Treatment of Persistent Viremia (Virus in Blood) in Chronic Hepatitis B Subjects Already Receiving Adefovir Dipivoxil

Study Overview
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Brief Summary
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This study explores the efficacy, safety and tolerability of tenofovir DF (TDF) 300 mg once daily monotherapy versus the combination of emtricitabine 200 mg plus tenofovir DF 300 mg (FTC/TDF) once daily in subjects currently being treated with adefovir dipivoxil (Hepsera) for chronic hepatitis B who have persistent viral replication (detectable hepatitis B virus deoxyribonucleic acid [HBV DNA]). Subjects with confirmed (within 4 weeks) plasma HBV DNA ≥ 400 copies/mL during double blind treatment at Week 24 or any time thereafter have the option of receiving 12 weeks of open-label FTC/TDF which may be continued through the end of the 168-week treatment period if there is a virologic response (HBV DNA < 400 copies/mL). Alternatively, subjects with confirmed HBV DNA < 400 copies/mL at or any time after Week 24 of double-blind treatment may continue blinded therapy up to Week 168 at the discretion of the investigator. If, in the investigator's opinion, it is felt that continued blinded treatment beyond 24 weeks in subjects with confirmed HBV DNA ≥ 400 copies/mL is not beneficial, the subject may discontinue the study and begin commercially available HBV therapy rather than initiate open-label FTC/TDF.

Official Title
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A Phase 2, Randomized, Double-Blind Study Exploring the Efficacy, Safety and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine Plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects Currently Being Treated With Adefovir Dipivoxil for Chronic Hepatitis B and Having Persistent Viral Replication

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: tenofovir DF
* Drug: emtricitabine /tenofovir DF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 through 69 years of age, inclusive Chronic HBV infection, defined as positive serum HBsAg for at least 6 months Active chronic HBV infection with all the following: Currently treated with adefovir dipivoxil 10 mg QD (for at least 24 weeks but not more than 96 weeks) HBeAg positive or negative at screening Plasma HBV DNA >/= 1000 copies/mL at screening (irrespective of HBeAg status) Serum ALT less than 10 times the upper limit of normal (ULN) Calculated creatinine clearance of at least 70 mL/min using the Cockcroft-Gault formula Hemoglobin at least 8 g/dL Neutrophils at least 1,000 /mm3 Nucleoside naive except for lamivudine (>/= 12 weeks of therapy) Negative serum beta human chorionic gonadotropin Compliant with adefovir dipivoxil Willing and able to provide written informed consent Exclusion Criteria: Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study Male or females of reproductive potential who are unwilling to use an effective method of contraceptive while enrolled in the study. For males, condoms should be used and for females, a barrier contraception method should be used Decompensated liver disease defined as conjugated bilirubin greater than 1.5 times ULN, prothrombin time (PT) greater than 1.5 times ULN, platelets less than 75,000/mm3, serum albumin less than 3.0 g/dL, or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, variceal hemorrhage) Prior use of tenofovir DF or entecavir Received treatment with interferon or pegylated interferon within 6 months of the screening visit Evidence of hepatocellular carcinoma (HCC); for example, alpha-fetoprotein greater than 50 ng/mL or by any other standard of care measure. Co-infection with HCV (based on serology), human immunodeficiency virus (HIV), or hepatitis delta virus (HDV) Significant renal, cardiovascular, pulmonary, or neurological disease. Received solid organ or bone marrow transplantation. Is currently receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion Has proximal tubulopathy Known hypersensitivity to the study drugs (tenofovir DF or emtricitabine/tenofovir DF), the metabolites (tenofovir or emtricitabine) or formulation excipients

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>TDF | Drug: tenofovir DF<br>* 300 mg tablet, once daily (QD)<br>|
| Experimental: 2<br>FTC/TDF | Drug: emtricitabine /tenofovir DF<br>* emtricitabine 200 mg/tenofovir DF 300 mg once daily (combination tablet)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 48 |  | 48 weeks | 
| Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48 |  | 48 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in log10 Plasma HBV DNA Levels at Week 48 |  | 48 Weeks | 
| Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 48 |  | 48 Weeks | 
| Percentage of Participants With Normal ALT at Week 48 | ULN for males = 43 U/L; 34 U/L for females | 48 Weeks | 
| Percentage of Participants With Normalized ALT at Week 48 | Subjects with elevated ALT at baseline that return to normal by Week 48. | 48 Weeks | 
| Hepatitis B Early Antigen (HBeAg) Loss at Week 48 | Defined as having negative serum HBeAg for subjects with positive HBeAg at baseline. | 48 Weeks | 
| HBeAg Seroconversion at Week 48 | Defined as having negative serum HBeAg and positive serum antibody to HBeAg [anti-HBe] for subjects with positive serum HBeAg at baseline. | 48 Weeks | 
| HBsAg Loss at Week 48 | Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline. | 48 Weeks | 
| Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 48 | Defined as having negative serum HBsAg and positive serum antibody to HBsAg [anti-HBs] for subject with positive serum HBsAg at baseline. | 48 Weeks | 
| Change From Baseline in log10 Plasma HBV DNA Levels at Week 168 |  | 168 weeks | 
| Change From Baseline in Alanine Aminotransferase (ALT) Levels at Week 168 |  | 168 weeks | 
| Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168 |  | 168 weeks | 
| Percentage of Participants With Normal ALT at Week 168 | ULN for males = 43 U/L; ULN for females = 34 U/L | 168 weeks | 
| Percentage of Participants With Normalized ALT at Week 168 | Subjects with elevated ALT at baseline that return to normal by Week 48. | 168 weeks | 
| Hepatitis B Early Antigen (HBeAg) Loss at Week 168 | Defined as having negative serum HBeAg for subjecst with positive HBeAg at baseline. | 168 weeks | 
| Hepatitis B Surface Antigen (HBsAg) Seroconversion at Week 168 | Defined as having negative serum BHsAg and positive serum antibody to HBsAg (anti-HBs) for subject with positive serum BHsAg at baseline. | 168 weeks | 
| HBsAg Loss at Week 168 | Defined as having negative serum HBsAg for subjects with positive HBsAg at baseline. | 168 weeks | 
| Percentage of Participants With Plasma HBV DNA < 169 Copies/mL at Week 168 | P-values were from a Cochran-Mantel-Haenszel test, controlling for baseline HBeAg status and prior lamivudine use. | 168 weeks |