A Study to Compare Tenofovir Versus Hepsera (Adefovir) for the Treatment of Hepatitis Be Antigen (HBeAg) Positive Chronic Hepatitis B

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00116805
First received: June 30, 2005
Last updated: October 31, 2011
Last verified: October 2011
Results First Received: February 11, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Chronic Hepatitis B
Interventions: Drug: tenofovir disoproxil fumarate
Drug: adefovir dipivoxil

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
There were 90 enrolling sites in 15 countries. The first participant was screened on 09 June 2005, and the last participant was randomized on 15 June 2006. The last participant observation (LPO) for the primary endpoint analysis (Week 48) was 11 May 2007. The LPO for the Week 96 analysis was 27 May 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Six of the 272 participants who were successfully screened and randomized discontinued prior to the first dose of study drug due to being erroneously randomized via interactive voice response system, withdrawal of consent, loss to follow-up, or failure to meet screening criteria. The screening process involved a liver biopsy.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Participant Flow for 2 periods

Period 1:   Double-blind Period Through Week 48
    TDF 300 mg QD     ADV 10 mg QD  
STARTED     176 [1]   90 [1]
COMPLETED     154 [2]   84 [2]
NOT COMPLETED     22     6  
Lost to Follow-up                 8                 2  
Protocol Violation                 1                 1  
Withdrawal by Subject                 10                 3  
Seroconversion                 2                 0  
Declined extension                 1                 0  
[1] Randomized-and-treated participants
[2] Completed through Week 48 with end-of-double-blind-treatment liver biopsy results

Period 2:   Open-Label TDF Period Through Week 96
    TDF 300 mg QD     ADV 10 mg QD  
STARTED     154 [1]   84 [1]
COMPLETED     145 [2]   83 [2]
NOT COMPLETED     9     1  
Physician Decision                 1                 0  
Lost to Follow-up                 2                 0  
Protocol Violation                 2                 0  
Safety, tolerability, or efficacy reason                 1                 0  
Seroconversion                 1                 0  
Withdrawal by Subject                 2                 1  
[1] Entered the open-label TDF period
[2] Completed through Week 96



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks
Total Total of all reporting groups

Baseline Measures
    TDF 300 mg QD     ADV 10 mg QD     Total  
Number of Participants  
[units: participants]
  176     90     266  
Age  
[units: participants]
     
<=18 years     3     1     4  
Between 18 and 65 years     173     89     262  
>=65 years     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  34  ± 11.3     34  ± 12.2     34  ± 11.6  
Gender  
[units: participants]
     
Female     57     26     83  
Male     119     64     183  
Region of Enrollment  
[units: participants]
     
United States     30     14     44  
Greece     1     2     3  
Spain     7     2     9  
Turkey     10     4     14  
Italy     0     1     1  
United Kingdom     6     1     7  
France     11     3     14  
Czech Republic     3     5     8  
Canada     17     10     27  
Poland     16     8     24  
Australia     22     6     28  
Bulgaria     17     11     28  
Germany     20     8     28  
Netherlands     6     4     10  
New Zealand     10     11     21  
Baseline Alanine Aminotransferase (ALT) above the Upper Limit of the Normal (ULN) Range [1]
[units: Participants]
     
Yes     169     90     259  
No     7     0     7  
Prior Lamivudine or Emtricitabine Exposure [1]
[units: Participants]
     
Yes     8     1     9  
No     168     89     257  
Baseline Hepatitis B Deoxyribonucleic Acid (HBV DNA) [1]
[units: Log10 copies/mL]
Mean ± Standard Deviation
  8.64  ± 1.076     8.88  ± 0.930     8.72  ± 1.033  
Baseline Knodell Necroinflammatory Score [2]
[units: Units on a scale]
Mean ± Standard Deviation
  8.3  ± 2.11     8.5  ± 2.07     8.4  ± 2.09  
[1] Randomized-and-treated analysis set
[2] Randomized-and-treated analysis set. Based on Knodell numerical scoring of liver biopsy specimens. This scale consists of 5 domains (Periportal with or without Bridging Necrosis [scored numerically from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [scored best to worst 0 to 4]; Portal Inflammation [also scored best to worst 0 to 4]; and Fibrosis [also scored best to worst 0 to 4]). The necroinflammatory score is the combined score for Necrosis and Inflammation, excluding the Fibrosis score. Scores may range from 0 (best) to 14 (worst).



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) <400 Copies/mL and Histological Improvement (2-point or Higher Reduction in the Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48   [ Time Frame: Week 48 ]

Measure Type Primary
Measure Title Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) <400 Copies/mL and Histological Improvement (2-point or Higher Reduction in the Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48
Measure Description Complete response was a composite endpoint defined as histological response and HBV DNA below 400 copies/mL. Histological response was defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell scale consists of 5 domains, (Periportal +/- Bridging Necrosis [scored from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [0 to 4]; Portal Inflammation [0 to 4]; and Fibrosis [0 to 4]). The necroinflammatory score is the combined score for necrosis + inflammation (0 [best] to 14 [worst]).
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Based on the randomized-and-treated (RAT) analysis set, which included all participants who were randomized and received at least 1 dose of study drug. A participant was a nonresponder for the primary endpoint if either biopsy (baseline or end-of-blinded treatment) was missing or if there was not an HBV DNA value available at or beyond Week 40.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values
    TDF 300 mg QD     ADV 10 mg QD  
Number of Participants Analyzed  
[units: participants]
  176     90  
Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) <400 Copies/mL and Histological Improvement (2-point or Higher Reduction in the Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48  
[units: Percentage of participants]
  67     12  


Statistical Analysis 1 for Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) <400 Copies/mL and Histological Improvement (2-point or Higher Reduction in the Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] <0.001
Difference in proportions [5] 54.1
Standard Error of the mean ± 4.8
95% Confidence Interval ( 44.6 to 63.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  2-sided 95% confidence interval (CI), stratified by baseline ALT was used to evaluate difference between groups in proportion of complete responders.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted (baseline ALT </=4 x upper limit of the normal range [ULN] or >4 x ULN) difference is 0.
[5] Other relevant estimation information:
  No text entered.



2.  Secondary:   Percentage of Participants With Histological Response at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Percentage of Participants With Histological Response at Week 48
Measure Description Histological response was defined as Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis score. The Knodell scale consists of 5 domains, (Periportal +/- Bridging Necrosis [scored from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [0 to 4]; Portal Inflammation [0 to 4]; and Fibrosis [0 to 4]). The necroinflammatory score is the combined score for necrosis + inflammation (0 [best] to 14 [worst]).
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized-and-treated analysis set; missing-equals-failure approach.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values
    TDF 300 mg QD     ADV 10 mg QD  
Number of Participants Analyzed  
[units: participants]
  176     90  
Percentage of Participants With Histological Response at Week 48  
[units: Percentage of participants]
   
Yes     74     68  
No     26     32  


Statistical Analysis 1 for Percentage of Participants With Histological Response at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.320
Difference in proportions [5] 5.8
Standard Error of the mean ± 5.8
95% Confidence Interval ( -5.6 to 17.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference in zero. Difference, standard error of the difference, and the CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[5] Other relevant estimation information:
  No text entered.



3.  Secondary:   Percentage of Participants With HBV DNA <400 Copies/mL at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Percentage of Participants With HBV DNA <400 Copies/mL at Week 48
Measure Description No text entered.
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized-and-treated analysis set; missing-equals-failure approach

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values
    TDF 300 mg QD     ADV 10 mg QD  
Number of Participants Analyzed  
[units: participants]
  176     90  
Percentage of Participants With HBV DNA <400 Copies/mL at Week 48  
[units: Percentage of participants]
  76     13  


Statistical Analysis 1 for Percentage of Participants With HBV DNA <400 Copies/mL at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] <0.001
Difference in proportions [5] 63.1
Standard Error of the mean ± 4.7
95% Confidence Interval ( 53.8 to 72.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Difference, standard error of the difference, and the CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference in zero.
[5] Other relevant estimation information:
  No text entered.



4.  Secondary:   Percentage of Participants With HBV DNA <400 Copies/mL at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Percentage of Participants With HBV DNA <400 Copies/mL at Week 96
Measure Description Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at Week 96.
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis set included all participants who received at least one dose of open-label TDF (Open-label Extension [OLE] analysis set). Participants with missing values at Week 96 or who added emtricitabine to their open-label TDF regimen were considered failures.

Reporting Groups
  Description
TDF-TDF Double-blind TDF 300 mg QD for 48 weeks followed by open-label TDF 300 mg once daily for an additional 336 weeks (TDF-TDF)
ADV-TDF Double-blind ADV 10 mg QD for 48 weeks followed by open-label TDF 300 mg once daily for an additional 336 weeks.

Measured Values
    TDF-TDF     ADV-TDF  
Number of Participants Analyzed  
[units: participants]
  154     84  
Percentage of Participants With HBV DNA <400 Copies/mL at Week 96  
[units: Percentage of Participants]
   
Yes     81     76  
No     12     18  
Missing     7     6  


Statistical Analysis 1 for Percentage of Participants With HBV DNA <400 Copies/mL at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.361
Difference in proportions [5] 5.0
Standard Error of the mean ± 5.5
95% Confidence Interval ( -5.8 to 15.9 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Two-sided 95% CIs, stratified by baseline ALT (baseline ALT</= 4 x ULN or >4 x ULN), were used to evaluate treatment group differences.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test of the null hypothesis that the stratum-adjusted difference is zero.
[5] Other relevant estimation information:
  No text entered.



5.  Secondary:   Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48
Measure Description Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at the end of blinded treatment.
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis set used included only participants with ALT above the ULN at baseline. A missing-equals-failure approach was used.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values
    TDF 300 mg QD     ADV 10 mg QD  
Number of Participants Analyzed  
[units: participants]
  169     90  
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48  
[units: Percentage of participants]
  68     54  


Statistical Analysis 1 for Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.032
Difference in proportions [5] 13.6
Standard Error of the mean ± 6.4
95% Confidence Interval ( 1.1 to 26.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Difference, standard error of the difference, and CI are stratum adjusted (baseline ALT </= 4 x ULN or >4 x ULN).
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test. Statistical tests were not adjusted for baseline ALT stratum.
[5] Other relevant estimation information:
  No text entered.



6.  Secondary:   Percentage of Participants With ALT Normalization at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Percentage of Participants With ALT Normalization at Week 96
Measure Description Normalized ALT was defined as ALT above the ULN at baseline and at or below the ULN at Week 96.
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The biochemically evaluable analysis set was used, which included those participants in the Open-label Extension (OLE) analysis set with ALT outside the normal range at baseline. A missing/switch-equals-failure approach was used.

Reporting Groups
  Description
TDF-TDF Double-blind TDF 300 mg QD for 48 weeks, followed by open-label TDF 300 mg once daily for an additional 336 weeks (TDF-TDF).
ADV-TDF Double-blind ADV 10 mg QD for 48 weeks, followed by open-label TDF 300 mg once daily for an additional 336 weeks (ADV-TDF).

Measured Values
    TDF-TDF     ADV-TDF  
Number of Participants Analyzed  
[units: participants]
  148     84  
Percentage of Participants With ALT Normalization at Week 96  
[units: Percentage of Participants]
  64     67  


Statistical Analysis 1 for Percentage of Participants With ALT Normalization at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.371
Difference in proportions [5] -5.8
Standard Error of the mean ± 6.4
95% Confidence Interval ( -18.4 to 6.9 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Difference, standard error of the difference, and CI are stratum adjusted (baseline ALT </= 4 x ULN or >4 x ULN).
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero.
[5] Other relevant estimation information:
  No text entered.



7.  Secondary:   Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48
Measure Description Hepatitis B e-antigen (HBeAg) loss was defined as negative HBeAg result for those subjects with HBeAg-positive result at baseline. Seroconversion to anti-HBe was defined as HBeAg loss and positive anti-HBe result.
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
HBeAg loss and seroconversion analysis was based upon the serologically evaluable analysis set, which consisted of all randomized-and-treated participants with a positive HBeAg result at baseline. Denominator used was the number of serologically evaluable participants.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values
    TDF 300 mg QD     ADV 10 mg QD  
Number of Participants Analyzed  
[units: participants]
  173     89  
Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48  
[units: Percentage of participants]
   
HBeAg Loss     20     16  
HBeAg Seroconversion     19     16  


Statistical Analysis 1 for Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.257
Difference in proportions [5] 5.4
Standard Error of the mean ± 4.8
95% Confidence Interval ( -3.9 to 14.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value above for HBeAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[5] Other relevant estimation information:
  This information pertains to HBeAg loss.

Statistical Analysis 2 for Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.378
Difference in proportions [5] 4.1
Standard Error of the mean ± 4.7
95% Confidence Interval ( -5.1 to 13.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Difference, standard error of difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value for HBeAg seroconversion corresponds to Z-test of the null hypothesis that stratum-adjusted difference is zero.
[5] Other relevant estimation information:
  This information pertains to HBeAg seroconversion.



8.  Secondary:   Percentage of Participants With HBeAg Loss or Seroconversion at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Percentage of Participants With HBeAg Loss or Seroconversion at Week 96
Measure Description HBeAg loss was defined as a negative HBeAg result for those participants with a positive HBeAg result at baseline. Seroconversion to anti-HBe was defined as HBeAg loss and positive anti-HBe result.
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The analysis set included all participants who received at least one dose of open-label TDF (Open-label Extension [OLE] analysis set). Participants with missing values at Week 96 or who added emtricitabine to their open-label regimen were considered failures.

Reporting Groups
  Description
TDF-TDF Double-blind TDF 300 mg QD for 48 weeks, followed by open-label TDF 300 mg once daily for an additional 336 weeks.
ADV-TDF Double-blind ADV 10 mg QD for 48 weeks, followed by open-label TDF 300 mg once daily for an additional 336 weeks.

Measured Values
    TDF-TDF     ADV-TDF  
Number of Participants Analyzed  
[units: participants]
  151     83  
Percentage of Participants With HBeAg Loss or Seroconversion at Week 96  
[units: Percentage of Participants]
   
HBeAg Loss     27     24  
Seroconversion to Anti-HBe     23     21  


Statistical Analysis 1 for Percentage of Participants With HBeAg Loss or Seroconversion at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.696
Difference in proportions [5] 2.3
Standard Error of the mean ± 5.8
95% Confidence Interval ( -9.1 to 13.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value above for HBeAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero.
[5] Other relevant estimation information:
  This information pertains to HBeAg loss.

Statistical Analysis 2 for Percentage of Participants With HBeAg Loss or Seroconversion at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Difference in proportions
P Value [4] 0.648
Difference in proportions [5] 2.5
Standard Error of the mean ± 5.5
95% Confidence Interval ( -8.2 to 13.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value above for HBeAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero.
[5] Other relevant estimation information:
  This information pertains to seroconversion to anti-HBe.



9.  Secondary:   Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48
Measure Description Hepatitis B s-antigen (HBsAg) loss was defined as negative HBsAg result for those participants with positive HBsAg result at baseline. Seroconversion to anti-HBs was defined as HBsAg loss and positive anti-HBs result.
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized-and-treated analysis set. Denominator is the number of participants with a Week 48 result. Missing-equals-failure approach.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values
    TDF 300 mg QD     ADV 10 mg QD  
Number of Participants Analyzed  
[units: participants]
  173     89  
Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48  
[units: Percentage of participants]
   
HBsAg Loss     3     0  
HBsAg Seroconversion     1     0  


Statistical Analysis 1 for Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.019
Difference in proportions [5] 9.4
Standard Error of the mean ± 4.0
95% Confidence Interval ( 1.6 to 17.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero. Difference, standard error of the difference, and confidence interval (CI) are stratum adjusted (baseline ALT </=4 x ULN or >4 x ULN).
[5] Other relevant estimation information:
  This information pertains to HBsAg loss.

Statistical Analysis 2 for Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion at Week 48
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.148
Difference in proportions [5] 3.8
Standard Error of the mean ± 2.6
95% Confidence Interval ( -1.4 to 8.9 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value corresponds to a Z-test of the null hypothesis that the ALT stratum-adjusted difference is zero. Difference, standard error of the difference, and confidence interval (CI) are stratum adjusted (baseline ALT </=4 x ULN or >4 x ULN).
[5] Other relevant estimation information:
  This information pertains to HBsAg seroconversion.



10.  Secondary:   Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96
Measure Description HBsAg loss was defined as a negative HBsAg result for those participants with a positive HBsAg result at baseline. Seroconversion to anti-HBs was defined as HBsAg loss and positive anti-HBs result.
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The serologically evaluable analysis set was used, which incuded only participants in the Open-label Extension (OLE) analysis set with a positive baseline HBsAg result.

Reporting Groups
  Description
TDF-TDF Double-blind TDF 300 mg QD for 48 weeks followed by open-label TDF 300 mg once daily for an additional 336 weeks.
ADV-TDF Double-blind ADV 10 mg QD for 48 weeks followed by open-label TDF 300 mg once daily for an additional 336 weeks.

Measured Values
    TDF-TDF     ADV-TDF  
Number of Participants Analyzed  
[units: participants]
  154     84  
Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96  
[units: Percentage of participants]
   
HBsAg Loss     5     6  
Seroconversion to anti-HBs     4     5  


Statistical Analysis 1 for Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Difference in proportions
P Value [4] 0.930
Difference in proportions [5] 0.3
Standard Error of the mean ± 3.1
95% Confidence Interval ( -5.7 to 6.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value above for HBsAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[5] Other relevant estimation information:
  This information pertains to HBsAg loss.

Statistical Analysis 2 for Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.885
Difference in proportions [5] 0.4
Standard Error of the mean ± 2.7
95% Confidence Interval ( -4.9 to 5.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  With a sample size of 160 subjects in the TDF group and 80 subjects in the ADV group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value above corresponds to Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[5] Other relevant estimation information:
  This information pertains to seroconversion to anti-HBs.



11.  Secondary:   Percentage of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)   [ Time Frame: Week 48 ]

Measure Type Secondary
Measure Title Percentage of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)
Measure Description No text entered.
Time Frame Week 48  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Based upon the randomized-and-treated analysis set. Participants evaluated for resistance included those with HBV DNA >/= 400 copies/mL, those with viral rebound, and those who discontinued after Week 24 with HBV DNA </= 400 copies/mL.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values
    TDF 300 mg QD     ADV 10 mg QD  
Number of Participants Analyzed  
[units: participants]
  176     90  
Percentage of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)  
[units: Participants]
   
Participants evaluated     31     75  
Changes at conserved sites in HBV polymerase     2     8  
Polymorphic site changes (wild-type virus)     14     17  
No genotypic changes from baseline     5     8  
Unable to be genotyped     10     7  

No statistical analysis provided for Percentage of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)



12.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)   [ Time Frame: Week 96 ]

Measure Type Secondary
Measure Title Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)
Measure Description Participants evaluated for resistance included those with HBV DNA >/= 400 copies/mL at Week 96 in TDF monotherapy, those who discontinued after Week 48 with HBV DNA >/= 400 copies/mL, and those who added emtricitabine to their open-label TDF regimen and had HBV DNA >/= 400 copies/mL at the time of the addition.
Time Frame Week 96  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of the participants who entered the OL TDF period, those evaluated for resistance included those with HBV DNA </= 400 copies/mL at Week 96 on TDF monotherapy, those who discontinued after Week 48 with HBV DNA >/= 400 copies/mL, and those who added emtricitabine to the OL TDF regimen and had HBV DNA >/= 400 copies/mL at the time of the addition.

Reporting Groups
  Description
TDF-TDF Double-blind TDF 300 mg QD for 48 weeks followed by open-label TDF for an additional 336 weeks.
ADV-TDF Double-blind ADV 10 mg QD for 48 weeks, then switch to open-label TDF for an additional 336 weeks.

Measured Values
    TDF-TDF     ADV-TDF  
Number of Participants Analyzed  
[units: participants]
  154     84  
Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)  
[units: Participants]
   
Participants evaluated     18     15  
Changes at conserved sites in HBV polymerase     2     2  
Polymorphic site changes (wild-type virus)     3     1  
No genotypic changes     10     12  
Unable to be genotyped     3     1  

No statistical analysis provided for Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)




  Serious Adverse Events


  Other Adverse Events


  More Information
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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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.  


Results Point of Contact:  
Name/Title: Jane Anderson, Associate Director Clinical Research
Organization: Gilead Sciences
phone: 919-294-7160
e-mail: Jane.anderson@gilead.com


No publications provided by Gilead Sciences

Publications automatically indexed to this study:

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00116805     History of Changes
Other Study ID Numbers: GS-US-174-0103
Study First Received: June 30, 2005
Results First Received: February 11, 2010
Last Updated: October 31, 2011
Health Authority: United States: Food and Drug Administration