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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00116805
First received: June 30, 2005
Last updated: February 22, 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 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 for the primary endpoint analysis (Week 48) was 11 May 2007. The last participant observation for the Week 384 analysis was 22 October 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) to their treatment regimen (as part of FTC 200 mg/TDF 300 mg fixed-dose combination (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.

Participant Flow for 8 periods

Period 1:   Double-blind Period Through Week 48
    TDF-TDF   ADV-TDF
STARTED   176   90 
COMPLETED   165   85 
NOT COMPLETED   11   5 
Lost to Follow-up                6                2 
Protocol Violation                1                1 
Withdrew Consent                4                2 

Period 2:   Open-label Period Weeks 49 - 96
    TDF-TDF   ADV-TDF
STARTED   154 [1]   84 [2] 
COMPLETED   144   83 
NOT COMPLETED   10   1 
Investigator's Discretion                1                0 
Lost to Follow-up                2                0 
Protocol Violation                2                0 
Safety, Tolerability, or Efficacy Reason                1                0 
Seroconversion                2                0 
Withdrew Consent                2                1 
[1] 11 participants completed 48 weeks but did not continue on study.
[2] 1 participant completed 48 weeks but did not continue on study.

Period 3:   Open-label Period Weeks 97 - 144
    TDF-TDF   ADV-TDF
STARTED   144   83 
COMPLETED   133   74 
NOT COMPLETED   11   9 
Completed Study                1                0 
Investigator's Discretion                2                0 
Lost to Follow-up                5                2 
Protocol Violation                0                1 
Seroconversion                2                3 
Withdrew Consent                1                3 

Period 4:   Open-label Period Weeks 145 - 192
    TDF-TDF   ADV-TDF
STARTED   133   74 
COMPLETED   123   68 
NOT COMPLETED   10   6 
Completed Study                1                1 
Investigator's Discretion                2                0 
Lost to Follow-up                3                1 
Protocol Violation                1                0 
Safety, Tolerability, or Efficacy Reason                0                1 
Seroconversion                0                1 
Withdrew Consent                3                2 

Period 5:   Open-label Period Weeks 193 - 240
    TDF-TDF   ADV-TDF
STARTED   123   68 
COMPLETED   110   64 
NOT COMPLETED   13   4 
Completed Study                0                1 
Investigator's Discretion                1                0 
Lost to Follow-up                3                0 
Safety, Tolerability, or Efficacy Reason                2                2 
Withdrew Consent                7                1 

Period 6:   Open-label Period Weeks 241 - 288
    TDF-TDF   ADV-TDF
STARTED   110   64 
COMPLETED   104   64 
NOT COMPLETED   6   0 
Safety, Tolerability, or Efficacy Reason                2                0 
Withdrew Consent                4                0 

Period 7:   Open-label Period Weeks 289 - 336
    TDF-TDF   ADV-TDF
STARTED   104   64 
COMPLETED   98   57 
NOT COMPLETED   6   7 
Completed Study                0                1 
Investigator's Discretion                3                2 
Lost to Follow-up                1                1 
Protocol Violation                0                1 
Safety, Tolerability, or Efficacy Reason                0                1 
Study Site Discontinued                0                1 
Withdrew Consent                2                0 

Period 8:   Open-label Period Weeks 337 - 384
    TDF-TDF   ADV-TDF
STARTED   98   57 
COMPLETED   90   56 
NOT COMPLETED   8   1 
Completed Study                1                0 
Investigator's Discretion                1                0 
Lost to Follow-up                2                0 
Protocol Violation                1                0 
Withdrew Consent                3                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]
 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 
[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   8   1   9 
No   168   89   257 
Baseline Hepatitis B Deoxyribonucleic Acid (HBV DNA) 
[Units: Log10 copies/mL]
Mean (Standard Deviation)
 8.64  (1.076)   8.88  (0.930)   8.72  (1.033) 
Baseline Knodell Necroinflammatory Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 8.3  (2.11)   8.5  (2.07)   8.4  (2.09) 
[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 ]

3.  Secondary:   Percentage of Participants With HBV DNA < 400 Copies/mL at Week 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 ]
  Hide Outcome Measure 8

Measure Type Secondary
Measure Title Percentage of Participants With Histological Response at Week 240
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 240  
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 observed data were analyzed; the missing-equals-excluded approach was used where participants with missing data were excluded from the analysis. Data for participants who added FTC to their open-label TDF regimen were included in the analysis.

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]
 76   48 
Percentage of Participants With Histological Response at Week 240 
[Units: Percentage of participants]
   
Yes   88.2   89.6 
No   11.8   10.4 

No statistical analysis provided for Percentage of Participants With Histological Response at 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 Alanine Aminotransferase (ALT) Normalization at Week 48   [ Time Frame: Baseline; Week 48 ]

14.  Secondary:   Percentage of Participants With ALT Normalization at Week 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 e Antigen (HBeAg) Loss/Seroconversion at Week 48   [ Time Frame: Baseline; Week 48 ]

19.  Secondary:   Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96   [ Time Frame: Baseline to Week 96 ]

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

21.  Secondary:   Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Week 96   [ Time Frame: Baseline; Weeks 96, 144, 192, 240, 288, 336, and 384 ]

22.  Secondary:   Percentage of Participants With HBsAg Loss 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 ]

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

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

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

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

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

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

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

30.  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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  More Information