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A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00117676
First received: June 30, 2005
Last updated: February 4, 2016
Last verified: February 2016
History of Changes
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: TDF
Drug: ADV
Drug: TDF placebo
Drug: ADV placebo
Drug: FTC/TDF

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
There were 79 enrolling sites in 15 countries. The first participant was screened on 07 June 2005, and the last participant was randomized on 15 May 2006. The last participant observation for the primary endpoint analysis (Week 48) was 13 April 2007. The last participant observation for the Week 384 analysis was 20 September 2013.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
TDF-TDF Tenofovir disoproxil fumarate (TDF) 300 mg plus placebo to match adefovir dipivoxil (ADV) (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added emtricitabine (FTC; as part of FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet) to their treatment regimen in the open-label period.
ADV-TDF ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC (as part of FTC 200 mg/TDF 300 mg FDC tablet) to their treatment regimen in the open-label period.

Participant Flow for 8 periods

 Period 1:   Double-blind Period Through Week 48
    TDF-TDF     ADV-TDF  
STARTED     250     125  
COMPLETED     244     121  
NOT COMPLETED     6     4  
Lost to Follow-up                 1                 0  
Protocol Violation                 0                 1  
Safety, Tolerability, or Efficacy Reason                 5                 2  
Withdrew Consent                 0                 1  

Period 2:   Open-label Period: Weeks 49 - 96
    TDF-TDF     ADV-TDF  
STARTED     235 [1]   112 [1]
COMPLETED     225     110  
NOT COMPLETED     10     2  
Lost to Follow-up                 2                 0  
Safety, Tolerability, or Efficacy Reason                 3                 1  
Withdrew Consent                 5                 1  
[1] 9 participants completed 48 weeks but did not continue on study.

Period 3:   Open-label Period: Weeks 97 - 144
    TDF-TDF     ADV-TDF  
STARTED     225     110  
COMPLETED     219     109  
NOT COMPLETED     6     1  
Lost to Follow-up                 4                 1  
Safety, Tolerability, or Efficacy Reason                 1                 0  
Withdrew Consent                 1                 0  

Period 4:   Open-label Period: Weeks 145 - 192
    TDF-TDF     ADV-TDF  
STARTED     219     109  
COMPLETED     209     106  
NOT COMPLETED     10     3  
Investigator's Discretion                 2                 0  
Lost to Follow-up                 3                 1  
Withdrew Consent                 5                 2  

Period 5:   Open-label Period: Weeks 193 - 240
    TDF-TDF     ADV-TDF  
STARTED     209     106  
COMPLETED     202     103  
NOT COMPLETED     7     3  
Investigator's Discretion                 1                 1  
Lost to Follow-up                 0                 1  
Safety, Tolerability, or Efficacy Reason                 2                 0  
Withdrew Consent                 4                 1  

Period 6:   Open-label Period: Weeks 241 - 288
    TDF-TDF     ADV-TDF  
STARTED     202     103  
COMPLETED     192     100  
NOT COMPLETED     10     3  
Investigator's Discretion                 0                 1  
Lost to Follow-up                 2                 1  
Protocol Violation                 2                 0  
Safety, Tolerability, or Efficacy Reason                 1                 0  
Withdrew Consent                 5                 1  

Period 7:   Open-label Period: Weeks 289 - 336
    TDF-TDF     ADV-TDF  
STARTED     192     100  
COMPLETED     183     93  
NOT COMPLETED     9     7  
Investigator's Discretion                 7                 4  
Lost to Follow-up                 2                 2  
Withdrew Consent                 0                 1  

Period 8:   Open-label Period: Weeks 337 - 384
    TDF-TDF     ADV-TDF  
STARTED     183     93  
COMPLETED     176     90  
NOT COMPLETED     7     3  
Investigator's Discretion                 1                 1  
Lost to Follow-up                 3                 1  
Study Site Discontinued                 1                 0  
Withdrew Consent                 2                 1  



  Baseline Characteristics
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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: all participants who were randomized and received at least one dose of study medication

Reporting Groups
  Description
TDF-TDF TDF 300 mg plus placebo to match ADV (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added emtricitabine (FTC) to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.
ADV-TDF ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.
Total Total of all reporting groups

Baseline Measures
    TDF-TDF     ADV-TDF     Total  
Number of Participants  
[units: participants]
 		  250     125     375  
Age  
[units: participants]
 		     
<=18 years     0     1     1  
Between 18 and 65 years     247     123     370  
>=65 years     3     1     4  
Age  
[units: years]
Mean (Standard Deviation) 		  44  (10.6)     43  (10.0)     44  (10.4)  
Gender  
[units: participants]
 		     
Female     57     28     85  
Male     193     97     290  
Race/Ethnicity, Customized  
[units: participants]
 		     
American Indian or Alaska Native     0     0     0  
Asian     63     30     93  
Native Hawaiian or Other Pacific Islander     7     2     9  
Black or African American     8     4     12  
White     161     81     242  
More than one race     0     0     0  
Unknown or Not Reported     11     8     19  
Region of Enrollment  
[units: participants]
 		     
United States     25     11     36  
Greece     19     9     28  
Spain     15     6     21  
Turkey     11     3     14  
Italy     6     0     6  
United Kingdom     5     2     7  
France     13     5     18  
Czech Republic     7     5     12  
Canada     29     18     47  
Poland     13     11     24  
Australia     14     8     22  
Bulgaria     49     23     72  
Germany     19     11     30  
Netherlands     1     1     2  
New Zealand     24     12     36  
Baseline Alanine Aminotransferase (ALT) Above the Upper Limit of the Normal (ULN) Range [1]
[units: participants]
 		     
Yes     236     118     354  
No     14     7     21  
Prior Lamivudine or FTC Treatment  
[units: participants]
 		     
Yes     43     23     66  
No     207     102     309  
Baseline Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA)  
[units: log10 copies/mL]
Mean (Standard Deviation) 		  6.86  (1.308)     6.98  (1.266)     6.90  (1.294)  
Baseline Knodell Necroinflammatory Score [2]
[units: units on a scale]
Mean (Standard Deviation) 		  7.8  (2.45)     7.8  (2.20)     7.8  (2.37)  
[1] The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.
[2] Based on Knodell numerical scoring of liver biopsy specimens. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges 0 (best) to 14 (worst).



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 1

2.  Secondary:   Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 2

3.  Secondary:   Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96   [ Time Frame: Week 96 ]
  Hide Outcome Measure 3

Measure Type Secondary
Measure Title Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96
Measure Description No text entered.
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.
Participants in the Randomized and Treated Analysis Set with available data were analyzed. Data included for participants who had discontinued unless the reason for discontinuation was unrelated to protocol criteria.

Reporting Groups
  Description
TDF-TDF TDF 300 mg plus placebo to match ADV (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.
ADV-TDF ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.

Measured Values
    TDF-TDF     ADV-TDF  
Number of Participants Analyzed  
[units: participants]
 		  234     122  
Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96  
[units: percentage of participants]
 		  90.6     89.3  


Statistical Analysis 1 for Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.672
Difference in proportions [4] 1.4
Standard Error of the mean (3.4)
95% Confidence Interval -5.2 to 8.0
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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. Two-sided 95% confidence intervals, stratified by baseline ALT (baseline ALT ≤ 2 x ULN, > 2 x ULN), were used to evaluate treatment arm differences.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384   [ Time Frame: Weeks 144, 192, 240, 288, 336, and 384 ]
  Show Outcome Measure 4

5.  Secondary:   Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384 ]
  Show Outcome Measure 5

6.  Secondary:   Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384 ]
  Show Outcome Measure 6

7.  Secondary:   Percentage of Participants With Histological Response at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 7

8.  Secondary:   Percentage of Participants With Histological Response at Week 240   [ Time Frame: Baseline; Week 240 ]
  Show Outcome Measure 8

9.  Secondary:   Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 9

10.  Secondary:   Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240   [ Time Frame: Baseline; Week 240 ]
  Show Outcome Measure 10

11.  Secondary:   Ranked Assessment of Necroinflammation and Fibrosis at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 11

12.  Secondary:   Ranked Assessment of Necroinflammation and Fibrosis at Week 240   [ Time Frame: Baseline; Week 240 ]
  Show Outcome Measure 12

13.  Secondary:   Percentage of Participants With ALT Normalization at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 13

14.  Secondary:   Percentage of Participants With ALT Normalization at Weeks 96   [ Time Frame: Baseline; Week 96 ]
  Show Outcome Measure 14

15.  Secondary:   Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384 ]
  Show Outcome Measure 15

16.  Secondary:   Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384 ]
  Show Outcome Measure 16

17.  Secondary:   Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384 ]
  Show Outcome Measure 17

18.  Secondary:   Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 18

19.  Secondary:   Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96   [ Time Frame: Baseline; Week 96 ]
  Show Outcome Measure 19

20.  Secondary:   Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384 ]
  Show Outcome Measure 20

21.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 21

22.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 49 to 95 ]
  Show Outcome Measure 22

23.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 97 to 144 ]
  Show Outcome Measure 23

24.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 145 to 192 ]
  Show Outcome Measure 24

25.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 193 to 240 ]
  Show Outcome Measure 25

26.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 241 to 288 ]
  Show Outcome Measure 26

27.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 289 to 336 ]
  Show Outcome Measure 27

28.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 337 to 384 ]
  Show Outcome Measure 28


  Serious Adverse Events
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  Other Adverse Events
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  Limitations and Caveats
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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.


  More Information
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