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

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ClinicalTrials.gov Identifier: NCT00117676
Recruitment Status : Completed
First Posted : July 8, 2005
Results First Posted : May 19, 2010
Last Update Posted : March 7, 2017
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, 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

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were enrolled at study sites in North America, Europe, and Australia/New Zealand. The first participant was screened on 07 June 2005. The last study visit occurred on 19 January 2016.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
846 participants were screened.

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 10 periods

 Period 1:   Double-blind Period Through Week 48
    TDF-TDF   ADV-TDF
STARTED   254   128 
COMPLETED   244   121 
NOT COMPLETED   10   7 
Randomized but Not Treated                4                3 
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 

Period 9:   Open-label Period: Weeks 385 - 432
    TDF-TDF   ADV-TDF
STARTED   82 [1]   46 [2] 
COMPLETED   82   44 
NOT COMPLETED   0   2 
Investigator’s Discretion                0                1 
Safety, Tolerability, or Efficacy Reason                0                1 
[1] 94 participants completed 384 weeks but did not continue on study.
[2] 44 participants completed 384 weeks but did not continue on study.

Period 10:   Open-label Period: Weeks 433 - 480
    TDF-TDF   ADV-TDF
STARTED   82   43 [1] 
COMPLETED   80   41 
NOT COMPLETED   2   2 
Lost to Follow-up                1                0 
Safety, Tolerability, or Efficacy Reason                1                1 
Withdrew Consent                0                1 
[1] 1 participant completed 432 weeks but did not continue on study.



  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.
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 
Overall Participants Analyzed 
[Units: Participants]
 		 250   125   375 
Age 
[Units: Participants]
Count of Participants 		     
<=18 years      0   0.0%      1   0.8%      1   0.3% 
Between 18 and 65 years      247  98.8%      123  98.4%      370  98.7% 
>=65 years      3   1.2%      1   0.8%      4   1.1% 
Age 
[Units: Years]
Mean (Standard Deviation) 		 44  (10.6)   43  (10.0)   44  (10.4) 
Gender 
[Units: Participants]
Count of Participants 		     
Female      57  22.8%      28  22.4%      85  22.7% 
Male      193  77.2%      97  77.6%      290  77.3% 
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 
[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.
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 [1] 
[Units: Units on a scale]
Mean (Standard Deviation) 		 7.8  (2.45)   7.8  (2.20)   7.8  (2.37) 
[1] 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

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  

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 
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
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Z-test
P Value [4] 0.672
Difference in proportions [5] 1.4
95% Confidence Interval -5.2 to 8.0
Standard Error of the mean (3.4)
[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:
  No text entered.
[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 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.
[5] 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:   Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480   [ Time Frame: Weeks 432 and 480 ]
  Show Outcome Measure 5

6.  Secondary:   Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  Show Outcome Measure 6

7.  Secondary:   Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  Show Outcome Measure 7

8.  Secondary:   Percentage of Participants With Histological Response at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 8

9.  Secondary:   Percentage of Participants With Histological Response at Week 240   [ Time Frame: Baseline; Week 240 ]
  Show Outcome Measure 9

10.  Secondary:   Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 10

11.  Secondary:   Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240   [ Time Frame: Baseline; Week 240 ]
  Show Outcome Measure 11

12.  Secondary:   Ranked Assessment of Necroinflammation and Fibrosis at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 12

13.  Secondary:   Ranked Assessment of Necroinflammation and Fibrosis at Week 240   [ Time Frame: Baseline; Week 240 ]
  Show Outcome Measure 13

14.  Secondary:   Percentage of Participants With ALT Normalization at Week 48   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 14

15.  Secondary:   Percentage of Participants With ALT Normalization at Weeks 96   [ Time Frame: Baseline; Week 96 ]
  Show Outcome Measure 15

16.  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 16

17.  Secondary:   Percentage of Participants With ALT Normalization at Weeks 432 and 480   [ Time Frame: Baseline; Weeks 432 and 480 ]
  Show Outcome Measure 17

18.  Secondary:   Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  Show Outcome Measure 18

19.  Secondary:   Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]
  Show Outcome Measure 19

20.  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 20

21.  Secondary:   Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96   [ Time Frame: Baseline; Week 96 ]
  Show Outcome Measure 21

22.  Secondary:   Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480 ]
  Show Outcome Measure 22

23.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)   [ Time Frame: Baseline; Week 48 ]
  Show Outcome Measure 23

24.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 49 to 96 ]
  Show Outcome Measure 24

25.  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 25

26.  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 26

27.  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 27

28.  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 28

29.  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 29

30.  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 30

31.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 385 to 432 ]
  Show Outcome Measure 31

32.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 433 to 480 ]
  Show Outcome Measure 32


  Serious Adverse Events


  Other Adverse Events


  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.


  More Information