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

Hepatitis B, Chronic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00410072
• Other study ID #: AI463-110
• Status: Completed
• Phase: Phase 3
• First received: December 11, 2006
• Last updated: March 13, 2013
• Start date: April 2007
• Est. completion date: October 2010

Study information

• Verified date: March 2013
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 669
• Est. completion date: October 2010
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Entecavir
Tablets, Oral, ETV = 0.5 mg, once daily, 100 weeks
• Entecavir + Tenofovir
Tablets, Oral, ETV = 0.5 mg + TFV = 300 mg, once daily, 100 weeks

Locations

Country	Name	City	State
Argentina	Local Institution	Ciudad De Buenos Aires	Buenos Aires
Argentina	Local Institution	Ciudad De Buenos Aires	Buenos Aires
Argentina	Local Institution	Ciudad De Buenos Aires	Buenos Aires
Argentina	Local Institution	Rosario	Prov De Santa
Australia	Local Institution	Clayton Vic	Victoria
Australia	Local Institution	Fitzroy	Victoria
Australia	Local Institution	Heidelberg	Victoria
Australia	Local Institution	Prahan	Victoria
Australia	Local Institution	Westmead Nsw	New South Wales
Brazil	Local Institution	Belo Horizonte	Minas Gerais
Brazil	Local Institution	Porto Alegre Rs	Rio Grande Do Sul
Canada	Local Institution	Calgary	Alberta
Canada	Local Institution	Toronto	Ontario
Canada	Local Institution	Toronto	Ontario
Canada	Local Institution	Toronto	Ontario
Canada	Local Institution	Vancouver	British Columbia
Canada	Local Institution	Winnipeg	Manitoba
France	Local Institution	Grenoble Cedex 09
France	Local Institution	Marseille Cedex 08
France	Local Institution	Paris
France	Local Institution	Paris Cedex 12
France	Local Institution	Paris Cedex 13
France	Local Institution	Strasbourg
India	Local Institution	Hyderabad	Andhra Pradesh
India	Local Institution	Lucknow
India	Local Institution	Ludhiana
India	Local Institution	Vellore
Italy	Local Institution	Antella Firenze
Italy	Local Institution	Brescia
Italy	Local Institution	Pisa
Italy	Local Institution	Roma
Mexico	Local Institution	Durango
Poland	Local Institution	Bialystok
Poland	Local Institution	Chorzow
Poland	Local Institution	Krakow
Poland	Local Institution	Lublin
Poland	Local Institution	Warszawa
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Smolensk
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
South Africa	Local Institution	Bellville	Western Cape
South Africa	Local Institution	N1 City Goodwood	Western Cape
South Africa	Local Institution	Pretoria	Gauteng
Turkey	Local Institution	Bornova Izmir
Turkey	Local Institution	Cebeci Ankara
Turkey	Local Institution	Sihhiye Ankara
Turkey	Local Institution	Trabzon
United States	University Of Michigan Health System	Ann Arbor	Michigan
United States	Atlanta Gastroenterology Associates	Atlanta	Georgia
United States	Digestive Healthcare Of Georgia	Atlanta	Georgia
United States	Digestive Disease Associates, P.A.	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Sing Chan, Md	Flushing	New York
United States	Maryland Digestive Disease Research, Llc	Laurel	Maryland
United States	Sergio E. Rojter	Los Angeles	California
United States	North Shore University	Manhasset	New York
United States	University Of Miami	Miami	Florida
United States	Yale University School Of Medicine	New Haven	Connecticut
United States	Beth Israel Medical Center	New York	New York
United States	Concorde Medical Group	New York	New York
United States	Mount Sinai School Of Medicine	New York	New York
United States	Tuan Nguyen, Md	San Diego	California
United States	San Jose Gastroenterology	San Jose	California

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  France,  India,  Italy,  Mexico,  Poland,  Russian Federation,  South Africa,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
•   Investigator Inquiry form