Adefovir Dipivoxil For The Treatment Of Chinese Compensated Chronic Hepatitis B(CHB)Patients

Study Overview
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Brief Summary
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This 48-week open-label study of local manufactured adefovir dipivoxil Tablet evaluates the efficacy and safety of adefovir 10mg once daily in Chinese subjects with compensated CHB. Primary endpoint is proportion of subjects achieving HBV DNA undetectable (<=1000 copies/mL by by Roche COBAS AMPLICOR HBV MONITOR Test) at week 48. Approximately 1250 patients will be recruited in 30 study centers in China. The subjects are offered 48 weeks of open label adefovir dipivoxil treatment, with assessments every three months, after with is a 12-week post study treatment follow-up prior to study completion.

Official Title
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A 48-week Multi-centre, Open-label, Local Phase IV Study to Demonstrate the Efficacy and Safety of Adefovir Dipivoxil Tablets (10mg) in Chinese Subjects With Compensated Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: adefovir dipivoxil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged 18-65 years inclusive Documented chronic hepatitis B infection determined by the presence of serum HBsAg for a least 6 months Serum HBV DNA ≥105 copies/ml for HBeAg positive subjects or ≥104 copies/ml for HBeAg negative subjects (Real-time PCR, LLQ=1000cp/ml) at study screening (within 2 weeks before baseline), respectively. ALT value ≥2 times the upper limit of normal (ULN) at the time of screening, as determined using laboratory ranges and documented ALT abnormal within 6 month prior the study screening. Compensated liver disease with the following laboratory and clinical parameters study screening: prothrombin time ≤ 2 seconds above normal direct bilirubin Albumin≥35g/L Total bilirubin ≤2.5mg/dL (≤ 43 µmol/L) or normal direct bilirubin No history of variceal bleeding No history of encephalopathy No history of ascites Willing and able to undergo two liver biopsies (prior to dosing, and after 48 weeks of therapy; only apply to subjects who are enrolled to the sites where liver biopsy is required). Agree not to participate in any other investigational trials or to undertake other HBV systemic antiviral regimens during participation in this study Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: Any serious or active medical or psychiatric illnesses other than hepatitis B which, in the opinion of the investigator, would interfere with patient treatment, assessment or compliance with the protocol. This would include, may not limit to, renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic (diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders, active infection or cancer. Documented evidence of active liver disease due to other causes including co-infection hepatitis C (HCV), Subjects who are anti-HCV positive and in whom HCV RNA is undetectable are considered to be HCV seropositive and will not be eligible co-infection with hepatitis delta (HDV) co-infection with HIV autoimmune hepatitis (antinuclear antibody titre>1:160) Alanine aminotransferase(ALT) > 10 times ULN at screening or history of acute exacerbation leading to transient decompensation Serum alpha fetoprotein (AFP) >50 ng/mL. Hepatocellular carcinoma as evidenced by one of the following: suspicious foci on ultrasound or radiological examination where no positive ultrasound finding, but serum alpha-fetoprotein > 100ng/ml Adequate renal function defined as serum creatinine >1.5 mg/dL (>130 µmol/L) Adequate hematological function defined as: Absolute neutrophil count <1 x 10³/mm³ (1 x 10^9/L) Platelets<80 x 10³/mm³ (80 x 10^9/L); platelets<100 x 10³/mm³ (100 x 10^9/L) Hemoglobin<12g/dL (120 g/L)(males) or <10 g/dL (100 g/L) (females) Active alcohol or drug abuse or history of alcohol or drug abuse considered by the investigator to be sufficient to hinder compliance with treatment, participation in the study or interpretation of results. Use of immunosuppressive therapy, immunomodulatory therapy (including interferon or thymosin), systemic cytotoxic agents within the previous 6 months or during the study. Use of chronic anti-viral agents(e.g. lamivudine, adefovir dipivoxil, entecavir, famciclovir, tenofovir, FTC, ganciclovir, DAPD, LfMA, HBIg, etc.), Chinese herbal medicines known to have activity against HBV within the previous 3 months or during the study; use of agents with effect of ALT reduction (e.g. schisandra agents) during the study. Received nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cis-platinum, pentamidine etc.) or competitors of renal excretion (e.g., probenecid within 2 months prior to study screening or the expectation that patient will receive any of these during the course of the study. Received hepatotoxic drugs (e.g., anabolic steroids, ketaconazole, itraconazole, isoniazid, rifampin, rifabutin) within 2 months prior to study screening or expected to receive these during the course of the study. Previous (or planned) participation in an investigational trial involving administration of investigational compound within 2 months prior to the study screening.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm adefovir dipivoxil<br>adefovir dipivoxil once daily orally 10 mg | Drug: adefovir dipivoxil<br>* adefovir dipivoxil once daily one tablet 10mg orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving HBV DNA (Hepatitis B Virus Deoxyribonucleic Acid) <1000 Copies/Milliliter at Week 48 | HBV (Hepatitis B Virus) DNA level was tested by real-time Polymerase Chain Reaction at Week 48. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of HBeAg Positive Participants Achieving Histological Improvement at Week 48 | Histological improvement (defined as a ≥2 point reduction in the Knodell necroinflammation score without worsening fibrosis) was accessed by two pathologists in HBeAg-positive participants undergoing liver biopsy at baseline and week 48/withdrawal. Knodell/Histological Activity Index (HAI) score = combined scores for necrosis, inflammation, and fibrosis and is the sum of scores for periportal bridging necrosis (0-10: none=0, multilobular necrosis=10), intralobular degeneration and focal necrosis and portal inflammation (0-4: none=0, marked=4), and fibrosis (0-4: none=0, cirrhosis=4). | Week 48 | 
| Ranked Assessment of Liver Histology in HBeAg Positive Participants From Baseline to Week 48 | A ranked assessment with the Knodell/HAI scoring system that represents the sum of scores for periportal bridging necrosis (0-10: none=0, moderate piecemeal necrosis plus bridging necrosis=5, multilobular necrosis=10); interlobular degeneration and focal necrosis (0-4: none=0, marked=4); portal inflammation (0-4: none=0, marked=4) and fibrosis (0-4: none=0, fibrous portal expansion=1, bridging fibrosis=3, cirrhosis=4) was carried out by two pathologists in the HBeAg positive participants who underwent liver biopsy at baseline and Week 48/withdrawal. | Baseline to Week 48 | 
| Change From Screening in Median Serum HBV DNA at Weeks 24 and 48 | The HBV DNA level was tested in blood serum by real-time Polymerase Chain Reaction with the LLD (lower limit of detection) as 300 copies/milliliter (cp/mL) at screening, week 24, and week 48 in a central laboratory. The change in HBV DNA from screening to week 24 and week 48 was conducted. | Weeks 24 and 48 | 
| Number of Participants Achieving ALT (Alanine Aminotransferase) Normalization at Week 48 | Elevated serum ALT levels are defined as serum ALT levels greater than the upper limit of the normal range (ULN), as determined using local laboratory ranges. ALT normalization was defined as ALT measurements at or below the ULN after a baseline value above the ULN. | Week 48 | 
| Number of HBeAg Positive Participants Achieving HBeAg Loss and HBeAg Seroconversion at Week 48 | HBeAg loss and HBeAg seroconversion (HBeAg loss and HBeAb detected) were assessed in participants who were HBeAg positive at Weeks 0 and 48. Confirmed HBeAg loss was defined as undetectable HBeAg. | Week 48 | 
| Number of Participants With ADV-associated Resistance at Week 48 | Week 48 serum samples from participants, who reached a HBV DNA breakthrough or have HBV DNA≥5 log copies/mL at Weeks 24 and 48 were assessed for the development of ADV (Adefovir dipivoxil) mutation (N236T and A181V) in the HBV polymerase. Virologic breakthrough was defined as an increase in the level of HBV DNA 1 log10 copy/mL from Week 24 to Week 48. ADV-associated resistance was defined as participants with both virologic breakthrough and ADV mutation. | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adefovir dipivoxil, compensated, chronic hepatitis B, Chinese