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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:
ClinicalTrials.gov Identifier:
NCT00116805
First Posted: July 1, 2005
Last Update Posted: March 9, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Gilead Sciences
Results First Submitted: February 11, 2010  
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
  Hide 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 09 June 2005. The last study visit occurred on 28 January 2016.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
603 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) 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 10 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 

Period 9:   Open-label Period Weeks 385 - 432
    TDF-TDF   ADV-TDF
STARTED   59 [1]   30 [2] 
COMPLETED   57   30 
NOT COMPLETED   2   0 
Investigator’s Discretion                1                0 
Withdrew Consent                1                0 
[1] 31 participants completed 384 weeks but did not continue on study.
[2] 26 participants completed 384 weeks but did not continue on study.

Period 10:   Open-label Period Weeks 433 - 480
    TDF-TDF   ADV-TDF
STARTED   57   29 [1] 
COMPLETED   53   29 
NOT COMPLETED   4   0 
Investigator’s Discretion                1                0 
Withdrew Consent                3                0 
[1] 1 participant completed 432 weeks but did not continue on study.



  Baseline Characteristics
  Hide 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]
 176   90   266 
Age 
[Units: Participants]
Count of Participants
     
<=18 years      3   1.7%      1   1.1%      4   1.5% 
Between 18 and 65 years      173  98.3%      89  98.9%      262  98.5% 
>=65 years      0   0.0%      0   0.0%      0   0.0% 
Age 
[Units: Years]
Mean (Standard Deviation)
 34  (11.3)   34  (12.2)   34  (11.6) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      57  32.4%      26  28.9%      83  31.2% 
Male      119  67.6%      64  71.1%      183  68.8% 
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:   Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480   [ Time Frame: Weeks 432 and 480 ]

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 ]

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 ]

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

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

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

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

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

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

14.  Secondary:   Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48   [ Time Frame: Baseline; Week 48 ]

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

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 ]

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

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 ]

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 ]

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

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

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

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

24.  Secondary:   Percentage of Participants With HBsAg Loss 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 ]

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

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

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

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

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

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

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

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

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

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


  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
No text entered.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Clinical Trial Disclosures
Organization: Gilead Sciences, Inc.
e-mail: ClinicalTrialDisclosures@gilead.com


Publications of Results:
Corsa A, Liu Y, Flaherty JF, Marcellin P, Miller M, Kitrinos KM. No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) in HBeAg+ and HBeAg- Patients With Chronic Hepatitis B (CHB) After Eight Years of Treatment [Abstract 1707]. The 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2014 08-10 November; Boston MA.
Marcellin P, Gane EJ, Flisiak R, Trinh HN, Petersen J, Gurel S, et al. Long Term Treatment with Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Infection is Safe and Well Tolerated and Associated with Durable Virologic Response with no Detectable Resistance: 8 Year Results from Two Phase 3 Trials [Abstract]. 55th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2014 November 7-11; Boston, MA.
Gane EJ, Marcellin P, Sievert W, Trinh HN, Shiffman ML, Washington MK, et al. Five years of Treatment with Tenofovir DF for Chronic Hepatitis B Infection in Asian Patients is Associated with Sustained Viral Suppression and Significant Regression of Histological Fibrosis and Cirrhosis [Poster Number 1429]. 62nd Annual Meeting of the American Association for the Study of Liver Diseases; 2011 November 4-8; San Francisco, California.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00116805     History of Changes
Other Study ID Numbers: GS-US-174-0103
2004-005120-41 ( EudraCT Number )
First Submitted: June 30, 2005
First Posted: July 1, 2005
Results First Submitted: February 11, 2010
Results First Posted: May 19, 2010
Last Update Posted: March 9, 2017