Adefovir Dipivoxil Tablets (10mg) In Chinese Subjects With HBe Antigen Negative Chronic Hepatitis B

Study Overview
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Brief Summary
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This is a phase IV, 2-year, multi-center, single arm and open-label study, evaluating the efficacy and safety with using local manufactured adefovir dipivoxil in Chinese subjects with HBeAg negative chronic hepatitis B

Official Title
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A 2-year Multi-centre, Open-label, Local Phase IV Study to Demonstrate the Efficacy and Safety of Adefovir Dipivoxil Tablets (10mg) in Chinese Subjects With HBe Antigen Negative Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: adefovir dipivoxil tablets


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 at least 6 months Documented HBeAg negative and HBeAb positive at the screening visit and with at least a 6 months history of HBeAg negativity. Serum HBV DNA ≥ 104 copies/mL (Roche COBAS AMPLICORTM HBV MONITOR Test, LLOD 300 copies/mL) at study screening (within 4 weeks before baseline) ALT value ≥1.3 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 to the study screening. Serum alpha fetoprotein (AFP) < 50 ng/mL at the first screening visit. If the AFP level is ≥ 50 ng/mL but declined to < 50 ng/mL between screening and baseline, the patient is eligible. Compensated liver disease with the following laboratory and clinical parameters at study screening: Prothrombin time ≤ 2 second above normal range. Albumin ≥ 35 g/L. Total bilirubin ≤ 2.5 mg/dL (≤ 43 µmol/L) or normal direct bilirubin. No history of variceal bleeding. No history of encephalopathy. No history of ascites 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) recommended for the patients who will undergo liver biopsy. Hemoglobin ≥ 10 g/dL (≥ 100 g/L) (males) or ≥ 9 g/dL (≥ 9 g/L) (females). Willing and able to undergo a minimum of two liver biopsies (prior to dosing, and after 104 weeks of therapy; only apply to subjects who are enrolled to the sites where liver biopsy is required). A female is eligible to enter and participate in this study if she is of: non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); child-bearing potential with a negative serum pregnancy test at screen, and agrees to one of the following: Complete abstinence from intercourse from 2 weeks prior to administration of the study drug, throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the investigational drug, (a minimum of 5 half-lives or longer if the pharmacodynamic profile of the investigational drug warrants a longer time period); or, Female sterilization; or, Sterilization of male partner; or, Implants of levonorgestrel; or, Injectable progestogen; or, Oral contraceptive (combined or progestogen only); or, Any intrauterine device (IUD) with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criterion); or, Any other methods with published data showing that the lowest expected failure rate for that method is less than 1% per year; or, Barrier method only if used in combination with any of the above acceptable methods. Agree not to participate in any other investigational trials or to undertake other HBV systemic antiviral regimens during participation in this study Able to give written informed consent and comply with the requirements of the study Exclusion Criteria: 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 eligible; co-infection with hepatitis delta (HDV); co-infection with HIV; autoimmune hepatitis (antinuclear antibody titre > 1:160) Clinical signs of decompensated liver disease at baseline. These may include but are not limited to: serum bilirubin > 2.5 mg/dL (≤ 43 µmol/L) - prothrombin time > 2 second prolonged above ULN serum albumin < 35g/L history of ascites, variceal bleeding, or encephalopathy Alanine aminotransferase (ALT) >10 times ULN at screening or history of acute exacerbation leading to transient decompensation 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 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, chronic anti-viral agents excluding lamivudine (e.g. ganciclovir, adefovir dipivoxil, entecavir, famciclovir, FTC, DAPD, LFMAU, HBIg), Chinese herbal medicines known to have activity against HBV within the previous 12 months or during the study; use of agents with effect of ALT reduction (e.g. schisandra agents) during the study Use of lamivudine within the previous 3 months or during the study Planned for liver transplantation or previous liver transplantation 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. 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. Receiving systemic (intravenous or oral) steroids, immuno-suppressant therapies or chemotherapeutic agents within 2 months of study screening or expected to receive these agents during the course of the study. History of hypersensitivity to nucleoside and/or nucleotide analogues. Inability to comply with study requirements. Lactating females or females with a positive serum pregnancy test. Organ or bone marrow transplant recipients. Previous (or planned) participation in an investigational trial involving administration of investigational compound within 2 months prior to the study screening. Can not comply with the requirements of the study

Ages Eligible for Study
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Minimum Age: 18 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 open label adefovir dipivoxil<br>adefovir dipivoxil once daily 10 mg orally | Drug: adefovir dipivoxil tablets<br>* adefovir dipivoxil once daily 10 mg 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 ≤300 Copies/mL at Week 104 | Hepatitis B Virus (HBV) DNA level is tested in blood serum by real-time Polymerase Chain Reaction with the lower limit of detection (LLD) as 300 copies/milliliter in a central laboratory. | Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Histological Improvement After the 104-week Treatment | Histological improvement (defined as ≥2 point reduction in the Knodell necroinflammation score without worsening fibrosis) was assessed by 2 independent pathologists in the HBeAg-negative participants who underwent 2 sequential liver biopsies at baseline and week 104/withdrawal. The Knodell/histological activity index (HAI) scoring system represents the sum of scores for periportal, bridging necrosis (0-10: none=0, 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, cirrhosis=4) | Week 104 | 
| Liver Histology Scores in HBeAg Negative Participants With Two Sequential Liver Biopsies During the Period of 104 Weeks | The Knodell/histological activity index (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 independent pathologists in the HBeAg negative participants with 2 sequential liver biopsies during the period of 104 weeks. | Baseline to Week 104 | 
| Change From Baseline in Median Serum HBV DNA Over Time | The HBV DNA level was tested in blood serum by real-time PCR with the LLD as 300 copies/mL at baseline and Weeks 13, 26, 39, 52, 65, 78, 91, and 104 in a central laboratory. | Baseline and Weeks 13, 26, 39, 52, 65, 78, 91, and 104 | 
| Number of Participants Achieving ALT Normalization at Week 104 | Serum alanine aminotransferase (ALT) normalization was defined as a serum ALT level at or below the upper limit of the normal (ULN) range after a baseline value above the ULN, as determined using central laboratory ranges. | Week 104 | 
| Number of Participants Achieving HBsAg Loss and HBsAg Seroconversion at Week 104 | HBsAg loss and HBsAg seroconversion (HBsAg loss and HBsAb detected) were assessed for all participants who were HBeAg negative at Weeks 0 and 104. Confirmed HBsAg loss was defined as undetectable HBeAg. | Week 104 | 
| Number of Participants With ADV-associated Resistance at Week 104 | Week 104 serum samples from participants who reached a HBV DNA breakthrough were assessed for the development of ADV (Adefovir dipivoxil) mutations (N236T and A181V) in the HBV polymerase. HBV DNA breakthrough was defined as an increase in HBV DNA level by 1 log10 copies/mL or more from the treatment nadir during Weeks 0 to 104. | Week 104 | 
| Number of Participants Achieving HBV DNA ≤300 Copies/mL Over Time | Hepatitis B Virus (HBV) DNA level is tested in blood serum by real-time Polymerase Chain Reaction with the lower limit of detection (LLD) as 300 copies/milliliter in a central laboratory. | Weeks 13, 26, 39, 52, 65, 78, 91, and 104 | 
| Number of Participants Achieving Complete Response at Week 104 | Complete response was defined as an HBV DNA level ≤ 300 copies/mL by the Roche COBAS AMPLICOR HBV MONITOR Test and ALT normalized for two consecutive visits at least 3 months apart. | Week 104 | 
| Time to Protocol-defined Complete Response Over a 104-week Treatment Period | Time to response was defined as the time to participants achieving protocol-defined complete response at week 104 from baseline. Protocol-defined complete response was an HBV DNA level ≤ 300 copies/mL by Roche COBAS AMPLICOR HBV MONITOR Test and ALT normalized for two consecutive visits at least 3 months apart. | Baseline to Week 104 | 

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