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A Study in Korea of Entecavir Versus Lamivudine in Adults With Chronic Hepatitis B Infection

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ClinicalTrials.gov Identifier: NCT00393484
Recruitment Status : Completed
First Posted : October 27, 2006
Results First Posted : November 18, 2010
Last Update Posted : November 26, 2014
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Chronic Hepatitis B
Interventions Drug: Entecavir
Drug: Lamivudine Placebo
Drug: Lamivudine
Drug: Entecavir Placebo
Enrollment 122
Recruitment Details  
Pre-assignment Details A total of 122 participants were enrolled in this study; 2 did not receive treatment.
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period). Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Period Title: Double-blind Period (Day 1 to Week 96)
Started 56 [1] 64 [1]
Participants Excluded From Analysis 1 1
Completed 54 52
Not Completed 2 12
Reason Not Completed
Adverse Event             0             1
Withdrawal by Subject             2             0
No longer met inclusion criteria             0             3
Lack of Efficacy             0             6
Lost to Follow-up             0             2
[1]
Number treated
Period Title: Open-label Period (Weeks 96 to 240)
Started 48 44
Withdrew Consent 6 [1] 6 [1]
Lack of Efficacy 0 [1] 2 [1]
Completed 40 21
Not Completed 8 23
Reason Not Completed
Withdrawal by Subject             4             1
Death             1             0
Lost to Follow-up             1             2
Noncompliance             2             2
Lack of Efficacy             0             18
[1]
Did not participate in open-label period
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo Total
Hide Arm/Group Description Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period). Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period). Total of all reporting groups
Overall Number of Baseline Participants 56 64 120
Hide Baseline Analysis Population Description
All participants who received study drug
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 56 participants 64 participants 120 participants
45.73  (11.93) 48.98  (7.84) 47.46  (10.05)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 56 participants 64 participants 120 participants
Female
9
  16.1%
16
  25.0%
25
  20.8%
Male
47
  83.9%
48
  75.0%
95
  79.2%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Korea, Republic of Number Analyzed 56 participants 64 participants 120 participants
56 64 120
Prior interferon treatment status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 56 participants 64 participants 120 participants
No 54 64 118
Yes 2 0 2
Hepatitis B virus DNA by polymerase chain reaction  
Mean (Standard Deviation)
Unit of measure:  Log10 copies/mL
Number Analyzed 56 participants 64 participants 120 participants
6.06  (0.78) 5.79  (0.90) 5.91  (0.86)
Alanine aminotransferase  
Mean (Standard Deviation)
Unit of measure:  U/L
Number Analyzed 56 participants 64 participants 120 participants
110.46  (81.97) 93.94  (58.46) 101.65  (70.59)
1.Primary Outcome
Title Percentage of Participants Who Achieved a Virologic Response at Week 24
Hide Description Virologic response=Hepatitis B virus DNA <300 copies/mL by polymerase chain reaction assay.
Time Frame At Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Percentage of participants
92.86 67.19
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments A sample size of 60 per group provides 80% power for testing superiority of entecavir compared to lamivudine, assuming a response rate of 62% for lamivudine and 83% for entecavir.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The difference in proportion along with its standard error and 90% confidence interval was computed. If the lower limit of the confidence interval (CI) was great than -10%, noninferiority was established. Provided that noninferiority was established, a test for superiority was planned to check that the lower limit of the 90% CI was greater than zero.
Statistical Test of Hypothesis P-Value 0.0006
Comments There was no adjustment for the prior test of noninferiority because the test for superiority could succeed only if noninferiority was first established.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in proportion
Estimated Value 25.67
Confidence Interval (2-Sided) 90%
14.48 to 36.86
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants With Hepatitis B Virus (HBV) DNA <10^3, <10^4, or < 10^5 Copies/mL by Polymerase Chain Reaction (PCR) Assy at Weeks 24, 48, and 96
Hide Description The number and percentage of participants achieving the following endpoints will be tabulated at each visit through Week 240 by treatment group: HBV DNA <300 copies/mL by PCR assay; HBV DNA <10^3, <10^4, or < 10^5 copies/mL by PCR assay. Treatment comparisons will be assessed using the same method as the primary endpoint.
Time Frame At Weeks 24, 48, and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
Week 24: HBV DNA <10^3 54 46
Week 24: HBV DNA <10^4 54 53
Week 24: HBV DNA <10^5 54 59
Week 48: HBV DNA <10^3 54 45
Week 48: HBV DNA <10^4 55 50
Week 48: HBV DNA <10^5 55 52
Week 96: HBV DNA <10^3 53 38
Week 96: HBV DNA <10^4 53 42
Week 96: HBV DNA <10^5 53 45
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^3 copies/mL at 24 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments Treatment comparisons were assessed using the same method used in the primary endpoint.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 24.55
Confidence Interval (2-Sided) 90%
14.45 to 34.66
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^4 copies/mL at 24 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0167
Comments Treatment comparisons were assessed using the same method as the primary endpoint.
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 13.62
Confidence Interval (2-Sided) 90%
4.85 to 22.38
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^5 at 24 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4467
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 4.24
Confidence Interval (2-Sided) 90%
-2.62 to 11.10
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^3 copies/mL at 48 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 26.12
Confidence Interval (2-Sided) 90%
15.87 to 36.36
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^4 copies/mL at 48 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0009
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 20.09
Confidence Interval (2-Sided) 90%
11.10 to 29.07
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^5 at 48 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0029
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 16.96
Confidence Interval (2-Sided) 90%
8.43 to 25.50
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^3 copies/mL at 96 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 35.27
Confidence Interval (2-Sided) 90%
24.02 to 46.51
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^4 copies/mL at 96 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 29.02
Confidence Interval (2-Sided) 90%
18.07 to 39.97
Estimation Comments [Not Specified]
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments HBV DNA <10^5 copies/mL at 96 Weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0006
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 24.33
Confidence Interval (2-Sided) 90%
13.71 to 34.95
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Mean Log10 Reduction From Baseline in Hepatitis B Virus (HBV) DNA at Weeks 24, 48, 96, 144, 192, and 240
Hide Description Mean log10 reduction from Baseline in HBV DNA virus by the Roche Comprehensive Bio-Analytical System Amplicor polymerase chain reaction (PCR) assay at Week 24. The extent of the decrease was estimated by comparing HBV DNA levels of all participants in each group with a linear regression model with covariates of treatment and baseline HBV DNA by PCR assay.
Time Frame At Weeks 24, 48, 96, 144, 192, and 240
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg+ Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Mean (Standard Deviation)
Unit of Measure: log10 copies/mL
At 24 Weeks 3.58  (0.60) 2.95  (0.69)
At 48 Weeks 3.56  (0.53) 2.65  (0.61)
At 96 Weeks 3.59  (0.52) 2.42  (0.60)
At 144 Weeks -3.60  (0.60) -2.74  (0.70)
At 192 Weeks -3.60  (0.63) -2.75  (0.73)
At 240 Weeks -3.53  (0.85) -2.69  (0.98)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg+ Placebo
Comments Changes from baseline were based on patients with measurements at both Baseline and Week 24.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Treatment comparisons were based on 2-sided t-test for treatment difference (entecavir: lamivudine) estimated from the linear regression model with covariates of treatment and baseline hepatitis B DNA by PCR.
Method unpaired t-test
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg+ Placebo
Comments Changes from Baseline were based on patients with measurements at both Baseline and at Week 48.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Treatment comparisons were based on 2-sided t-test for treatment difference (entecavir: lamivudine) estimated from the linear regression model with covariants of treatment and Baseline hepatitis B DNA by PCR.
Method unpaired t-test
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg+ Placebo
Comments Changes from Baseline were based on patients with measurements at both Baseline and at 96 Weeks.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Treatment comparisons were based on 2-sided t-test for treatment difference (entecavir: lamivudine) estimated from the linear regression model with covariants of treatment and Baseline hepatitis B DNA by PCR.
Method unpaired t-test
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg+ Placebo
Comments Changes from Baseline were based on patients with measurements at both Baseline and at Week 144.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Treatment comparisons were based on 2-sided t-test for treatment difference (entecavir: lamivudine) estimated from the linear regression model with covariants of treatment and Baseline hepatitis B DNA by PCR.
Method unpaired t-test
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg+ Placebo
Comments Changes from Baseline were based on patients with measurements at both Baseline and at Week 192.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Treatment comparisons were based on 2-sided t-test for treatment difference (entecavir: lamivudine) estimated from the linear regression model with covariants of treatment and Baseline hepatitis B DNA by PCR.
Method unpaired t-test
Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg+ Placebo
Comments Changes from Baseline were based on patients with measurements at both Baseline and at Week 240.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Treatment comparisons were based on 2-sided t-test for treatment difference (entecavir: lamivudine) estimated from the linear regression model with covariants of treatment and Baseline hepatitis B DNA by PCR.
Method unpaired t-test
Comments [Not Specified]
4.Secondary Outcome
Title Mean Laboratory Test Values for Alanine Aminotransferase (ALT) at Week 24
Hide Description Mean ALT values from baseline by laboratory test. .
Time Frame At Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Mean (Standard Deviation)
Unit of Measure: U/L
31.5  (14.04) 43.26  (32.08)
5.Secondary Outcome
Title Number of Participants With Normalization of Serum Alanine Aminotransferase (ALT) Levels at Weeks 24, 48, and 96
Hide Description Normalization of serum ALT= ≤*institutional upper limit of normal.
Time Frame At Weeks 24, 48, and 96
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
At 24 Weeks 43 37
At 48 Weeks 48 38
At 96 Weeks 49 33
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0278
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 18.97
Confidence Interval (2-Sided) 90%
5.22 to 32.73
Estimation Comments At 24 Weeks
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 26.34
Confidence Interval (2-Sided) 90%
13.65 to 39.03
Estimation Comments At 48 Weeks
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 35.94
Confidence Interval (2-Sided) 90%
23.35 to 48.52
Estimation Comments At 96 Weeks
6.Secondary Outcome
Title Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Most Common AEs, and Grade 3/4 AEs at Week 24
Hide Description AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Most common AEs=AEs affecting ≥3 participants. Grade 3 (Severe)/Grade 4 (Very Severe)AEs per World Health Organization (WHO) criteria.Serious adverse events/deaths reported for enrolled patients regardless of treatment status.
Time Frame Start of dosing (Day 1) until end of treatment (Week 24) + 5 days and to end of 24-week follow-up period
Hide Outcome Measure Data
Hide Analysis Population Description
Treated cohort: includes participants who are randomized and received at least 1 dose of study drug (ETV or LVD).
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
Deaths 0 0
SAEs 0 3
Discontinuations Due to AEs 0 1
Any AEs 14 23
Most common AEs: Upper Respiratory Infection 3 7
Most common AEs: Nasopharyngitis 1 4
Most common AEs: Urticaria 0 3
WHO Grade 3/4 AEs 0 0
7.Secondary Outcome
Title Number of Participants With Elevations in Alanine Transaminase (ALT) and Aspartate Aminoaminase (AST) Levels, Elevations in ALT and AST Levels,Simultaneous Elevations in ALT and Total Bilirubin Levels, and ALT Flares at Week 24
Hide Description ALT flares=ALT>2*Baseline and 10*upper limit of normal. Serious adverse events/deaths reported for enrolled patients regardless of treatment status.
Time Frame Start of dosing (Day 1) until end of treatment (24 weeks) + 5 days and to end of 24-week follow-up period
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
ALT elevations >2*Baseline (BL) 0 1
AST elevations >2*BL 0 1
ALT elevations >3*BL & AST elevations >2*BL 0 1
Simultaneous ALT & Total bilirubin elevation 0 0
ALT flares 0 0
8.Secondary Outcome
Title Number of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results by World Health Organization (WHO) Criteria at Week 24
Hide Description ULN=upper limit of normal; ALT=alanine transaminase. WHO criteria: Grade 3=Severe (inability to carry out usual activity); Grade 4=Very severe (debilitating or significantly incapacitating patient despite symptomatic treatment).
Time Frame Start of dosing (Day 1) until end of treatment (Week 24) + 5 days and to the end of the 24-week follow-up period
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
Gr 4 Prothrombin time (>3*ULN) 1 0
Gr 3 Glucose (251-500 mg/dL) 1 2
Gr 3 ALT (5.1-10*ULN) 0 1
Gr 3 Lipase (2.0-5.0*ULN) 0 1
9.Secondary Outcome
Title Number of Participants With Clinically or Statistically Significant Changes in Vital Sign Measurements at Week 24
Hide Description Vital signs assessed included blood pressure, heart rate, body temperature, and respiration rate.
Time Frame Start of dosing (Day 1) until end of treatment (Week 24) + 5 days and to end of 24-week follow-up period
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
0 0
10.Secondary Outcome
Title Number of Participants With Virologic Rebound at Week 24
Hide Description Virologic rebound was defined as a confirmed ≥1 log10 increase in hepatitis B virus (HBV) DNA from nadir on blinded treatment (as determined by 2 sequential HBV DNA measurements or last on-treatment measurement).
Time Frame At Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily for up to 240 weeks
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
0 3
11.Secondary Outcome
Title Percentage of Participants With a Virologic Response as Defined by Undetectable Hepatitis B Virus DNA at Weeks 48, 96, 144, 192, and 240
Hide Description Undetectable HBV DNA= <300 copies/mL by polymerase chain reaction assay
Time Frame At Weeks 48, 96, 144, 192, and 240
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Percetage of participants
At 48 Weeks 94.64 60.94
At 96 Weeks 94.64 48.44
At 144 Weeks 67.86 34.38
At 192 Weeks 69.64 25.00
At 240 Weeks 67.86 15.63
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 33.71
Confidence Interval (2-Sided) 90%
22.52 to 44.89
Estimation Comments At 48 Weeks
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 46.21
Confidence Interval (2-Sided) 90%
34.80 to 57.61
Estimation Comments At 96 Weeks
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 33.48
Confidence Interval (2-Sided) 90%
19.31 to 47.65
Estimation Comments At 144 Weeks
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 44.64
Confidence Interval (2-Sided) 90%
31.17 to 58.11
Estimation Comments At 192 Weeks
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference
Estimated Value 52.23
Confidence Interval (2-Sided) 90%
39.54 to 64.93
Estimation Comments At 240 Weeks
12.Secondary Outcome
Title Number of Participants With Viral Rebound and Drug-resistant Hepatitis B Virus (HBV) DNA Mutations at Week 96
Hide Description Virologic rebound was defined as a confirmed ≥1 log10 increase in HBV DNA from nadir on blinded treatment (as determined by 2 sequential HBV DNA values or last on-treatment measurement).
Time Frame At 96 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received study drug and who had samples of measureable HBV DNA values
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 55 61
Measure Type: Number
Unit of Measure: Participants
Viral rebound 1 26
Drug-resistant mutations 0 13
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Entecavir, 0.5 mg + Placebo, Lamivudine, 100 mg + Placebo
Comments Viral rebound at 96 weeks
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
13.Secondary Outcome
Title Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Most Common AEs, and Grade 3/4 AEs at Week 240
Hide Description AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
Time Frame Start of dosing (Day 1) until end of treatment (Week 240) + 5 days
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were randomized and received at least 1 dose of study drug
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 56 64
Measure Type: Number
Unit of Measure: Participants
SAEs 7 17
Discontinuations due to AEs 0 1
Any nonserious AEs 48 49
Nonserious AEs related to study conditions 1 6
SAEs related to study conditions 0 0
14.Secondary Outcome
Title Number of Participants With Grade 3 or 4 Abnormalities in Laboratory Test Results by World Health Organization (WHO) Criteria at Week 96
Hide Description ULN=upper limit of normal; ALT=alanine transaminase. WHO criteria: Grade 3=Severe (inability to carry out usual activity); Grade 4=Very severe (debilitating or significantly incapacitating patient despite symptomatic treatment).
Time Frame Start of dosing (Day 1) until Week 96
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized participants who received at least 1 dose of study drug and who were evaluable.
Arm/Group Title Entecavir, 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description:
Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
Overall Number of Participants Analyzed 55 62
Measure Type: Number
Unit of Measure: Participants
Platelets 1 1
Prothrombin time 1 0
Neutrophils 0 1
AST 0 3
ALT 0 6
Total bilirubiin 1 3
Creatinine 2 0
Lipase 2 4
Potassium 0 1
Glucose, fasting 3 2
Time Frame Start of dosing (Day 1) until end of treatment (Week 240) + 5 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Entecavir , 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Hide Arm/Group Description Participants received entecavir, 0.5 mg, once daily, with lamivudine placebo tablets, once daily, administered orally through Week 96 (double-blind period). Then, participants received entecavir, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period). Participants received lamivudine, 100 mg, once daily, with entecavir placebo tablets, once daily, administered orally, through Week 96 (double-blind period). Then, participants received lamivudine, 0.5 mg, once daiy, administered orally for Weeks 96-240 (open-label period).
All-Cause Mortality
Entecavir , 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Entecavir , 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   7/56 (12.50%)   17/64 (26.56%) 
Eye disorders     
Optic neuropathy   1/56 (1.79%)  0/64 (0.00%) 
Gastrointestinal disorders     
Colonic polyp   0/56 (0.00%)  1/64 (1.56%) 
Hepatobiliary disorders     
Gallbladder polyp   1/56 (1.79%)  1/64 (1.56%) 
Cholelithiasis   0/56 (0.00%)  1/64 (1.56%) 
Infections and infestations     
Cellulitis   0/56 (0.00%)  1/64 (1.56%) 
Injury, poisoning and procedural complications     
Subdural hemorrhage   2/56 (3.57%)  0/64 (0.00%) 
Rib fracture   1/56 (1.79%)  1/64 (1.56%) 
Foot fracture   0/56 (0.00%)  1/64 (1.56%) 
Cerebral vertebral fracture   0/56 (0.00%)  1/64 (1.56%) 
Upper limb fracture   0/56 (0.00%)  1/64 (1.56%) 
Investigations     
Blood glucose increased   1/56 (1.79%)  0/64 (0.00%) 
Red blood cell count decreased   0/56 (0.00%)  1/64 (1.56%) 
Musculoskeletal and connective tissue disorders     
Tibia fracture   1/56 (1.79%)  0/64 (0.00%) 
Intervertebral disc herniation   0/56 (0.00%)  1/64 (1.56%) 
Back pain   0/56 (0.00%)  1/64 (1.56%) 
Pain in extremity   0/56 (0.00%)  1/64 (1.56%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Hepatic neoplasm malignant   1/56 (1.79%)  1/64 (1.56%) 
Liposarcoma recurrent   1/56 (1.79%)  0/64 (0.00%) 
Uterine leiomyoma   0/56 (0.00%)  1/64 (1.56%) 
Pituitary tumor benign   0/56 (0.00%)  1/64 (1.56%) 
Chondrosarcoma   0/56 (0.00%)  1/64 (1.56%) 
Adenocarcinoma   0/56 (0.00%)  1/64 (1.56%) 
Gastric cancer   0/56 (0.00%)  1/64 (1.56%) 
Nervous system disorders     
Hydrocephalus   1/56 (1.79%)  0/64 (0.00%) 
Subarachnoid hemorrhage   1/56 (1.79%)  0/64 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Cough   0/56 (0.00%)  1/64 (1.56%) 
Vascular disorders     
Deep vein thrombosis   0/56 (0.00%)  1/64 (1.56%) 
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Entecavir , 0.5 mg + Placebo Lamivudine, 100 mg + Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   28/56 (50.00%)   29/64 (45.31%) 
Gastrointestinal disorders     
Colonic polyp   0/56 (0.00%)  3/64 (4.69%) 
Reflux esophagitis   3/56 (5.36%)  2/64 (3.13%) 
Gastritis   5/56 (8.93%)  2/64 (3.13%) 
Dyspepsia   3/56 (5.36%)  2/64 (3.13%) 
General disorders     
Fatigue   5/56 (8.93%)  6/64 (9.38%) 
Infections and infestations     
Upper respiratory tract infection   9/56 (16.07%)  12/64 (18.75%) 
Nasopharyngitis   6/56 (10.71%)  6/64 (9.38%) 
Investigations     
Blood glucose increased   0/56 (0.00%)  3/64 (4.69%) 
Hepatic enzyme increased   0/56 (0.00%)  3/64 (4.69%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal pain   2/56 (3.57%)  3/64 (4.69%) 
Psychiatric disorders     
Insomnia   2/56 (3.57%)  3/64 (4.69%) 
Skin and subcutaneous tissue disorders     
Dermatitis, contact   1/56 (1.79%)  3/64 (4.69%) 
Indicates events were collected by systematic assessment
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: NCT00393484     History of Changes
Other Study ID Numbers: AI463-105
First Submitted: October 26, 2006
First Posted: October 27, 2006
Results First Submitted: October 21, 2010
Results First Posted: November 18, 2010
Last Update Posted: November 26, 2014