Tenofovir Disoproxil Fumarate (Tenofovir DF) Versus Emtricitabine/Tenofovir DF in Subjects Resistant to Lamivudine

Study Overview
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Brief Summary
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The aim of therapy for the treatment of chronic hepatitis B virus (HBV) is to maintain suppression of viral replication to prevent the emergence of complications, which requires long-term therapy. Durable suppression of viral replication is achieved in the treatment of chronic viral diseases by preventing of the emergence of drug-resistant mutations. The clinical guidelines for the management of lamivudine resistant patients are variable. Some recommend switching to another agent without cross-resistance, while others recommend adding on another agent without cross-resistance. Limited clinical data exists to demonstrate whether tenofovir disoproxil fumarate (tenofovir DF; TDF) is an effective monotherapy for lamivudine resistant patients or if it should be used as part of a combination therapy regimen. This study is designed to evaluate the effectiveness, safety, and tolerability of tenofovir DF monotherapy versus emtricitabine (FTC)/tenofovir DF combination therapy in participants with chronic HBV with lamivudine resistance (presence of the rtM204I/V mutation with or without the rtL180M mutation) over a 240-week period. Participants in this study must be receiving lamivudine treatment at the time of enrollment.

Official Title
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A Phase 3b, Randomized, Double-Blind, Double-Dummy Study Evaluating the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus Emtricitabine Plus Tenofovir DF Fixed-Dose Combination Therapy in Subjects With Chronic Hepatitis B Who Are Resistant to Lamivudine

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: TDF
* Drug: FTC/TDF
* Drug: TDF Placebo
* Drug: FTC/TDF Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Chronic HBV infection, defined as positive serum HBsAg for at least 6 months 18 through 75 years of age, inclusive HBV DNA ≥ 10^3 IU/mL Receiving treatment with lamivudine with confirmation of HBV reverse transcriptase mutation(s) known to confer resistance to lamivudine (rtM204I/V with or without rtL180M) by central laboratory assessment prior to randomization; adefovir dipivoxil treatment of ≤ 48 weeks at the time of screening (inclusive of combination adefovir dipivoxil + lamivudine at entry) was allowed Willing and able to provide written informed consent Negative serum pregnancy test (for females of childbearing potential only) Calculated creatinine clearance ≥ 50 mL/min Hemoglobin ≥ 10 g/dL Neutrophils ≥ 1000 /mm^3 No prior oral HBV therapy with approved nucleotide and/or nucleoside therapy or other investigational agents for HBV infection other than lamivudine or adefovir dipivoxil Exclusion Criteria Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study Males and females of reproductive potential who are not willing to use an effective method of contraception during the study Alanine aminotransferase (ALT) ≥ 10 × the upper limit of the normal range (ULN) Decompensated liver disease Interferon or pegylated interferon therapy within 6 months of the screening visit Alpha fetoprotein > 50 ng/mL Evidence of hepatocellular carcinoma Coinfection with hepatitis C virus, HIV, or hepatitis D virus Significant renal, cardiovascular, pulmonary, or neurological disease Received solid organ or bone marrow transplantation Receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion Proximal tubulopathy Known hypersensitivity to the study drugs, the metabolites or formulation excipients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir DF<br>TDF plus placebo to match FTC/TDF | Drug: TDF<br>* Tenofovir disoproxil fumarate (tenofovir DF; TDF) 300 mg tablet administered orally once daily<br>* Other names: Viread®;Drug: FTC/TDF Placebo<br>* FTC/TDF placebo tablet administered orally once daily<br>|
| Experimental: FTC/TDF<br>FTC/TDF plus placebo to match TDF | Drug: FTC/TDF<br>* Emtricitabine (FTC)/TDF 200/300 mg fixed-dose combination tablet administered orally once daily<br>* Other names: Truvada®;Drug: TDF Placebo<br>* TDF placebo tablet administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBV DNA < 400 Copies/mL at Week 96 |  | Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 144, 192, and 240 |  | Weeks 48, 144, 192, and 240 | 
| Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, 192, and 240 |  | Weeks 48, 96, 144, 192, and 240 | 
| HBV DNA Level at Weeks 48, 96, 144, 192, and 240 |  | Weeks 48, 96, 144, 192, and 240 | 
| Percentage of Participants With Normal ALT at Weeks 48, 96, 144, 192, and 240 | Normal ALT was defined as having a value less than or equal to the ULN. The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69. | Weeks 48, 96, 144, 192, and 240 | 
| Percentage of Participants With HBeAg Loss at Weeks 48, 96, 144, 192, and 240 | The percentage of participants who were HBeAg positive at baseline and who had HBeAg Loss at the given time point was summarized. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. | Baseline; Weeks 48, 96, 144, 192, and 240 | 
| Percentage of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, 192, and 240 | The percentage of participants who were HBeAg positive at baseline and who had seroconversion to anti-HBe at the given time point was summarized. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive. | Baseline; Weeks 48, 96, 144, 192, and 240 | 
| Percentage of Participants With HBV Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, 192, and 240 | The percentage of participants with HBsAg Loss at the given time point was summarized. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. | Baseline; Weeks 48, 96, 144, 192, and 240 | 
| Percentage of Participants With Seroconversion to Antibody Against HBV Surface Antigen (Anti-HBs) at Weeks 48, 96, 144, 192, and 240 | The percentage of participants with seroconversion to anti-HBs at the given time point was summarized. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive. | Baseline; Weeks 48, 96, 144, 192, and 240 | 
| Percentage of Participants With Virologic Breakthrough at Weeks 48, 96, 144, 192, and 240 | The percentage of participants with virologic breakthrough at the given time point was summarized. Virologic breakthrough was defined as having two consecutive 1.0 log10 or greater increases in serum HBV DNA from on-treatment nadir, or two consecutive HBV DNA values ≥ 400 copies/mL after being < 400 copies/mL. | Baseline; Weeks 48, 96, 144, 192, and 240 | 
| Percent Change From Baseline in Bone Mineral Density (BMD) of the Spine at Weeks 24, 48, 72, 96, 144, 192, and 240 | BMD is calculated as grams per cubic centimeter (g/cm^2); the mean (SD) percentage change is presented. | Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240 | 
| Percent Change From Baseline in BMD of the Hip at Weeks 24, 48, 72, 96, 144, 192, and 240 | BMD is calculated as g/cm^2; the mean (SD) percentage change is presented. | Baseline; Weeks 24, 48, 72, 96, 144, 192, and 240 | 
| Development of Drug-resistant Mutations (DRMs) | The development of DRMs was summarized, either as development of new DRMs or enrichment of existing DRMs. | Baseline to Week 240 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenofovir DF, Emtricitabine, Chronic hepatitis B, Combination therapy