A Phase IIIb Study to Compare Entecavir Plus Tenofovir vs. Adefovir Added to Continuing Lamivudine Therapy in Adult Patients With Lamivudine-Resistant Hepatitis B Infection

Study Overview
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Brief Summary
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The purpose of this clinical research study is to find out whether a combination of entecavir (ETV) plus tenofovir (TNF) works better against Hepatitis B virus than adefovir (ADV) added to continuing lamivudine (LVD) therapy in patients whose Hepatitis B virus (HBV) is resistant against lamivudine. The safety of this treatment will also be studied.

Official Title
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A Comparative Study of the Antiviral Efficacy and Safety of Entecavir Plus Tenofovir Versus Adefovir Added to Continuing Lamivudine in Adults With Lamivudine- Resistant Chronic Hepatitis B Virus Infection

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Entecavir + Tenofovir
* Drug: Adefovir + continuing Lamivudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic HBV infection History of lamivudine (LVD) treatment, and lamivudine resistance (LVDr), receiving LVD at screening visit Compensated liver function HBV DNA ≥ 172,000 IU/mL Hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative Exclusion Criteria: Evidence of decompensated cirrhosis Coinfection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis D virus (HDV) Recent history of pancreatitis Serum alpha fetoprotein > 100 ng/mL Except lamivudine, any prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Entecavir + Tenofovir<br>* Tablets, Oral Entecavir 1 mg + Tenofovir 300 mg, once daily, 100 weeks<br>* Other names: Baraclude;|
| Experimental: 2<br> | Drug: Adefovir + continuing Lamivudine<br>* Tablets, Oral, Adefovir 10 mg + Lamivudine, 100 mg, once daily, 100 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved an Hepatitis B Virus DNA (HBV DNA) Level < 50 IU/mL at Week 48 | using the Roche COBAS® TaqMan HBV Test for use with the High Pure System (HPS) assay, by Polymerase Chain Reaction (PCR); HBV DNA < 50 IU/mL = approximately 300 copies/mL | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved an HBV DNA Level <50 IU/mL at Week 96 | by PCR, using the Roche COBAS®TaqMan - HPS assay; HBV DNA < 50 IU/mL = approximately 300 copies/mL. | Week 96 | 
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs or Laboratory Abnormalities | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or is an important medical event. | Day 1 through end of treatment (Week 100 +/- 5 days) | 
| Number of Participants Who Achieved HBV DNA < the Lower Limit of Detection (LLD) at Weeks 48 and 96 | by PCR, using the Roche for the Roche COBAS® TaqMan - HPS assay. LLD = 4.8 IU/mL (approximately 28 copies/mL) | Week 48, Week 96 | 
| HBV DNA Values at Weeks 48 and 96 | Number of Participants with HBV DNA <LLD (4.8); LLD to <50; 50 to <172; 172 to <1,720; 1,720 to <17,200; and ≥17,200 IU/mL (<LLD (28); 28 to <300; 300 to <1,000; 1,000 to <10,000; 10,000 to <100,000; and ≥100,000 copies/mL by PCR, using the Roche COBAS®TaqMan - HPS assay | Weeks 48, Week 96 | 
| Mean log10 Reduction From Baseline in HBV DNA at Weeks 48 and 96 | by PCR, using the Roche COBAS®TaqMan - HPS assay | Week 48, Week 96 | 
| Number of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieved ALT Normalization (≤ 1 x ULN) at Weeks 48 and 96 |  | Week 48, Week 96 | 
| Number of Participants Who Were Hepatitis B E-antigen (HBeAg)-Positive at Baseline With Loss of HBeAg at Weeks 48 and 96 | HBeAg is a hepatitis B viral protein. It is an indicator of active viral replication. | Baseline, Week 48, Week 96 | 
| Number of Participants Who Were HBeAg-positive at Baseline With HBe Seroconversion at Weeks 48 and 96 | HBe seroconversion = HBeAg loss and presence of hepatitis B e-antibody (HBeAb) | Baseline, Week 48, Week 96 | 
| Number of Participants With Hepatitis-B-Virus Surface Antigen of the (HBsAg) Loss at Weeks 48 and 96 | Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection | Week 48, Week 96 | 
| Number of Participants With HBs Seroconversion (HBsAg Loss and Presence of HBsAb) at Weeks 48 and 96 | Hepatitis B surface antigen (HBsAg) = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. HBsAb = HBsAg antibodies. HBs Seroconversion = HBsAg loss and presence of HBseAb | Week 48, Week 96 | 
| Number of Participants With Genotypic Resistance Based on Analysis of Samples From Participants With HBV DNA ≥ 50 IU/mL at Weeks 48 and 96 | HBV DNA ≥ 50 IU/mL = approximately 300 copies/mL | Week 48, Week 96 |