A Study to Compare Tenofovir Versus Hepsera (Adefovir) for the Treatment of HBeAg Negative Chronic Hepatitis B

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by:
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00117676
First received: June 30, 2005
Last updated: January 5, 2011
Last verified: January 2011
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: Tenofovir DF (TDF) 300 mg
Drug: Double-blind adefovir dipivoxil (ADV) 10 mg (switch to open-label TDF 300 mg post Week 48)

  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 (LPO) for the primary endpoint analysis (Week 48) was 13 April 2007. The LPO for the Week 96 analysis was 06 May 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Seven of the 382 participants who were randomized discontinued prior to the first dose of study drug either due to screening failure (after erroneously being randomized via interactive voice response system) or withdrawal of consent. The screening process involved a liver biopsy.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg once daily for 48 weeks followed by OL TDF for an additional 336 weeks.
ADV 10 mg QD Double-blind ADV 10 mg once daily for 48 weeks then switch to OL TDF 300 mg once daily for an additional 336 weeks.

Participant Flow for 2 periods

Period 1:   Double-blind Period Through Week 48
    TDF 300 mg QD     ADV 10 mg QD  
STARTED     250 [1]   125 [1]
COMPLETED     234 [2]   113 [2]
NOT COMPLETED     16     12  
Lost to Follow-up                 1                 0  
Safety, Tolerability, or Efficacy                 5                 2  
Withdrawal by Subject                 0                 1  
Protocol Violation                 0                 1  
No end-of-blinded-treatment liver biopsy                 6                 5  
Unusable end-of-blinded-treatment biopsy                 4                 3  
[1] Randomized-and-treated participants
[2] Completed through Week 48 with usable end-of-blinded treatment liver biopsy result

Period 2:   Open-label TDF Period Through Week 96
    TDF 300 mg QD     ADV 10 mg QD  
STARTED     235 [1]   112 [2]
COMPLETED     225 [3]   110 [3]
NOT COMPLETED     10     2  
Lost to Follow-up                 3                 0  
Safety, Tolerability, or Efficacy                 2                 1  
Withdrawal by Subject                 5                 1  
[1] Entered the OL TDF phase. One participant entered OL without a usable Week 48 biopsy specimen.
[2] Entered the OL TDF phase
[3] Completed through Week 96



  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.
No text entered.

Reporting Groups
  Description
TDF 300 mg QD Double-blind TDF 300 mg once daily for 48 weeks followed by OL TDF for an additional 336 weeks.
ADV 10 mg QD Double-blind ADV 10 mg once daily for 48 weeks then switch to OL TDF 300 mg once daily for an additional 336 weeks.
Total Total of all reporting groups

Baseline Measures
    TDF 300 mg QD     ADV 10 mg QD     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 [1]
[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 Emtricitabine Experience [1]
[units: Participants]
     
Yes     43     23     66  
No     207     102     309  
Baseline Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) [1]
[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] Randomized-and-treated analysis set
[2] Randomized-and-treated analysis set. Based on Knodell numerical scoring of liver biopsy specimens. This scale consists of 5 domains (Periportal with or without Bridging Necrosis [scored numerically from best to worst 0, 1, 3, 4, 5, 6, or 10]; Intralobular Degeneration and Focal Necrosis [scored best to worst 0 to 4]; Portal Inflammation [also scored best to worst 0 to 4]; and Fibrosis [also scored best to worst 0 to 4]). The necroinflammatory score is the combined score for necrosis and inflammation, excluding the fibrosis score. Scores may range from 0 (best) to 14 (worst).



  Outcome Measures
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1.  Primary:   Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (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: 48 weeks ]

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 Histological Response at Week 48   [ Time Frame: Week 48 ]

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

6.  Secondary:   Percentage of Participants With ALT Normalization at Week 96   [ Time Frame: Week 96 ]
  Hide Outcome Measure 6

Measure Type Secondary
Measure Title Percentage of Participants With ALT Normalization at Week 96
Measure Description ALT normalization was defined as ALT outside the normal range at baseline and within the normal range at Week 96.
Time Frame Week 96  
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.
The biochemically evaluable analysis set was used, which included those participants in the open-label extension (OLE) analysis set with ALT outside the normal range at baseline. A missing/switch-equals-failure approach was used.

Reporting Groups
  Description
TDF-TDF Double-blind TDF 300 mg once daily for 48 weeks followed by open-label TDF 300 mg once daily for an additional 336 weeks (TDF-TDF)
ADV-TDF Double-blind ADV 10 mg once daily for 48 weeks then switch to open-label TDF 300 mg once daily for an additional 336 weeks (ADV-TDF)

Measured Values
    TDF-TDF     ADV-TDF  
Number of Participants Analyzed  
[units: participants]
  222     106  
Percentage of Participants With ALT Normalization at Week 96  
[units: Percentage of participants]
  71     71  


Statistical Analysis 1 for Percentage of Participants With ALT Normalization at Week 96
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] Z-test
P Value [4] 0.825
Difference in proportions [5] 1.2
Standard Error of the mean ± 5.3
95% Confidence Interval ( -9.2 to 11.5 )
[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:
  With a sample size of 200 subjects in the tenofovir DF group and 100 subjects in the adefovir dipivoxil group, a two group large-sample normal approximation test of proportions with a one-sided 0.025 significance level would have 95% power to reject the null hypothesis that the tenofovir DF treatment was inferior to the adefovir dipivoxil treatment (difference in proportions was less than 0.100) in favor of the alternative hypothesis that the tenofovir DF treatment was not inferior.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Difference, standard error of the difference, and confidence interval are stratum adjusted (baseline ALT </= 2 x ULN or >2 x ULN).
[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 ALT stratum-adjusted difference is zero.
[5] Other relevant estimation information:
  No text entered.



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

8.  Secondary:   Percentage of Participants With HBsAg Loss or Seroconversion at Week 96   [ Time Frame: Week 96 ]

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

10.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)   [ Time Frame: Week 96 ]


  Serious Adverse Events


  Other Adverse Events


  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.


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.  


Results Point of Contact:  
Name/Title: Jane Anderson, Associate Director Clinical Research
Organization: Gilead Sciences
phone: 919-294-7160
e-mail: Jane.anderson@gilead.com


No publications provided by Gilead Sciences

Publications automatically indexed to this study:

Responsible Party: Jeffrey D. Bornstein, MD/ Sr. Director, Clinical Research, Gilead Sciences
ClinicalTrials.gov Identifier: NCT00117676     History of Changes
Other Study ID Numbers: GS-US-174-0102
Study First Received: June 30, 2005
Results First Received: February 11, 2010
Last Updated: January 5, 2011
Health Authority: United States: Food and Drug Administration