Entecavir Plus Tenofovir Combination Therapy Versus Entecavir Monotherapy in Naive Subjects With Chronic Hepatitis B

Study Overview
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Brief Summary
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The purpose of this study is to compare the effectiveness of entecavir plus tenofovir combination therapy with that of entecavir monotherapy. Safety will also be studied.

Official Title
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A Comparative Study of Chronic Hepatitis B Subjects Treated With Entecavir Plus Tenofovir Combination Therapy vs. Entecavir Monotherapy in Adults Who Are Treatment-Naive to Nucleosides and Nucleotides: The BE-LOW Study

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: Entecavir
* Drug: Entecavir + Tenofovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hepatitis B virus (HBV) infection (hepatitis B e antigen [HbeAg]-positive or negative) disease Nucleoside- and nucleotide-naive Males or females ≥16 years of age (or minimum age of consent in a given country) Compensated liver function HBV DNA >1.72*10*5*IU/mL (approximately 10*6*copies/mL) for HbeAg-positive participants HBV DNA >1.72*10*4*IU/mL (approximately 10*5*copies/mL) for Hbe-Ag-negative participants Alanine aminotransferase level ≥*upper limit of normal (ULN) and ≤10*ULN Exclusion Criteria: Evidence of decompensated cirrhosis Coinfection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus Laboratory values out of protocol-specified range

Ages Eligible for Study
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Minimum Age: 16 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: TDF 0.5 mg<br>TDF=tenofovir | Drug: Entecavir<br>* Tablets, Oral, ETV = 0.5 mg, once daily, 100 weeks<br>* Other names: BMS-200475;|
| Experimental: ETV 0.5 mg +TDF 300 mg<br>ETV=entecavir; TDF=tenofovir | Drug: Entecavir + Tenofovir<br>* Tablets, Oral, ETV = 0.5 mg + TFV = 300 mg, once daily, 100 weeks<br>* Other names: BMS-200475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96 | HBV DNA levels <50 IU/mL=approximately 300 copies/mL. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. | At Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved HBV DNA Levels <50 IU/mL by PCR at Week 48 and Week 96 by Hepatitis B e Antigen (HBeAg) Status | HBV DNA levels <50 IU/mL=approximately 300 copies/mL. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. | At Weeks 48 and 96 | 
| Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96 | LOQ=lower limit of quantitation. LOQ=29 IU/mL, or approximately 169 copies/mL. LOQ is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. | At Weeks 48 and 96 | 
| Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96 | LOD=Lower limit of detection. LOD) LOD=10 IU/mL, or approximately 58 copies/mL. LOD is the lowest concentration level that can be determined to be statistically different from a blank (99% confidence). The LOD is typically determined to be in the region where the signal to noise ratio is greater than 5. Limits of detection are matrix-, method-, and analyte-specific.Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. | At Weeks 48 and 96 | 
| Mean Log 10 HBV DNA at Weeks 48 and 96 | HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan - HPS assay. Reduction in Log 10 HBV count=reduced viral load. | Baseline, Weeks 48 and 96 | 
| Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96 | ALT normalization= ≤1*upper limit of normal (ULN). Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. | At Weeks 48 and 96 | 
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96 | HBeAg is a hepatitis B viral protein and is an indicator of active viral replication. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. | At Weeks 48 and 96 | 
| Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96 | HBeAg seroconversion=HBeAg loss and presence of hepatitis B e antibody (HBeAb). HBeAg is a hepatitis B viral protein and is an indicator of active viral replication. | At Weeks 48 and 96 | 
| Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96 | HBsAg = A part of the hepatitis B virus. When found in the blood, HBsAg is an early marker of infection. Analyses of binary efficacy endpoint during on-treatment period focused on participants who received treatment and used the analysis of noncompleter=failure (NC=F). All participants who received treatment were included in the denominator, and participants with missing measurements were counted as nonresponders for the specific endpoints. | At Weeks 48 and 96 | 
| Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96 | HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection. | At Weeks 48 and 96 | 
| Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 | Using the Roche COBAS TaqMan - HPS assay. Lower limit of Quantitation (LOQ) is the level above which quantitative results may be obtained with a specified degree of confidence. The LOQ is mathematically defined as equal to 10 times the standard deviation of the results for a series of replicates used to determine a justifiable limit of detection. Limits of quantitation are matrix-, method-, and analyte-specific. | At Weeks 48 and 96 | 
| Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities | AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to any AEs were recorded. | From enrollment through Week 100 + 24-week follow-up | 
| Number of Participants With HBV Resistance Through Week 48 | ETVr=entecavir resistance; TDFr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used. | Week 48 | 
| Number of Participants With HBV Resistance at Week 96 | ETVr=entecavir resistance; TFDr=tenofovir resistance. HBV polymerase using the Trugene® HBV Genotyping Kit. HBV resistance: genotyping of HBV polymerase will be performed on stored viral samples at any timepoint when considered appropriate based on virologic response, including any specimen with detectable HBV DNA. When appropriate, phenotyping will also be used. | Week 96 | 
| Number of Participants With Virologic Breakthrough at Week 48 | ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough= confirmed >= 1 log10 increase in HBV DNA from the on-treatment nadir | Week 48 | 
| Number of Participants With Virologic Breakthrough at Week 96 | ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough=confirmed >=1 log10 increase in HBV DNA from moving nadir | Week 96 |