Effects of Telbivudine and Tenofovir Disoproxil Fumarate Treatment on the Hepatitis B Virus DNA Kinetics in CHB

Study Overview
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Brief Summary
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The purpose of this study is to compare the safety, tolerability and effectiveness of 12 weeks of treatment with telbivudine 600 mg daily plus tenofovir DF 300 mg one daily (OD) taken together vs. tenofovir DF 300 mg once daily (QD) or vs telbivudine 600 mg monotherapy daily (QD). This is an open labeled, active controlled, viral kinetics study which means the subjects and study doctor will know what study drug subjects have been assigned. This study is open to male and female subjects, <40 years of age, who have been infected with HBV for at least 6 months and have not received oral treatment for HBV.

Official Title
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A Randomized, Open-label, Controlled, Exploratory Trial to Characterize the Results of Daily Oral Administration of Telbivudine 600 mg and Tenofovir Disproxil Fumarate 300 mg in Combination or Telbivudine 600 mg or Tenofovir Disproxil Fumarate 300 mg Monotherapy Given Over 12 Weeks on the Kinetics of Hepatitis B Virus DNA in Adults With HBeAg Positive Compensated CHB

Conditions
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Hepatitis B Virus

Intervention / Treatment
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* Drug: Telbivudine
* Drug: Tenofovir
* Drug: Telbivudine plus tenofovir


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 negative for IgM anti-HBc and positive for IgG anti-HBc Age < 40 years old HBeAg positive HBV DNA > or = to 10^7 copies/mL by Abbott real-time PCR ALT < or = to 1 ULN Willing and able to provide written informed consent No prior oral HBV therapy (e.g., nucleotide and/or nucleoside therapy or other investigational agents for HBV infection) Is willing and able to comply with the study drug regimen and all other study procedures and requirements Is willing and able to provide written informed consent before any study assessment is perform Exclusion Criteria: Decompensated liver disease defined as direct (conjugated) bilirubin > 1.2 × ULN, PT > 1.2 × ULN, platelets < 150,000/mm3, serum albumin < 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g. ascites, jaundice, encephalopathy, variceal hemorrhage). Received interferon (pegylated or not) therapy within 6 months of the screening visit α-fetoprotein > 50 ng/mL Evidence of hepatocellular carcinoma (HCC) Co-infection with HCV (by serology), or HIV, Significant renal, cardiovascular, pulmonary, or neurological disease. Received solid organ or bone marrow transplantation. Is currently receiving therapy with immunomodulators (e.g., corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion. Has proximal tubulopathy. Use of other investigational drugs at the time of enrollment, or within 30 days History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes Is pregnant or breastfeeding. Is a women of child-bearing potential (WOCBP)unless post-menopausal or using one or more acceptable method of contraception. Patient has any other concurrent medical or social condition likely to preclude compliance with the schedule of evaluations in the protocol, or likely to confound the efficacy or safety observations of the study. Patient is currently abusing alcohol or illicit drugs, or has a history of alcohol abuse or illicit substance abuse within the preceding two years. Patient has a medical condition that requires prolonged or frequent use of systemic acyclovir or famciclovir. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Telbivudine 600 mg monotherapy<br>All patients in this arm were randomized to receive Telbivudine (LDT) 600 mg QD. Patients were randomized prior to the first dose of study medication, which was defined as the study Baseline (Day 1) Visit. Subsequently, patients returned to the clinic at Days 2, 4, 6, 8, 11, 15 (Wk 2), 22 (Wk 3), 29 (Wk 4), 43 (Wk 6), 57 (Wk 8), and 85 (Wk 12) during the 12 weeks treatment phase. | Drug: Telbivudine<br>* 600 mg monotherapy supplied in film-coated tablets.<br>|
| Active Comparator: Tenofovir disproxil fumarate 300 mg monotherapy<br>All patients in this arm were randomized to receive Tenofovir disoproxil fumarate 300 mg(equivalent to tenofovir disoproxil 245 mg)QD. Patients were randomized prior to the first dose of study medication, which was defined as the study Baseline (Day 1) Visit. Subsequently, patients returned to the clinic at Days 2, 4, 6, 8, 11, 15 (Wk 2), 22 (Wk 3), 29 (Wk 4), 43 (Wk 6), 57 (Wk 8), and 85 (Wk 12) during the 12 weeks treatment phase. | Drug: Tenofovir<br>* Tenofovir disoproxil fumarate was supplied in 300 mg tablets<br>|
| Active Comparator: Telbivudine 600 mg and Tenofovir 300 mg<br>All patients in this arm were randomized to receive Telbivudine (LDT) 600 mg QD and Tenofovir (TDF) 300 mg (equivalent to Tenofovir disoproxil 245 mg)QD. Patients were randomized prior to the first dose of study medication, which was defined as the study Baseline (Day 1) Visit. Subsequently, patients returned to the clinic at Days 2, 4, 6, 8, 11, 15 (Wk 2), 22 (Wk 3), 29 (Wk 4), 43 (Wk 6), 57 (Wk 8), and 85 (Wk 12) during the 12 weeks treatment phase. | Drug: Telbivudine plus tenofovir<br>* Telbivudine 600 mg and Tenofovir 300 mg were purchased in commercial packs. Patients were instructed to take medication(s) orally every morning either with or without food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Level From Baseline to Week 12. | Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA. Serum HBV DNA determinations were performed at a central laboratory through use of the COBAS TaqMan™ HBV DNA assay (Roche Molecular Systems, Pleasanton, CA, USA) which utilized the Real-time polymerase chain reaction (PCR) method and automated extraction by Cobas Ampliprep (threshold for detection 12 IU/mL). The Screening serum HBV DNA values must be ≥ 7 log10 copies/mL by COBAS TaqMan™ HBV DNA assay. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Level From Baseline to Weeks 2, 4 and 8. | Baseline HBV DNA is defined as the last pre-dose assessment of HBV DNA. Serum HBV DNA determinations were performed at a central laboratory through use of the COBAS TaqMan™ HBV DNA assay (Roche Molecular Systems, Pleasanton, CA, USA) which utilized the Real-time polymerase chain reaction (PCR) method and automated extraction by Cobas Ampliprep (threshold for detection 12 IU/mL). The Screening serum HBV DNA values must be ≥ 7 log10 copies/mL by COBAS TaqMan™ HBV DNA assay. | Baseline, Week 2, Week 4, Week 8 | 
| Percentage of Patients Who Are Polymerase Chain Reaction(PCR)Negative at Week 12 | Polymerase Chain Reaction (PCR) Negative is defined as HBV DNA levels <25 copies/ml. | Week 12 | 
| Percentage of Patients Who Achieve Hepatitis B e Antigen (HBeAg) Loss and HBeAg Seroconversion at Week 12 | HBeAg loss is defined as the loss of detectable serum HBeAg in a patient who was HBeAg positive at baseline. HBeAg seroconversion is defined as HBeAg loss with detectable Hepatitis B 'e' antibody (HBeAb). HBeAg stands for hepatitis B e antigen. This antigen is a protein from the hepatitis B virus that circulates in infected blood when the virus is actively replicating. The presence of HBeAg suggests that the person is infectious and is able to spread the virus to other people. | Week 12 | 
| Characterization of Very Early Viral Kinetics Through Estimated Viral Load | The underlying bi-phasic model of viral kinetics can be described as follows: V(t) (1 )pI(t) cV(t)I(t) (1 ) (T I(t))V(t) I(t)where V denotes serum viral load, I productively infected cells, ε the efficiency factor of blocking virus production, p the viral production rate, c the viral clearance rate, η the efficiency factor of blocking de novo infection, β the de novo infection rate, Tg comprise all infected and uninfected target cells, and δ the rate of infected cell loss | Week 12 | 
| Characterization of Very Early Viral Kinetics Through Viral Clearance | The underlying bi-phasic model of viral kinetics can be described as follows: V(t) (1 )pI(t) cV(t)I(t) (1 ) (T I(t))V(t) I(t)where V denotes serum viral load, I productively infected cells, ε the efficiency factor of blocking virus production, p the viral production rate, c the viral clearance rate, η the efficiency factor of blocking de novo infection, β the de novo infection rate, Tg comprise all infected and uninfected target cells, and δ the rate of infected cell loss | Week 12 | 
| Characterization of Very Early Viral Kinetics Through Rate of Infected Cell Loss | The underlying bi-phasic model of viral kinetics can be described as follows: V(t) (1 )pI(t) cV(t)I(t) (1 ) (T I(t))V(t) I(t)where V denotes serum viral load, I productively infected cells, ε the efficiency factor of blocking virus production, p the viral production rate, c the viral clearance rate, η the efficiency factor of blocking de novo infection, β the de novo infection rate, Tg comprise all infected and uninfected target cells, and δ the rate of infected cell loss | Week 12 | 
| Characterization of Very Early Viral Kinetics Through Efficiency Factor of Blocking Virus Production. | The underlying bi-phasic model of viral kinetics can be described as follows: V(t) (1 )pI(t) cV(t) I(t) (1 ) (T I(t))V(t) I(t) where V denotes serum viral load, I productively infected cells, ε the efficiency factor of blocking virus production, p the viral production rate, c the viral clearance rate, η the efficiency factor of blocking de novo infection, β the de novo infection rate, Tg comprise allinfected and uninfected target cells, and δ the rate of infected cell loss | Week 12 | 
| Characterization of Very Early Viral Kinetics Through Half-live of Free Virus | The underlying bi-phasic model of viral kinetics can be described as follows: V(t) (1 )pI(t) cV(t)I(t) (1 ) (T I(t))V(t) I(t)where V denotes serum viral load, I productively infected cells, ε the efficiency factor of blocking virus production, p the viral production rate, c the viral clearance rate, η the efficiency factor of blocking de novo infection, β the de novo infection rate, Tg comprise all infected and uninfected target cells, and δ the rate of infected cell loss | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic HBV, Asian adult subjects with chronic HBV, in immune tolerant phase, and positive for hepatitis B e antigen (HBeAg)