Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) 300mg in Chinese Subjects With Chronic Hepatitis B (CHB)

Study Overview
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Brief Summary
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This is a multi-centre, double blind, double dummy, randomised, controlled study to evaluate the efficacy and safety of TDF 300mg QD versus ADV 10mg QD in Chinese subjects with CHB. This study is designed to demonstrate the superiority of TDF 300mg QD over ADV 10mg QD in treating Chinese subjects with CHB (hepatitis B e antigen [HBeAg] positive subjects and HBeAg negative subjects). It will also provide long-term efficacy and safety data (up to 240 weeks) for TDF 300 mg administered once daily.

Detailed Description
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This is a multi-centre, double-blind, double-dummy, randomised, controlled study to evaluate the efficacy and safety of TDF 300mg QD versus ADV 10mg QD in Chinese subjects with CHB. Four hundred and ninety-four subjects with CHB (200 HBeAg positive subjects and 294 HBeAg negative subjects) will be randomised (1:1ratio) to either TDF 300mg QD or ADV 10mg QD treatment arms. The primary endpoint is the proportion of subjects with blood hepatitis B virus (HBV) deoxyribonucleic acid (DNA) <400copies/mL (Roche COBAS Taqman HBV test) at Week 48 in HBeAg positive subjects with CHB and HBeAg negative subjects with CHB. This is a two-part study. The first treatment period (baseline to Week 48) will investigate the effects of TDF and ADV on safety and efficacy endpoints; dosing will be double-blind. This period will be followed by 192 weeks in which all subjects will receive open-label TDF (Week 49 to Week 240). Subjects will undergo regular safety and efficacy assessments every 4 weeks for the first 12 weeks followed by every 12 weeks for a total of up to 5 years.

Official Title
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A Multi-centre, Double Blind, Double Dummy, Randomised, Controlled Study to Evaluate the Efficacy and Safety of TDF 300mg Once Daily (QD) Versus Adefovir Dipivoxil (ADV) 10mg QD in Chinese Subjects With CHB

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: Tenofovir disoproxil fumarate (TDF) tablets
* Drug: Adefovir dipivoxil (ADV) tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HBeAg positive/negative CHB with blood HBVDNA≥10^5 copies/mL and elevated ALT Nucleoside and nucleotide naïve CHB subjects. Previous lamivudine treatment is allowed in less than 10% of the total study population Exclusion Criteria: subjects with hepatocellular carcinoma (HCC) potential or decompensated liver disease subjects with acute liver disease due to other causes subjects with medication history of immunosuppressive therapy, immunomodulatory therapy, systemic cytotoxic agents, chronic antiviral agents including Chinese herbal medicines known to have activity against HBV (e.g., lamivudine, hepatitis B immunoglobulin (HBIg)) within the previous 6 months prior to randomisation into this study

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A (TDF tablets)<br>Tenofovir disoproxil fumarate (TDF) tablets | Drug: Tenofovir disoproxil fumarate (TDF) tablets<br>* white, almond-shaped, film-coated tablets containing 300mg of TDF<br>* Other names: TDF tablet;|
| Active Comparator: B (ADV tablets)<br>Adefovir dipivoxil (ADV) tablets | Drug: Adefovir dipivoxil (ADV) tablets<br>* white to off-white, round, biconvex tablets containing 10mg of ADV<br>* Other names: ADV tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) <400 Copies/Milliliter (mL) at Week 48 | The number of participants with Hepatitis B Virus (HBV) deoxyribonucleic acid (DNA) <400 copies/milliliter (mL) at Week 48 in the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative population was assessed. HBeAg is a viral protein that is secreted by hepatitis B-infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a participant's degree of infectiousness. A positive result indicates that the participant has high levels of virus in the blood and greater infectiousness. Usually, a negative result indicates that the participant has lower levels of virus in the blood and is less infectious. A non-completers equal failures approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With HBV DNA <400 Copies/mL at Weeks 96, 144, 192, and 240 | The number of participants with HBV DNA <400 copies/mL in the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative population was assessed. HBeAg is a viral protein that is secreted by hepatitis B-infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a participant's degree of infectiousness. A positive result indicates that the participant has high levels of virus in the blood and greater infectiousness. Usually, a negative result indicates that the participant has lower levels of virus in the blood and is less infectious. Week 96, 144, 192, and 240 data are not yet available, as this report includes data up to and including Week 48. A non-completers equal failures approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed. | Weeks 96, 144, 192, and 240 | 
| Change From Baseline of Log 10 Copies/mL HBV DNA at Weeks 48, 96, 144, 192 and 240 | Change from Baseline of log 10 copies/mL HBV DNA at Weeks 48, 96, 144, 192 and 240 in the HBeAg-positive and HBeAg-negative population was assessed. HBeAg is a viral protein that is secreted by hepatitis B-infected cells. It is associated with chronic hepatitis B infections and is used as a marker of active viral disease and a participant's degree of infectiousness. A positive result indicates that the participant has high levels of virus in the blood and greater infectiousness. Usually a negative result indicates that the participant has lower levels of virus in the blood and less infectious. Values at Day 0 were considered as Baseline values. Change from Baseline was calculated as post Baseline values minus Baseline values. A non-completers equal failures approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed. | Baseline, Weeks 48, 96, 144, 192 and 240 | 
| Number of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48, 96, 144, 192 and 240 in Participants Who Had Abnormal ALT at Baseline | Participants who had abnormal ALT at Baseline and had normalized ALT at Weeks 48, 96, 144, 192 and 240 were assessed. This report includes data up to and including Weeks 48, 96, 144, 192 and 240. An increased level of ALT is referred to as abnormal ALT (the normal range is 0 to 48 units per liter [U/L]). Values at Day 0 were considered as Baseline values. A non-completers equal failures approach is used for the analysis in ITT population. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed. | Baseline; Weeks 48, 96, 144, 192 and 240 | 
| Number of Participants With Histological Improvement at Weeks 48 and 240 Who Had a Baseline Knodell Necroinflammatory Score (KNS) >=2. | Histological improvement is defined as a reduction of >=2 points in the KNS with no increase in fibrosis at Week 48 and Week 240 in participants with Baseline KNS >=2 which was derived from the American Association for the Study of Liver Diseases Practice Guidelines for Management of Chronic Hepatitis B (2009) and the European Association for the Study of the Liver Clinical Practice Guidelines Management of chronic hepatitis B virus infection (2012). The Knodell scale consists of 5 domains: periportal +/- bridging necrosis (scored from best to worst: 0, 1, 3, 4, 5, 6, or 10); intralobular degeneration and focal necrosis (0 to 4); portal inflammation (0 to 4); and fibrosis (0 to 4). The necroinflammatory score (ranging from 0 [best] to 14 [worst]) is the combined score for necrosis (0 to 10) plus inflammation (0 to 4; the participant is scored for only one inflammatory condition). Liver biopsy slides within 6 months prior to randomization could be accepted as Baseline evaluation. | Baseline; Week 48 and Week 240 | 
| Number of HBeAg-positive Participants Achieving HBeAg Loss and HBeAg Seroconversion at Weeks 24, 48, 96, 144, 192 and 240. | HBeAg loss is defined as a negative HBeAg result for those participants who were HBeAg positive at Baseline. Seroconversion to anti-HBe is defined as HBeAg loss and a positive anti-HBe result. This report includes data up to and including Weeks 24, 48, 96, 144, 192 and 240. | Weeks 24, 48, 96, 144, 192 and 240 | 
| Number of HBeAg-positive Participants Achieving Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Weeks 24, 48, 96, 144, 192 and 240 | HBsAg loss is defined as negative HBsAg results for those participants with who were HBsAg positive at Baseline. Seroconversion to anti-HBs is defined as HBsAg loss and a positive anti-HBs result. This report includes data up to and including Week 240. | Weeks 24, 48, 96, 144, 192 and 240 | 
| Number of HBeAg-negative Participants Achieving HBsAg Loss and HBsAg Seroconversion at Weeks 24, 48, 96, 144, 192, 240 | HBsAg loss is defined as a negative HBsAg result for those participants with who were HBsAg positive at Baseline. Seroconversion to anti-HBs is defined as HBsAg loss and a positive anti-HBs result. This report includes data up to and including Week 240. | Weeks 24, 48, 96, 144, 192 and 240 | 
| Number of Participants Achieving Durable HBsAg Loss From Weeks 24 to Week 48 | Durable HBsAg loss is defined as the loss of HBsAg and no detectable HBV DNA and ALT normalization at any three consecutive visits at least 12 Weeks apart. This report includes data up to and including Week 48. A non-completers equal failures approach was used for the analysis in ITT population. | Week 24 to Week 48 | 
| Number of Participants Achieving Durable HBsAg Loss From Weeks 96 to Week 240 | Durable HBsAg loss is defined as the loss of HBsAg and no detectable HBV DNA and ALT normalization at any three consecutive visits at least 12 Weeks apart from Week 96 to 240. This report includes data up to and including Week 240. A non-completers equal failures approach was used for the analysis in ITT population. | Week 96 to Week 240 | 
| Number of Participants With Virological Breakthrough at Weeks 48, 96, 144, 192 and 240 | The number of HBeAg-positive and HBeAg-negative participants who had virological breakthrough at Weeks 48, 96, 144, 192 and 240 were assessed. Virological breakthrough is defined by >= one log increase in HBV DNA from NADIR (as determined by two sequential HBV DNA measurements at least one month apart or last on treatment measurement). A non-completers equal failures approach was used for the analysis in ITT population. | Weeks 48, 96, 144, 192 and 240 | 
| Number of Participants With Any Serious Adverse Event (SAE) and Any Non-serious Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is Grade 4 (life threatening or disabling). Participants with any non-serious AEs and SAEs has been reported. | Up to Week 240 treatment period and 24 weeks follow-up visit off treatment | 
| Number of Participants With the Indicated Grade 3 and Grade 4 Treatment-emergent (TE) Laboratory Abnormalities (LAs) | TE grade 3 or grade 4 LAs are defined as values that increase by >=1 grade from Baseline (Day 0) to Grade 3 (severe) or 4 (potentially life threatening) at any post-Baseline value. The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version 21, September 2011 was referred for grading. Laboratory parameters assessed included Sodium for hyponatremia and hypernatremia; Potassium for hypokalemia and hyperkalemia; glucose for hypoglycemia and hyperglycemia non-fasting; Phosphate for hypophosphatemia; alanine aminotransferase/aspartate aminotransferase, bilirubin, creatinine kinase, hemoglobin, platelets, neutrophils, lymphocytes, prothrombin time and amylase. | Up to Week 240 | 
| Number of Participants With the Indicated Treatment-emergent Laboratory Abnormalities for Serum Creatinine and Serum Phosphorus | The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version 21, September 2011 was referred for grading. Serum creatinine: Grade 1, > 133 to 177 micromoles per Liter (µmoles/Liter), Grade 2, >177 to 265 µmoles/Liter, Grade 3, >265 to 530 µmoles/Liter, Grade 4, >530 µmoles/Liter. Serum phosphorus: Grade 2, 0.63 to <0.80 millimoles per Liter (mmoles/L), Grade 3, 0.31 to <0.63 mmoles/L, Grade 4, <0.31 mmoles/L. The normal range for serum phosphorus was 0.8 to 1.45 mmoles/L; the upper limit for a Grade 2 abnormality is 0.80 mmoles/L. Therefore, no Grade 1 abnormalities could be attributed, as values were contained within the normal range. NA indicates the value was not available for the indicated time point. | Up to Week 240 | 
| Number of Participants in the Indicated Category for Renal Laboratory Abnormalities | The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities, version 21, September 2011 was used for grading. Confirmed is defined as two consecutive visits. mg=milligrams. dL=deciliter, G= Grade. | Up to Week 240 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tenofovir disoproxil fumarate, chronic hepatitis B, adefovir dipivoxil