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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00117676
First received: June 30, 2005
Last updated: August 21, 2015
Last verified: August 2015
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
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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 ]

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

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 ]
  Hide Outcome Measure 7

Measure Type Secondary
Measure Title Percentage of Participants With Histological Response at Week 48
Measure Description Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4.
Time Frame Baseline; 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  
Number of Participants Analyzed  
[units: participants]
  250     125  
Percentage of Participants With Histological Response at Week 48  
[units: percentage of participants]
   
Yes     72.4     68.8  
No     27.6     31.2  


Statistical Analysis 1 for Percentage of Participants With Histological Response at Week 48
Groups [1] All groups
Method [2] Z-test
P Value [3] 0.293
Difference in proportions [4] 5.2
Standard Error of the mean (5.0)
95% Confidence Interval -4.5 to 14.9
[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. Confidence interval stratum adjusted based on baseline ALT (≤ 2 x ULN, > 2 x ULN).
[4] Other relevant estimation information:
  No text entered.



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
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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
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