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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
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 
Overall Participants Analyzed 
[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 
[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
  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 ]

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

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; the missing-equals-failure approach was used where participants with missing data were considered to have failed to reach the endpoint.

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]
 250   125 
Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48 
[Units: Percentage of participants]
 93.2   63.2 


Statistical Analysis 1 for Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48
Groups [1] All groups
Method [2] Z-test
P Value [3] <0.001
Difference in proportions [4] 30.3
Standard Error of the mean (4.6)
95% Confidence Interval 21.3 to 39.2
[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. Difference, standard error of the difference, and the CI are stratum adjusted based on baseline ALT category (≤ 2 x ULN or > 2 x ULN).
[4] Other relevant estimation information:
  No text entered.



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

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 ]

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 ]

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 ]

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

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

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

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

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

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

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

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

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 ]

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 ]

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 ]

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 ]

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

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 ]

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

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

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

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

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

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

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

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


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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
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  More Information