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

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ClinicalTrials.gov Identifier: NCT00410072
Recruitment Status : Completed
First Posted : December 12, 2006
Results First Posted : February 3, 2012
Last Update Posted : March 15, 2013
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hepatitis B, Chronic
Interventions Drug: Entecavir
Drug: Entecavir + Tenofovir
Enrollment 669
Recruitment Details  
Pre-assignment Details 669 participants were enrolled; 384 were randomized. Among 285 who were not randomized, 266 did not meet the study criteria, 11 other, 1 poor compliance/noncompliance, 4 lost to follow-up, 1 withdrew consent, and 2 for administrative reasons.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Period Title: Day 1 to Week 48
Started 182 [1] 197 [2]
Completed 176 185
Not Completed 6 12
Reason Not Completed
Adverse Event             1             2
Lost to Follow-up             5             2
Not specified             0             1
poor compliance/noncompliance             0             3
Pregnancy             0             2
Withdrawal by Subject             0             2
[1]
Number of participants randomized and treated; 4 more were randomized but not treated.
[2]
Number of participants randomized and treated; 1 more was randomized but not treated.
Period Title: After Week 48 to Week 96
Started 176 185
Completed 170 174
Not Completed 6 11
Reason Not Completed
Adverse Event             1             2
Death             0             1
Lack of Efficacy             1             0
Lost to Follow-up             2             4
Not specified             2             0
Poor compliance/noncompliance             0             1
Pregnancy             0             2
Withdrawal by Subject             0             1
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg Total
Hide Arm/Group Description Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks Total of all reporting groups
Overall Number of Baseline Participants 182 197 379
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
16 - 20 years 13 19 32
21 - 64 years 157 169 326
>=65 years 12 9 21
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
Female
66
  36.3%
51
  25.9%
117
  30.9%
Male
116
  63.7%
146
  74.1%
262
  69.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
Asian 84 102 186
Black/African American 10 4 14
Native Hawaiian/Other Pacific Islander 1 1 2
White 83 87 170
Other 4 3 7
Country  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
United States 35 43 78
Turkey 11 11 22
Russian Federation 24 23 47
Italy 12 15 27
India 5 9 14
France 8 5 13
Canada 29 33 62
Argentina 12 15 27
Poland 15 13 28
Brazil 5 3 8
Australia 24 24 48
South Africa 2 3 5
Region  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
Africa 2 3 5
Asia 29 33 62
Europe 70 67 137
North America 64 76 140
South America 17 18 35
Hepatitis B e antibody (HBeAb) at baseline  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
Positive 60 60 120
Negative 122 137 259
Hepatitis B e antigen (HBeAg) status at baseline  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
Positive (> 172,000 IU/mL; approx 10^6 copies/mL) 126 138 264
Negative (> 17,200 IU/mL; approx 10^5 copies/mL) 56 59 115
Hepatitis B surface antigen (HBsAg) status at baseline  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 182 participants 197 participants 379 participants
Positive 182 196 378
Negative 0 1 1
1.Primary Outcome
Title Percentage of Participants Who Achieved Hepatitis B Virus DNA (HBV DNA) Levels <50 IU/mL by Polymerase Chain Reaction (PCR) at Week 96
Hide Description 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.
Time Frame At Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and is counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Measure Type: Number
Unit of Measure: Percentage of participants
76.4 83.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Week 96
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0882
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 6.9
Confidence Interval (2-Sided) 95%
-1.0 to 14.9
Estimation Comments [Not Specified]
2.Secondary Outcome
Title 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
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable participants. If a participant is missing the efficacy assessments for a visit, this is considered a failure and is counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Measure Type: Number
Unit of Measure: Percentage of participants
HBeAg+ at Week 48 (n=126, n=138) 61.1 74.6
HBeAg- at Week 48 (n=56, n=59) 91.1 93.2
HBeAg+ at Week 96 (n=126, n=138) 69.8 80.4
HBeAg- at Week 96 (n=56, n=59) 91.1 89.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 13.5
Confidence Interval (2-Sided) 95%
2.3 to 24.8
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.2
Confidence Interval (2-Sided) 95%
-7.7 to 12.0
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0460
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 10.6
Confidence Interval (2-Sided) 95%
0.2 to 21.0
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.2
Confidence Interval (2-Sided) 95%
-12.0 to 9.5
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants Who Achieved HBV DNA Levels <LOQ by PCR at Weeks 48 and 96
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and is counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Measure Type: Number
Unit of Measure: Percentage of participants
Overall at Week 48 67.6 74.6
Overall at Week 96 74.7 81.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at week 48. The stratified analysis was based on HBeAg strata at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 7.1
Confidence Interval (2-Sided) 95%
-1.8 to 16.0
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at week 96. The stratified analysis was based on HBeAg strata at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 7.1
Confidence Interval (2-Sided) 95%
-1.1 to 15.2
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants Who Achieved HBV DNA Levels <LOD by PCR at Weeks 48 and 96
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and is counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Measure Type: Number
Unit of Measure: Percentage of participants
Overall at Week 48 58.2 66.0
Overall at Week 96 68.1 76.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 48. The stratified analysis was based on HBeAg strata at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 7.8
Confidence Interval (2-Sided) 95%
-1.5 to 17.1
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 96. The stratified analysis was based on HBeAg strata at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 8.6
Confidence Interval (2-Sided) 95%
-0.2 to 17.3
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Mean Log 10 HBV DNA at Weeks 48 and 96
Hide Description HBV DNA was analyzed by PCR, using the Roche COBAS®TaqMan - HPS assay. Reduction in Log 10 HBV count=reduced viral load.
Time Frame Baseline, Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable participants at given time point. If a participant is missing the efficacy assessments for a visit, this is considered a failure and is counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Mean (Standard Error)
Unit of Measure: log10 copies/mL
Baseline (n=182, 197) 7.48  (0.109) 7.53  (0.100)
Overall at Week 48 (n=176, 180) 1.88  (0.065) 1.56  (0.026)
Overall at Week 96 (n=165, 170) 1.68  (0.048) 1.51  (0.038)
6.Secondary Outcome
Title Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Weeks 48 and 96
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable participants. A participant missing the efficacy assessments for a visit is considered a failure and counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Measure Type: Number
Unit of Measure: Percentage of participants
Overall at Week 48 83.0 72.6
Overall at Week 96 81.9 68.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 48. The stratified analysis is based on HBeAg strata at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC+F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -10.4
Confidence Interval (2-Sided) 95%
-18.8 to -2.0
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 96. The stratified analysis is based on HBeAg strata at randomization.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.8
Confidence Interval (2-Sided) 95%
-21.5 to -4.1
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Weeks 48 and 96
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Treated HBeAg-positive participants. If a participant was missing the efficacy assessments for a visit, this is considered a failure and was counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 126 138
Measure Type: Number
Unit of Measure: Percentage of participants
Week 48 25.4 19.6
Week 96 3.97 29.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 48
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.8
Confidence Interval (2-Sided) 95%
-15.9 to 4.2
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 96
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -9.2
Confidence Interval (2-Sided) 95%
-20.6 to 2.3
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Percentage of Participants With HBeAg Seroconversion [( at Weeks 48 and 96
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Treated HBeAg-positive participants. A participant missing the efficacy assessments for a visit was considered a failure and was counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 126 138
Measure Type: Number
Unit of Measure: Percentage of participants
Week 48 22.2 18.1
Week 96 32.5 21.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 48
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.1
Confidence Interval (2-Sided) 95%
-13.8 to 5.6
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 96
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -10.8
Confidence Interval (2-Sided) 95%
-21.5 to -0.1
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48 and 96
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Treated HBeAg-positive participants. If a participant was missing the efficacy assessments for a visit, this is considered a failure and was counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 126 138
Measure Type: Number
Unit of Measure: Percent of participants
Week 48 3.2 1.4
Week 96 4.0 5.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 48
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.7
Confidence Interval (2-Sided) 95%
-5.3 to 1.9
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 96
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.1
Confidence Interval (2-Sided) 95%
-3.9 to 6.1
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Percentage of Participants With HBsAg Seroconversion at Weeks 48 and 96
Hide Description HBsAg = a part of the hepatitis B virus that, when in the blood, is an early marker of infection.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Treated HBeAg-positive participants. If a participant was missing the efficacy assessments for a visit, this is considered a failure and was counted as evaluable.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 126 138
Measure Type: Number
Unit of Measure: Percentage of participants
Week 48 0.8 0.7
Week 96 1.6 2.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 48
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-2.2 to 2.0
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ETV 0.5 mg, ETV 0.5 mg +TDF 300 mg
Comments Analysis at Week 96
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method NC=F
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.3
Confidence Interval (2-Sided) 95%
-2.3 to 4.9
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Number of Participants With HBV DNA in Relevant Categories at Weeks 48 and 96
Hide Description 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.
Time Frame At Weeks 48 and 96
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Measure Type: Number
Unit of Measure: Percentage of participants
< LOQ (29 IU/mL) at Week 48 67.6 74.6
LOQ - <50 IU/mL at Week 48 2.7 5.6
50 - <172 IU/mL at Week 48 7.1 6.6
172 - <1720 IU/mL at Week 48 7.7 4.1
1720 - <17,200 IU/mL at Week 48 9.3 0.5
17,200 - <172,000 IU/mL at Week 48 1.6 0
≥172,000 IU/mL at Week 48 0.5 0
Missing at Week 48 3.3 8.6
< LOQ (29 IU/mL) at Week 96 74.7 81.7
LOQ - <50 IU/mL at Week 96 1.6 1.5
50 - <172 IU/mL at Week 96 3.3 1.0
172 - <1720 IU/mL at Week 96 5.5 1.5
1720 - <17,200 IU/mL at Week 96 4.9 0
17,200 - <172,000 IU/mL at Week 96 0.5 0
≥172,000 IU/mL at Week 96 0 0.5
Missing at Week 96 9.3 13.7
12.Secondary Outcome
Title Number of Participants With Adverse Events, Serious Adverse Events, and Discontinuations From Study Drug Due to Adverse Events or Laboratory Abnormalities
Hide Description 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.
Time Frame From enrollment through Week 100 + 24-week follow-up
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Hide Analysis Population Description
All treated participants.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 182 197
Measure Type: Number
Unit of Measure: Participants
Deaths 0 3
SAEs 12 14
Adverse events 132 131
Discontinuations due to AEs 2 5
Related AEs 39 49
13.Secondary Outcome
Title Number of Participants With HBV Resistance Through Week 48
Hide Description 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.
Time Frame Week 48
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Hide Analysis Population Description
All participants who received study drug and with HBV DNA levels >=50 IU/mL
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 51 33
Measure Type: Number
Unit of Measure: Participants
ETVr 0 0
TDFr 0 0
14.Secondary Outcome
Title Number of Participants With HBV Resistance at Week 96
Hide Description 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.
Time Frame Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received study drug and with HBV DNA levels >=50 IU/mL.
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 33 10
Measure Type: Number
Unit of Measure: Participants
ETVr 0 0
TDFr 0 0
15.Secondary Outcome
Title Number of Participants With Virologic Breakthrough at Week 48
Hide Description ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough= confirmed >= 1 log10 increase in HBV DNA from the on-treatment nadir
Time Frame Week 48
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with confirmed >=1 log10 increase in HBV DNA from the on-treatment nadir
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 1 7
Measure Type: Number
Unit of Measure: Participants
ETVr 0 0
TDFr 0 0
16.Secondary Outcome
Title Number of Participants With Virologic Breakthrough at Week 96
Hide Description ETVr=entecavir resistance; TFDr=tenofovir resistance. Virologic breakthrough=confirmed >=1 log10 increase in HBV DNA from moving nadir
Time Frame Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with confirmed >= 1 log10 increase in HBV DNA from moving nadir
Arm/Group Title ETV 0.5 mg ETV 0.5 mg +TDF 300 mg
Hide Arm/Group Description:
Entecavir (ETV) 0.5 mg monotherapy given once daily (QD) for 100 weeks
ETV 0.5 mg plus Tenofovir (TDF) 300 mg combination therapy given QD for 100 weeks
Overall Number of Participants Analyzed 1 7
Measure Type: Number
Unit of Measure: Participants
ETVr 0 0
TDFr 0 0
Time Frame Week 0 to Week 100 (on study), Post-dosing follow-up - 24 Weeks
Adverse Event Reporting Description Participants who have study medication completed or discontinued permanently were followed for 24 weeks post-dosing for safety.
 
Arm/Group Title ETV 0.5 mg ETV/TDF 0.5 mg +TDF 300 mg
Hide Arm/Group Description ETV 0.5 mg monotherapy given QD for 100 weeks ETV 0.5 mg plus TDF 300 mg combination therapy given once daily (QD) for 100 weeks
All-Cause Mortality
ETV 0.5 mg ETV/TDF 0.5 mg +TDF 300 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
ETV 0.5 mg ETV/TDF 0.5 mg +TDF 300 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   13/182 (7.14%)   14/197 (7.11%) 
Cardiac disorders     
CARDIAC ARREST  1  0/182 (0.00%)  1/197 (0.51%) 
Gastrointestinal disorders     
COLITIS ULCERATIVE  1  0/182 (0.00%)  1/197 (0.51%) 
OESOPHAGEAL VARICES HAEMORRHAGE  1  0/182 (0.00%)  1/197 (0.51%) 
GASTRIC ULCER HAEMORRHAGE  1  0/182 (0.00%)  1/197 (0.51%) 
PEPTIC ULCER  1  0/182 (0.00%)  1/197 (0.51%) 
DIVERTICULUM INTESTINAL HAEMORRHAGIC  1  1/182 (0.55%)  0/197 (0.00%) 
GASTRIC ULCER  1  0/182 (0.00%)  1/197 (0.51%) 
HAEMORRHOIDS  1  1/182 (0.55%)  0/197 (0.00%) 
Hepatobiliary disorders     
HEPATITIS  1  0/182 (0.00%)  1/197 (0.51%) 
CHOLELITHIASIS  1  1/182 (0.55%)  0/197 (0.00%) 
Infections and infestations     
HEPATITIS A  1  0/182 (0.00%)  1/197 (0.51%) 
HEPATITIS B  1  0/182 (0.00%)  1/197 (0.51%) 
ACUTE SINUSITIS  1  0/182 (0.00%)  1/197 (0.51%) 
Injury, poisoning and procedural complications     
ANKLE FRACTURE  1  0/182 (0.00%)  1/197 (0.51%) 
HAND FRACTURE  1  0/182 (0.00%)  1/197 (0.51%) 
TRAUMATIC BRAIN INJURY  1  0/182 (0.00%)  2/197 (1.02%) 
Investigations     
BLOOD AMYLASE INCREASED  1  1/182 (0.55%)  0/197 (0.00%) 
Metabolism and nutrition disorders     
DIABETIC COMPLICATION  1  1/182 (0.55%)  0/197 (0.00%) 
Musculoskeletal and connective tissue disorders     
SPINAL OSTEOARTHRITIS  1  0/182 (0.00%)  1/197 (0.51%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
HEPATIC NEOPLASM MALIGNANT  1  3/182 (1.65%)  0/197 (0.00%) 
BREAST CANCER  1  0/182 (0.00%)  1/197 (0.51%) 
GASTRIC CANCER  1  1/182 (0.55%)  0/197 (0.00%) 
HEPATIC NEOPLASM  1  0/182 (0.00%)  1/197 (0.51%) 
Nervous system disorders     
CEREBRAL ISCHAEMIA  1  1/182 (0.55%)  0/197 (0.00%) 
CEREBROVASCULAR ACCIDENT  1  1/182 (0.55%)  0/197 (0.00%) 
ISCHAEMIC STROKE  1  1/182 (0.55%)  0/197 (0.00%) 
SUBARACHNOID HAEMORRHAGE  1  1/182 (0.55%)  0/197 (0.00%) 
Psychiatric disorders     
ACUTE PSYCHOSIS  1  1/182 (0.55%)  0/197 (0.00%) 
Reproductive system and breast disorders     
OVARIAN CYST  1  1/182 (0.55%)  0/197 (0.00%) 
Vascular disorders     
RAYNAUD'S PHENOMENON  1  1/182 (0.55%)  0/197 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
ETV 0.5 mg ETV/TDF 0.5 mg +TDF 300 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   69/182 (37.91%)   73/197 (37.06%) 
Gastrointestinal disorders     
DIARRHOEA  1  11/182 (6.04%)  13/197 (6.60%) 
ABDOMINAL PAIN UPPER  1  13/182 (7.14%)  8/197 (4.06%) 
NAUSEA  1  9/182 (4.95%)  20/197 (10.15%) 
General disorders     
FATIGUE  1  11/182 (6.04%)  12/197 (6.09%) 
Infections and infestations     
NASOPHARYNGITIS  1  11/182 (6.04%)  18/197 (9.14%) 
Musculoskeletal and connective tissue disorders     
BACK PAIN  1  13/182 (7.14%)  9/197 (4.57%) 
Nervous system disorders     
HEADACHE  1  19/182 (10.44%)  22/197 (11.17%) 
Respiratory, thoracic and mediastinal disorders     
COUGH  1  7/182 (3.85%)  13/197 (6.60%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: BMS Study Director
Organization: Bristol-Myers Squibb
EMail: Clinical.Trials@bms.com
Layout table for additonal information
Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00410072     History of Changes
Other Study ID Numbers: AI463-110
First Submitted: December 11, 2006
First Posted: December 12, 2006
Results First Submitted: November 4, 2011
Results First Posted: February 3, 2012
Last Update Posted: March 15, 2013