A Study to Compare Tenofovir DF Versus the Combination of Emtricitabine Plus Tenofovir DF for the Treatment of Chronic Hepatitis B in Patients With Normal Alanine Aminotransferase (ALT)

Study Overview
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Brief Summary
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The main objective of the study was to evaluate the antiviral activity of tenofovir disoproxil fumarate (tenofovir DF) monotherapy versus emtricitabine (FTC) plus tenofovir DF combination therapy for the treatment of chronic hepatitis B (HBV) in participants in the immune tolerant phase of HBV infection. The efficacy of tenofovir DF monotherapy versus FTC plus tenofovir DF combination therapy was evaluated for suppression of the virus (decrease in HBV DNA), serological response (generation of antibodies to the virus), biochemical response (changes in liver enzymes), and the development of drug-resistant mutations. The safety and tolerability of both tenofovir DF monotherapy and FTC plus tenofovir DF were evaluated by routine monitoring for adverse events and changes in laboratory parameters. Participants were randomized in a 1:1 ratio to receive tenofovir DF monotherapy or FTC plus tenofovir DF. All subjects were to continue on blinded study medication until the last subject reached Week 192. Participants who permanently discontinued study drug (on or before Week 192) were followed for a 24-week treatment-free follow-up period, or until initiation of alternative HBV therapy, whichever occurred first. Subjects who discontinued study drug on or after Week 48 because of hepatitis B surface antigen (HBsAg) loss or seroconversion to antibody to hepatitis B surface antigen (anti-HBs), however, were to have returned for their regularly scheduled through Week 192 and every 16 weeks thereafter until the last subject reached Week 192.

Official Title
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A Randomized, Double-Blind Study Evaluating Tenofovir Disoproxil Fumarate (DF) Monotherapy Versus the Combination of Emtricitabine and Tenofovir DF for the Treatment of Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Tenofovir DF
* Drug: FTC
* Drug: 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 or HBsAg positive > 3 months and positive for immunoglobulin G antibody against hepatitis B core antigen 18 through 69 years of age, inclusive Hepatitis B e antigen (HBeAg) positive HBV DNA ≥ 10^8 copies/mL ALT ≤ the upper limit of the normal range (ULN) Willing and able to provide written informed consent Negative serum beta-human chorionic gonadotropin (for females of childbearing potential only) Calculated creatinine clearance ≥ 70 mL/min Hemoglobin ≥ 10 g/dL Neutrophils ≥ 1,500/mm^3 No prior oral HBV therapy (eg, nucleotide and/or nucleoside therapy or other investigational agents for HBV infection) Exclusion Criteria: Pregnant women, women who were breast feeding, or who believed they may have wished to become pregnant during the course of the study Males and females of reproductive potential unwilling to use an effective method of contraception during the study Decompensated liver disease defined as direct (conjugated) bilirubin > 1.2 x ULN, prothrombin time > 1.2 x ULN, platelets < 150,000/mm^3, serum albumin < 3.5 g/dL, or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, or variceal hemorrhage) Received interferon (pegylated or not) therapy within 6 months of the screening visit Alpha-fetoprotein > 50 ng/mL Evidence of hepatocellular carcinoma Coinfection with hepatitis C virus (by serology), HIV, or hepatitis D virus Significant renal, cardiovascular, pulmonary, or neurological disease Received solid organ or bone marrow transplantation Was currently receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion Had 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: 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir DF<br>Participants were randomized to receive tenofovir DF plus placebo to match FTC once daily. | Drug: Tenofovir DF<br>* Tenofovir disoproxil fumarate (tenofovir DF) 300 mg tablet taken orally once daily<br>* Other names: Viread®;Drug: Placebo<br>* Placebo to match FTC taken once daily<br>|
| Experimental: FTC+Tenofovir DF<br>Participants were randomized to receive FTC plus tenofovir DF once daily. | Drug: Tenofovir DF<br>* Tenofovir disoproxil fumarate (tenofovir DF) 300 mg tablet taken orally once daily<br>* Other names: Viread®;Drug: FTC<br>* Emtricitabine (FTC) 200 mg capsule taken orally once daily<br>* Other names: Emtriva®;|

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 192 | The percentage of participants with HBV DNA < 400 copies/mL at Week 192 was analyzed. Participants with missing data were considered to have failed to achieve the criteria for evaluation. | Week 192 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 96, and 144 | The percentage of participants with HBV DNA < 400 copies/mL at Weeks 48, 96, and 144 was analyzed. Participants with missing data were considered to have failed to achieve the criteria for evaluation. | Weeks 48, 96, and 144 | 
| Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 96, 144, and 192 | The percentage of participants with HBV DNA < 169 copies/mL at Weeks 48, 96, 144, and 192 was analyzed. Participants with missing data were considered to have failed to achieve the criteria for evaluation. | Weeks 48, 96, 144, and 192 | 
| Change From Baseline in HBV DNA at Week 48 | The change from baseline in HBV DNA at Week 48 was analyzed. | Baseline to Week 48 | 
| Change From Baseline in HBV DNA at Week 96 | The change from baseline in HBV DNA at Week 96 was analyzed. | Baseline to Week 96 | 
| Change From Baseline in HBV DNA at Week 144 | The change from baseline in HBV DNA at Week 144 was analyzed. | Baseline to Week 144 | 
| Change From Baseline in HBV DNA at Week 192 | The change from baseline in HBV DNA at Week 192 was analyzed. | Baseline to Week 192 | 
| Number of Participants With Normal Alanine Aminotransferase (ALT) at Weeks 48, 96, 144, and 192 | Range of normal ALT was 6 to 34 U/L for females, 6 to 43 U/L for males. Participants with missing data were considered to have failed to achieve the criteria for evaluation. | Weeks 48, 96, 144, and 192 | 
| Number of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48, 96, 144, and 192 | The number of participants with HBeAg loss at Weeks 48, 96, 144, and 192 was analyzed. Loss of HBeAg was defined as change of detectable HBeAg from positive to negative. No statistical analysis is presented for Week 48 because no participants met the criteria at that time point. | Weeks 48, 96, 144, and 192 | 
| Number of Participants With Seroconversion to Antibody Against HBeAg (Anti-HBe) at Weeks 48, 96, 144, and 192 | The number of participants with seroconversion to anti-HBe at Weeks 48, 96, 144, and 192 was analyzed. Seroconversion to anti-HBe was defined as change of detectable antibody to HBeAg from negative to positive. No statistical analysis is presented for Week 48 because no participants met the criteria at that time point. | Weeks 48, 96, 144, and 192 | 
| Number of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48, 96, 144, and 192 | The number of participants with HBsAg loss at Weeks 48, 96, 144, and 192 was analyzed. Loss of HBsAg was defined as change of detectable HBsAg from positive to negative. | Weeks 48, 96, 144, and 192 | 
| Number of Participants With Seroconversion to Antibody to HBsAg (Anti-HBs) at Weeks 48, 96, 144, and 192 | The number of participants with seroconversion to anti-HBs at Weeks 48, 96, 144, and 192 was analyzed. Seroconversion to anti-HBs was defined as change of detectable antibody to HBsAg from negative to positive. | Weeks 48, 96, 144, and 192 | 
| Occurrence of HBV Resistance Mutations | The development of HBV resistance mutations (occurrence of conserved site changes and/or polymorphic site changes) was analyzed for the overall study period (through Week 192). | Baseline to Week 192 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tenofovir, monotherapy, emtricitabine, combination, hepatitis B