0.25 log10 and non-responder values were >-0.25 log10 . Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Full analysis set (FAS) Population is defined as population of all participants enrolled in the study, excluding those who meet either of the following criteria: who have not received any dose of study treatment and who have no efficacy data (HBsAg, HBV-DNA, hepatitis B core-related antigen [HBcrAg], HBeAg, hepatitis B surface antibody [HBsAb],Hepatitis B envelope antibody [HBeAb], alanine aminotransferase [ALT]) from at least 15 days after the start of study treatment. Data for HBsAg responders have been presented. | Baseline (Day 1, Pre-dose) and at Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved 0.25 Log10 HBsAg Reduction From the Baseline at Weeks 24 and 96 | Blood samples were collected to evaluate the HBsAg reduction potential from Baseline at Weeks 24 and 96. HBsAg reduction potential was obtained by evaluating log10 observation values minus log10 Baseline values. Data for HBsAg responders have been presented. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 24 and 96 | 
| Percentage of Participants Who Achieved HBsAg Loss at Weeks 24, 48 and 96 | Blood samples were collected to evaluate the percentage of participants with HBsAg loss at Weeks 24, 48 and 96. A 'Loss' of HBsAg means antigen is negative. HBsAg loss percentage is defined as number of participants with HBsAg loss divided by number of participants with positive HBsAg at Baseline. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | At Weeks 24, 48 and 96 | 
| Percentage of Participants Who Achieved HBsAg/Ab Seroconversion at Weeks 24, 48 and 96 | Blood samples were collected to evaluate the percentage of participants who achieved HBsAg/Ab seroconversion at Weeks 24, 48 and 96. Seroconversion of HBsAg means antigen is negative and antibody is positive. HBsAg Seroconversion percentage is defined as number of participants with HBsAg/Ab Seroconversion divided by number of participants with positive HBsAg and Negative HBsAb at Baseline. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | At Weeks 24, 48 and 96 | 
| Percentage of Participants Who Achieved HBeAg Loss at Weeks 24, 48 and 96 | Blood samples were collected to evaluate the percentage of participants with HBeAg loss at Weeks 24, 48 and 96. A 'Loss' of HBeAg means antigen is negative. HBeAg Loss percentage is defined as number of participants with HBeAg loss divided by number of participants with positive HBeAg at Baseline. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | At Weeks 24, 48 and 96 | 
| Percentage of Participants Who Achieved HBeAg/Ab Seroconversion at Weeks 24, 48 and 96 | Blood samples were collected to evaluate the percentage of participants who achieved HBeAg/Ab seroconversion at Weeks 24, 48 and 96. Seroconversion of HBeAg means antigen is negative and antibody is positive. HBeAg Seroconversion percentage is defined as number of participants with HBeAg/Ab Seroconversion divided by number of participants with positive HBeAg and Negative HBeAb at Baseline. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | At Weeks 24, 48 and 96 | 
| Change From Baseline Log Values for HBsAg Titer at Weeks 24, 48 and 96 | Blood samples were collected to evaluate the HBsAg titer at Weeks 24, 48 and 96. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1, Pre-dose) and at Weeks 24, 48 and 96 | 
| Change From Baseline Log Values for HBcrAg Titer at Weeks 24, 48 and 96 | Blood samples were collected to evaluate the HBcrAg titer at Weeks 24, 48 and 96. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1, Pre-dose) and at Weeks 24, 48 and 96 | 
| Number of Participants Who Reported Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. Safety Population consists of participants who have received at least one dose of study treatment after enrolment. | Up to Week 96 | 
| Absolute Values for Clinical Chemistry Parameter: Alpha-fetoprotein (AFP) | Blood samples were collected for the analysis of clinical chemistry parameter, AFP. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Clinical Chemistry Parameters: Albumin and Total Protein | Blood samples were collected for the analysis of clinical chemistry parameters: albumin and total protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Clinical Chemistry Parameters: Alkaline Phosphate (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Creatinine Kinase (CPK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LDH) | Blood samples were collected for the analysis of clinical chemistry parameters: ALP, ALT, AST, CPK, GGT and LDH. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Clinical Chemistry Parameters: Amylase and Lipase | Blood samples were collected for the analysis of clinical chemistry parameters: amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid | Blood samples were collected for the analysis of clinical chemistry parameters: direct bilirubin, total bilirubin, creatinine and uric acid. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Clinical Chemistry Parameters: Calcium, Chloride, Glucose, Potassium, Lactic Acid, Sodium, Phosphorus and Blood Urea Nitrogen (BUN) | Blood samples were collected for the analysis of clinical chemistry parameters: calcium, chloride, glucose, potassium, lactic acid, sodium, phosphorus inorganic and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Clinical Chemistry Parameter: Creatinine Clearance | Blood samples were collected for the analysis of clinical chemistry parameter, creatinine clearance. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Clinical Chemistry Parameter: Glomerular Filtration Rate (GFR) | Blood samples were collected for the analysis of clinical chemistry parameter, GFR. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Percentage of Basophils at Indicated Time Points | Blood samples were collected for the analysis of hematology parameter: basophils. Mean and standard deviation values for percentage of basophils reported was presented. | At Weeks 36, 48, 60, 72, 84 and 96 | 
| Percentage of Eosinophils at Indicated Time Points | Blood samples were collected for the analysis of hematology parameter: eosinophils. Mean and standard deviation values for percentage of eosinophils reported was presented. | At Weeks 36 , 48, 60, 72, 84 and 96 | 
| Percentage of Lymphocytes at Indicated Time Points | Blood samples were collected for the analysis of hematology parameter: lymphocytes. Mean and standard deviation values for percentage of lymphocytes reported was presented. | At Weeks 36, 48, 60, 72, 84 and 96 | 
| Percentage of Monocytes at Indicated Time Points | Blood samples were collected for the analysis of hematology parameter: monocytes. Mean and standard deviation values for percentage of monocytes reported was presented. | At Weeks 36, 48, 60, 72, 84 and 96 | 
| Percentage of Total Neutrophils at Indicated Time Points | Blood samples were collected for the analysis of hematology parameter: total neutrophils. Mean and standard deviation values for percentage of neutrophils reported was presented. | At Weeks 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Hematology Parameter: Hemoglobin | Blood samples were collected for the analysis of hematology parameter, hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Hematology Parameter: Hematocrit | Blood samples were collected for the analysis of hematology parameter, hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Hematology Parameters: Platelet Count and White Blood Cell (WBC) Count | Blood samples were collected for the analysis of hematology parameters: platelet count and WBC count. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Hematology Parameter: Prothrombin Time | Blood samples were collected for the analysis of hematology parameter, prothrombin time. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Hematology Parameter: Red Blood Cell (RBC) Count | Blood samples were collected for the analysis of hematology parameter, RBC count. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Number of Participants With Abnormal Urinalysis Values at Weeks 4, 12, 24, 36 and 48 | Urine samples were collected for analysis of urinalysis data for glucose, protein and urinary sediment by dipstick method. The urine sediments analyzed were amorphous phosphate crystals, amorphous urate crystals, bacteria, calcium oxalate crystals, ammonium magnesium phosphate, renal tubular epithelial cells (RTEC), fungi, hyaline casts, mucous threads, RBCs, spermatozoa, squamous epithelial cells (SEC), transitional epithelial cells (TEC), uric acid crystals (UAC) and WBCs. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as Trace, 1+, 2+ and 3+, indicating proportional concentrations in the urine sample. Results for RTEC, hyaline casts, RBC, SEC, TEC and WBC can be read as counts per field (some/ every/ whole field). Only abnormal parameters and participants with abnormal data has been reported. | Weeks 4, 12, 24, 36 and 48 | 
| Number of Participants With Abnormal Urinalysis Values at Weeks 60, 72, 84 and 96 | Urine samples were collected for analysis of urinalysis data for glucose, protein and urinary sediment by dipstick method. The urine sediments analyzed were amorphous phosphate crystals, amorphous urate crystals, bacteria, calcium oxalate crystals, ammonium magnesium phosphate, renal tubular epithelial cells (RTEC), fungi, hyaline casts, mucous threads, RBCs, spermatozoa, squamous epithelial cells (SEC), transitional epithelial cells (TEC), uric acid crystals (UAC) and WBCs. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as Trace, 1+, 2+ and 3+, indicating proportional concentrations in the urine sample. Results for RTEC, hyaline casts, RBC, SEC, TEC and WBC can be read as counts per field (some/ every/ whole field). Only abnormal parameters and participants with abnormal data has been reported. | Weeks 60, 72, 84 and 96 | 
| Change From Baseline Values for Beta-2-microglobulin | Urine samples were collected for analysis of urinalysis data for beta-2-microglobulin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Change From Baseline Values for Urine Creatinine Concentration and Urine Phosphate | Urine samples were collected for analysis of urinalysis data for urine creatinine concentration and urine phosphate. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Blood pressure of participants were measured at indicated time points in supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Heart Rate | Heart rate of participants were measured at indicated time points in supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Absolute Values for Temperature | Temperature of participants were measured at indicated time points in supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. | Baseline (Day 1, Pre-dose) and at Weeks 4, 12, 24, 36, 48, 60, 72, 84 and 96 | 
| Number of Participants With Worst Case Post-Baseline Electrocardiogram (ECG) Values | Twelve-lead ECG was obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals. Abnormal values with clinically significant and not clinically significant values has been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. | Up to Week 96 | 
| Change From Baseline Values for Bone Density | Bone densitometry was performed on lumbar spine and femur using dual-energy X-ray absorptiometry (DEXA). Bone density percentage was calculated as bone density observation minus bone density Baseline divided by bone density Baseline. Baseline was considered as Day -1. Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value. | Baseline (Day -1) and at Weeks 24, 48, 72 and 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenofovir Disoproxil Fumarate, safety, chronic hepatitis B, virological effect