An Open Label, Multi Centre Phase IV Study of Adefovir Dipivoxil in Korean Patients With Chronic Hepatitis B (CHB)

Study Overview
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Brief Summary
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Objective(s) The primary study objective is to assess the antiviral effect of 12 weeks of adefovir dipivoxil treatment in Korean patients with chronic hepatitis B and compensated liver disease. The secondary study objectives are to assess the antiviral effect, clinical benefit and safety of 52 weeks of adefovir dipivoxil treatment. Endpoint(s) The primary efficacy endpoint is Mean log10 reduction in serum HBV DNA level from baseline to Week 12. The secondary efficacy endpoints include (a) the proportion of patients achieving serum ALT normalization at Week 52, (b) other assessments of antiviral effects (the proportion of patients achieving HBV DNA no less than 300 copies per mL at Week 52), (c)HBeAg loss, HBeAg seroconversion, HBsAg loss and HBsAg seroconversion, (d)the proportion of patients achieving serum ALT normalization at Week 12. Study Design This is an open label, multi centre phase IV study for Korean patients with chronic hepatitis B and compensated liver disease, assessing the antiviral effect of 12 weeks treatment of Adefovir dipivoxil as a primary objective and antiviral effect, clinical benefit and safety of 52 weeks treatment as secondary objectives. Patients will be screened for eligibility criteria and the baseline visit for the treatment initiation should occur no more than 4 weeks after screening. Total treatment period will be 52 weeks and patients will return to the clinic for assessments as scheduled during treatment period. After the 52 week study period, it is likely that the patient will benefit from continued treatment with commercial adefovir. If in the investigator's clinical judgement this is the case, the investigator should ensure that a routine prescription is available in a timely manner, and that no unnecessary interruption in treatment occurs. Study Population A minimum of 100 male or female Korean patients more than 18 years of age with HBeAg positive chronic hepatitis B and compensated liver disease who meet the eligibility criteria will be enrolled. Study Assessments and Procedures Potential patients will be screened prior to study entry and eligible patients who have given their consent will have further baseline assessments. Following the screening, the first doses of study medications will be given at baseline and patients will return to the clinic for assessment as scheduled during treatment period. Patients who discontinue treatment prematurely will be followed up every 4 weeks for 12 weeks following the withdrawal visit. The following key assessment and or measurement will be made at one or more visits during the study. (See section 14.1 Appendix 1. Time and event schedule): Pregnancy test (females of child-bearing potential only) Haematology and serum chemistry profile including prothrombin time(PT) and AFP HBV DNA (Roche COBAS AMPLICOR HBV MONITOR Test, LLOD 300 copies per ml) Hepatitis B markers: HBeAg(Anti HBe will be tested if HBeAg is negative), HBsAg(Anti HBs will be tested if HBsAg is negative) Investigational Product(s) Adefovir dipivoxil 10mg tablets will be supplied by GlaxoSmithKline and presented as a white to off white, round tablets, packaged in the bottle containing 30 tablets

Official Title
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An Open Label, Multicenter Phase IV Study of Adefovir Dipivoxil in Korean Patients With Chronic Hepatitis B (CHB)

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: Adefor dipivoxil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject will be eligible for inclusion in this study only if all of the following criteria apply: Age more than 18 years HBV Serology Presence of HBsAg for at least 6 months Presence of HBeAg at the time of screening Positive HBV DNA plasma assay with screening value at the time of screening 4. Evidence of at least one elevated serum alanine amonotransferase (ALT) levels greater than 2 times (inclusive) the upper limit of the normal range (ULN) in the previous 6 months. serum ALT levels greater than 2 times (inclusive) the ULN at screening visit. 5. Availability and willingness of subject to provide written informed consent. Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: Use of immunosuppressive therapy requiring use of more than 5mg of prednisone(or equivalent) per day, immunomodulatory therapy (including interferon or thymosin ) or systemic cytotoxic agents within previous 6 months or during the study Previous or current lamivudine or adefovir dipivoxil therapy or antiviral therapy with agents demonstrating potential anti-HBV activity Clinical signs of decompensated liver disease at screening according to the protocol Serum creatinine over 1.5mg per dL Alanine aminotransferase (ALT) over 10 times ULN at screening or history of acute exacerbation leading to transient decompensation Serum Amylase and/or lipase over 2 times ULN Inadequate haematological function Anti-HBe or Anti-HBs positive subjects Hepatocellular carcinoma as evidenced by the protocol Documented evidence of active liver disease 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 any uncontrolled clinically significant renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic (diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders or cancer. 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. Planned for liver transplantation or previous liver transplantation Receipt of any investigational drug within within 3 months prior to screening. Therapy with nephrotoxic drugs or competitors of renal excretion within 2 months prior to study screening or the expectation that patient will receive any of these during the course of the study. History of hypersensitivity to nucleoside and/or nucleotide analogues. Inability to comply with study requirements as determined by the study investigator.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adefovir Dipivoxil 10mg<br>All enrolled subject were enrolled to adefovir dipivoxil 10mg arm. | Drug: Adefor dipivoxil<br>* All enrolled subjects were enrolled to adefovir dipivoxil arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Log 10 Reduction in Serum Hepatitis B Virus (HBV), Deoxyribonucleic Acid (DNA) Level From Baseline to Week 12 | HBV DNA was tested with Roche Cobas Amplicor HBV monitor test, where the lower limit of detection was 300 copies/milliliter (mL), at baseline and other study visits. The mean log 10 reduction in serum HBV DNA level from baseline to week 12 was calculated as the week 12 value minus the baseline value. Baseline was the Day 1 for the study, when participant received study drug. Log 10 reduction implied reduced viral load. | Baseline (Day 1) and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Alanine Aminotransferase (ALT) Normalization at Week 52 | ALT normalization was defined as measurement less than or equal to the upper limit of the normal range. Only those set of participants with a baseline ALT value above the upper limit of the normal range was included in this analysis. The normal range for ALT is 7 to 43 Units/Liter. | At week 52 | 
| Number of Participants Achieving Virological Response at Week 52 | Virological response was defined as HBV DNA level < 300 copies/ml in serum. The number of participants achieving these DNA levels were reported. | At Week 52 | 
| HBV DNA Levels at Each Collection Timepoint Through Week 52 | Serum HBV DNA at different timepoints namely Baseline, Week 4, week 8, week 12, week 20, week 28, week 36, week 44 and week 52 were reported. The HBV DNA copies in the serum were reported in multiples of log 10 copies per mL, detected using Roche COBAS AMPLICOR HBV monitor. | Week 4, week 8, week 12, week 20, week 28, week 36, week 44 and week 52 | 
| Number of Participants With Hepatitis B e Viral Protein (HBeAg) Loss, HBeAg Seroconversion, Hepatitis B Virus Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 52 | The HBeAg loss, defined as the number of participants with an undetectable level of serum HBeAg. The percentage of participants with a HBeAg seroconversion, defined as an undetectable level of serum HBeAg and a detectable level of serum hepatitis B e antibody (HBeAb) at Week 52. The number of participants with HBsAg loss was defined as an undetectable level of serum HBsAg; and those participants with HBsAg seroconversion were defined as an undetectable level of serum HBsAg and a detectable level of serum HBsAb. All these participant were reported at week 52. Only the subset of participants, with above parameters detectable at baseline were included and for participants with post-baseline values missing were considered as non-responders. | Week 52 | 
| Number of Participants Achieving ALT Normalization at Week 12 | ALT normalization was defined as measurement less than or equal to the upper limit of the normal range. The normal range for ALT is 7-43 Units/Liter. Only those set of participants with a baseline ALT value above the upper limit of the normal range were included in this analysis, done at week 12. | at Week 12 | 
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAEs) | AE is defined as, any untoward medical occurrence in a participant or clinical investigation, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that at any dose, results in death; is life threatening; requires hospitalization or prolongation of hospitalization; results in disability or incapacity, is a congenital anomaly/birth defect or requires medical intervention. | From treatment initiation (Week 0) to follow-up (up to 52 weeks) | 
| Number of Participants With Shift From Baseline Hematology Parameters at Week 12 and Week 52 | The data for hematology parameters was summarized for Hemoglobin, Red blood cells (RBC), Platelets, Neutrophils, Lymphocytes, Monocytes, and Eosinophil as per the scheduled assessments and also according to maximum grade common terminology criteria (CTC) toxicity grade. The data for number of participants with shift in grade for hematology parameters at Week 12 and Week 52 were reported. | Baseline (Day 1), Week 12 and Week 52 | 
| Number of Participants With Shift From Baseline Clinical Chemistry Parameters at Week 12 and Week 52 | The data for clinical chemical parameters namely sodium, potassium, calcium, phosphorus, total protein, albumin, amylase, creatinine phospho kinase, creatinine, blood urea nitrogen, total bilirubin, alkaline phosphatase, aspartate transaminase, alanine transaminase, and prothrombin time as per the scheduled assessments and also according to maximum CTC toxicity grade was reported. The data for number of participants with shift in grade for clinical chemistry parameters at Week 12 and Week 52 were reported. | Baseline (Day 1), Week 12 and Week 52 | 
| Mean Log 10 Reduction in Serum HBV DNA Level From Baseline to Week 52 | HBV DNA was tested with Roche Cobas Amplicor HBV monitor test, HBV DNA was tested with Roche Cobas Amplicor HBV monitor test, Lower Limit of Detection 300 copies/mL), at baseline and other study visits. The mean log 10 reduction in serum HBV DNA level from baseline to Week 52 was calculated as the Week 52 value minus the baseline value. Baseline was the Day 1 for the study when participant received study drug. Log 10 reduction implied reduced viral load | Baseline (Day 1) and Week 52 |