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

This study is ongoing, but not recruiting participants.

Sponsor:

Information provided by (Responsible Party):

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT00116805

First received: June 30, 2005

Last updated: October 31, 2011

Last verified: October 2011

History of Changes

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 disoproxil fumarate Drug: adefovir dipivoxil

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 (LPO) for the primary endpoint analysis (Week 48) was 11 May 2007. The LPO for the Week 96 analysis was 27 May 2008.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Six of the 272 participants who were successfully screened and randomized discontinued prior to the first dose of study drug due to being erroneously randomized via interactive voice response system, withdrawal of consent, loss to follow-up, or failure to meet screening criteria. The screening process involved a liver biopsy.

Reporting Groups

	Description
TDF 300 mg QD	Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD	Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg 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	176 ^[1]	90 ^[1]
COMPLETED	154 ^[2]	84 ^[2]
NOT COMPLETED	22	6
Lost to Follow-up	8	2
Protocol Violation	1	1
Withdrawal by Subject	10	3
Seroconversion	2	0
Declined extension	1	0

[1]	Randomized-and-treated participants
[2]	Completed through Week 48 with end-of-double-blind-treatment liver biopsy results

Period 2: Open-Label TDF Period Through Week 96

	TDF 300 mg QD	ADV 10 mg QD
STARTED	154 ^[1]	84 ^[1]
COMPLETED	145 ^[2]	83 ^[2]
NOT COMPLETED	9	1
Physician Decision	1	0
Lost to Follow-up	2	0
Protocol Violation	2	0
Safety, tolerability, or efficacy reason	1	0
Seroconversion	1	0
Withdrawal by Subject	2	1

[1]	Entered the open-label TDF period
[2]	Completed through Week 96

Baseline Characteristics

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Reporting Groups

	Description
TDF 300 mg QD	Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD	Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg 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]	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
Prior Lamivudine or Emtricitabine Exposure ^[1] [units: Participants]
Yes	8	1	9
No	168	89	257
Baseline Hepatitis B Deoxyribonucleic Acid (HBV DNA) ^[1] [units: Log10 copies/mL] Mean ± Standard Deviation	8.64 ± 1.076	8.88 ± 0.930	8.72 ± 1.033
Baseline Knodell Necroinflammatory Score ^[2] [units: Units on a scale] Mean ± Standard Deviation	8.3 ± 2.11	8.5 ± 2.07	8.4 ± 2.09

[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).

[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 or Higher Reduction in the Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48 [ Time Frame: Week 48 ]

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2. Secondary:

Percentage of Participants With Histological Response at Week 48 [ Time Frame: Week 48 ]

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3. Secondary:

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

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4. Secondary:

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

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5. Secondary:

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

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6. Secondary:

Percentage of Participants With ALT Normalization at Week 96 [ Time Frame: Week 96 ]

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7. Secondary:

Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48 [ Time Frame: Week 48 ]

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Measure Type	Secondary
Measure Title	Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48
Measure Description	Hepatitis B e-antigen (HBeAg) loss was defined as negative HBeAg result for those subjects with HBeAg-positive result at baseline. Seroconversion to anti-HBe was defined as HBeAg loss and positive anti-HBe result.
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.
HBeAg loss and seroconversion analysis was based upon the serologically evaluable analysis set, which consisted of all randomized-and-treated participants with a positive HBeAg result at baseline. Denominator used was the number of serologically evaluable participants.

Reporting Groups

	Description
TDF 300 mg QD	Double-blind TDF 300 mg QD for 48 weeks, followed by OL TDF 300 mg for an additional 336 weeks
ADV 10 mg QD	Double-blind ADV 10 mg QD for 48 weeks, then switch to OL TDF 300 mg for an additional 336 weeks

Measured Values

	TDF 300 mg QD	ADV 10 mg QD
Number of Participants Analyzed [units: participants]	173	89
Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48 [units: Percentage of participants]
HBeAg Loss	20	16
HBeAg Seroconversion	19	16

Statistical Analysis 1 for Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48

Groups ^[1]	All groups
Non-Inferiority/Equivalence Test ^[2]	Yes
Method ^[3]	Z-test
P Value ^[4]	0.257
Difference in proportions ^[5]	5.4
Standard Error of the mean	± 4.8
95% Confidence Interval	( -3.9 to 14.7 )

[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 160 subjects in the TDF group and 80 subjects in the ADV 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 TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[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 above for HBeAg loss corresponds to a Z-test of the null hypothesis that stratum-adjusted difference is zero. Difference, standard error of the difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 x ULN).
[5]	Other relevant estimation information:
	This information pertains to HBeAg loss.

Statistical Analysis 2 for Percentage of Participants With Hepatitis B E-antigen (HBeAg) Loss/Seroconversion at Week 48

Groups ^[1]	All groups
Non-Inferiority/Equivalence Test ^[2]	Yes
Method ^[3]	Z-test
P Value ^[4]	0.378
Difference in proportions ^[5]	4.1
Standard Error of the mean	± 4.7
95% Confidence Interval	( -5.1 to 13.3 )

[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 160 subjects in the TDF group and 80 subjects in the ADV 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 TDF treatment was inferior to the ADV treatment (the difference in proportions was less than 0.080) in favor of the alternative hypothesis that the TDF treatment was not inferior.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Difference, standard error of difference, and CI are stratum adjusted based on baseline ALT category (</= 4 x ULN or >4 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 for HBeAg seroconversion corresponds to Z-test of the null hypothesis that stratum-adjusted difference is zero.
[5]	Other relevant estimation information:
	This information pertains to HBeAg seroconversion.

8. Secondary:

Percentage of Participants With HBeAg Loss or Seroconversion at Week 96 [ Time Frame: Week 96 ]

Show Outcome Measure 8

9. Secondary:

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

Show Outcome Measure 9

10. Secondary:

Percentage of Participants With HBsAg Loss or Serconversion to Anti-HBs at Week 96 [ Time Frame: Week 96 ]

Show Outcome Measure 10

11. Secondary:

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

Show Outcome Measure 11

12. Secondary:

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

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Serious Adverse Events

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Other Adverse Events

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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Institution and investigator may publish or present the results of the trial generated there with prior written consent of Gilead; or 2 years after the trial has ended at all institutions. Proposed publications/target venue must go to Gilead 30 days (manuscripts) or 15 days (abstracts/presentations) prior. Any Gilead confidential information in the document(s) must be deleted, or if requested publication delayed for up to 45 days to permit Gilead to obtain intellectual property protection.

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:

Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou E, Anderson J, Sorbel J, Rousseau F. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011 Jan;140(1):132-43. Epub 2010 Oct 16.

Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4;359(23):2442-55.

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00116805 History of Changes
Other Study ID Numbers:	GS-US-174-0103
Study First Received:	June 30, 2005
Results First Received:	February 11, 2010
Last Updated:	October 31, 2011
Health Authority:	United States: Food and Drug Administration

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