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

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

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.

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: Entecavir; Drug: Entecavir + Tenofovir

• Study Type: Interventional
• Enrollment (Actual): 669
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Ciudad De Buenos Aires, Buenos Aires, Argentina, C1121ABE
      • Local Institution
    • Ciudad De Buenos Aires, Buenos Aires, Argentina, C1181ACH
      • Local Institution
    • Ciudad De Buenos Aires, Buenos Aires, Argentina, C1282AEN
      • Local Institution
  • Prov De Santa
    • Rosario, Prov De Santa, Argentina, S2000PBJ
      • Local Institution
• Australia
  • New South Wales
    • Westmead Nsw, New South Wales, Australia, 2145
      • Local Institution
  • Victoria
    • Clayton Vic, Victoria, Australia, 3168
      • Local Institution
    • Fitzroy, Victoria, Australia, 3065
      • Local Institution
    • Heidelberg, Victoria, Australia, 3084
      • Local Institution
    • Prahan, Victoria, Australia, 3004
      • Local Institution
• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150
      • Local Institution
  • Rio Grande Do Sul
    • Porto Alegre Rs, Rio Grande Do Sul, Brazil, 90035
      • Local Institution
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Local Institution
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1H2
      • Local Institution
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Local Institution
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Local Institution
    • Toronto, Ontario, Canada, M5T 2S8
      • Local Institution
    • Toronto, Ontario, Canada, M3N 2V7
      • Local Institution
• France
  • Grenoble Cedex 09, France, 38043
    • Local Institution
  • Marseille Cedex 08, France, 13285
    • Local Institution
  • Paris, France, 75014
    • Local Institution
  • Paris Cedex 12, France, 75571
    • Local Institution
  • Paris Cedex 13, France, 75013
    • Local Institution
  • Strasbourg, France, 67090
    • Local Institution
• India
  • Lucknow, India, 226014
    • Local Institution
  • Ludhiana, India, 141001
    • Local Institution
  • Vellore, India, 632004
    • Local Institution
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500082
      • Local Institution
• Italy
  • Antella Firenze, Italy, 50012
    • Local Institution
  • Brescia, Italy, 25123
    • Local Institution
  • Pisa, Italy, 56124
    • Local Institution
  • Roma, Italy, 00149
    • Local Institution
• Mexico
  • Durango, Mexico, 34229
    • Local Institution
• Poland
  • Bialystok, Poland, 15-540
    • Local Institution
  • Chorzow, Poland, 41-500
    • Local Institution
  • Krakow, Poland, 31-531
    • Local Institution
  • Lublin, Poland, 20-081
    • Local Institution
  • Warszawa, Poland, 01-201
    • Local Institution
• Russian Federation
  • Moscow, Russian Federation, 105275
    • Local Institution
  • Moscow, Russian Federation, 115446
    • Local Institution
  • Moscow, Russian Federation, 117593
    • Local Institution
  • Smolensk, Russian Federation, 214018
    • Local Institution
  • St. Petersburg, Russian Federation, 194044
    • Local Institution
  • St. Petersburg, Russian Federation, 190103
    • Local Institution
  • St. Petersburg, Russian Federation, 191167
    • Local Institution
  • St. Petersburg, Russian Federation, 191163
    • Local Institution
• South Africa
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0001
      • Local Institution
  • Western Cape
    • Bellville, Western Cape, South Africa, 7530
      • Local Institution
    • N1 City Goodwood, Western Cape, South Africa, 7463
      • Local Institution
• Turkey
  • Bornova Izmir, Turkey, 35100
    • Local Institution
  • Cebeci Ankara, Turkey, 06620
    • Local Institution
  • Sihhiye Ankara, Turkey, 06100
    • Local Institution
  • Trabzon, Turkey, 61080
    • Local Institution
• United States
  • California
    • Los Angeles, California, United States, 90017
      • Sergio E. Rojter
    • San Diego, California, United States, 92105
      • Tuan Nguyen, Md
    • San Jose, California, United States, 95128
      • San Jose Gastroenterology
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Digestive Healthcare of Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Gastroenterology Associates
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Digestive Disease Associates, P.A.
    • Laurel, Maryland, United States, 20707
      • Maryland Digestive Disease Research, Llc
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • New York
    • Flushing, New York, United States, 11355
      • Sing Chan, MD
    • Manhasset, New York, United States, 11030
      • North Shore University
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10016
      • Concorde Medical Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TDF 0.5 mg; TDF=tenofovir	Drug: Entecavir; Tablets, Oral, ETV = 0.5 mg, once daily, 100 weeks; Other Names: Baraclude; BMS-200475
Experimental: ETV 0.5 mg +TDF 300 mg; ETV=entecavir; TDF=tenofovir	Drug: Entecavir + Tenofovir; Tablets, Oral, ETV = 0.5 mg + TFV = 300 mg, once daily, 100 weeks; Other Names: Baraclude; BMS-200475

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Lok AS, Trinh H, Carosi G, Akarca US, Gadano A, Habersetzer F, Sievert W, Wong D, Lovegren M, Cohen D, Llamoso C. Efficacy of entecavir with or without tenofovir disoproxil fumarate for nucleos(t)ide-naive patients with chronic hepatitis B. Gastroenterology. 2012 Sep;143(3):619-628.e1. doi: 10.1053/j.gastro.2012.05.037. Epub 2012 May 27.

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: December 11, 2006
• First Submitted That Met QC Criteria: December 11, 2006
• First Posted (Estimate): December 12, 2006

Study Record Updates

• Last Update Posted (Estimate): March 15, 2013
• Last Update Submitted That Met QC Criteria: March 13, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir; Entecavir
• Other Study ID Numbers: AI463-110