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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00410072
First received: December 11, 2006
Last updated: March 13, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention Phase
Hepatitis B, Chronic
Drug: Entecavir
Drug: Entecavir + Tenofovir
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96 [ Time Frame: At Week 96 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Mean Log 10 HBV DNA at Weeks 48 and 96 [ Time Frame: Baseline, Weeks 48 and 96 ] [ Designated as safety issue: No ]
    HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan - HPS assay. Reduction in Log 10 HBV count=reduced viral load.

  • Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection.

  • Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities [ Time Frame: From enrollment through Week 100 + 24-week follow-up ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With HBV Resistance Through Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With HBV Resistance at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Virologic Breakthrough at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough= confirmed >= 1 log10 increase in HBV DNA from the on-treatment nadir

  • Number of Participants With Virologic Breakthrough at Week 96 [ Time Frame: Week 96 ] [ Designated as safety issue: No ]
    ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough=confirmed >=1 log10 increase in HBV DNA from moving nadir


Enrollment: 669
Study Start Date: April 2007
Study Completion Date: October 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00410072

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

Additional Information:
No publications provided by Bristol-Myers Squibb

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00410072     History of Changes
Other Study ID Numbers: AI463-110
Study First Received: December 11, 2006
Results First Received: November 4, 2011
Last Updated: March 13, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Hepatitis, Chronic
DNA Virus Infections
Digestive System Diseases
Enterovirus Infections
Hepadnaviridae Infections
Hepatitis, Viral, Human
Liver Diseases
Picornaviridae Infections
RNA Virus Infections
Virus Diseases
Entecavir
Tenofovir
Tenofovir disoproxil
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014