Text Size

Entecavir Plus Adefovir Combination Therapy Versus Entecavir Monotherapy vs Therapy With Adefovir Plus Lamivudine for Chronic Hepatitis B Infected Subjects With Lamivudine-resistant Virus (DEFINE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00410202
First received: December 11, 2006
Last updated: April 23, 2013
Last verified: April 2013
History of Changes
Results First Received: April 24, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Hepatitis B, Chronic
Interventions: Drug: Entecavir
Drug: Tenofovir
Drug: Adefovir
Drug: Lamivudine

  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
A total of 629 participants were enrolled at 60 sites.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of the 629 participants enrolled, 416 were randomized (195 no longer met study criteria, 9 withdrew consent, and 9 had other reason). One participant randomized to ADV+LVD Arm withdrew consent before treatment.

Reporting Groups
  Description
Entecavir + Adefovir (ETV+ADV) Combination Therapy ETV 1.0 mg + ADV 10 mg; Combination therapy given once daily (QD) for 100 weeks
Entecavir (ETV) Monotherapy ETV 1.0 mg; QD, for 100 weeks with an option of adding tenofovir (TDF), where permitted by the local health authorities and ethic committees, starting at Week 48
Adefovir + Lamivudine (ADV+LVD) Combination Therapy ADV 10 mg + LVD 100 mg; Combination therapy given QD for 100 weeks

Participant Flow for 2 periods

 Period 1:   On-Treatment
    Entecavir + Adefovir (ETV+ADV) Combination Therapy     Entecavir (ETV) Monotherapy     Adefovir + Lamivudine (ADV+LVD) Combination Therapy  
STARTED     138     140     137  
Discontinued Prior to Week 48 Visit     4     2     2  
Discontinued at or After Week 48 Visit     2     6     3  
COMPLETED     63 [1]   61 [1]   66 [1]
NOT COMPLETED     75     79     71  
Continuing treatment                 69                 71                 66  
Adverse Event                 1                 3                 2  
Death                 1                 0                 0  
Lost to Follow-up                 1                 0                 1  
Lack of Efficacy                 1                 4                 0  
Withdrawal by Subject                 2                 1                 1  
Other Reason                 0                 0                 1  
[1] Completed the 100 week dosing

Period 2:   Off-treatment Follow up
    Entecavir + Adefovir (ETV+ADV) Combination Therapy     Entecavir (ETV) Monotherapy     Adefovir + Lamivudine (ADV+LVD) Combination Therapy  
STARTED     15     8     14  
COMPLETED     1     0     2  
NOT COMPLETED     14     8     12  
Continuing off-treatment follow up                 10                 8                 11  
Follow up not required per protocol                 3                 0                 1  
Lost to Follow-up                 1                 0                 0  



  Baseline Characteristics
  Hide Baseline Characteristics

Reporting Groups
  Description
Entecavir + Adefovir (ETV+ADV) Combination Therapy ETV 1.0 mg + ADV 10 mg; Combination therapy given once daily (QD) for 100 weeks
Entecavir (ETV) Monotherapy ETV 1.0 mg; QD, for 100 weeks with an option of adding tenofovir (TDF), where permitted by the local health authorities and ethic committees, starting at Week 48
Adefovir + Lamivudine (ADV+LVD) Combination Therapy ADV 10 mg + LVD 100 mg; Combination therapy given QD for 100 weeks
Total Total of all reporting groups

Baseline Measures
    Entecavir + Adefovir (ETV+ADV) Combination Therapy     Entecavir (ETV) Monotherapy     Adefovir + Lamivudine (ADV+LVD) Combination Therapy     Total  
Number of Participants  
[units: participants]
 		  138     140     137     415  
Age  
[units: years]
Median ( Full Range ) 		  46.0  
  ( 18 to 69 )   		  43.5  
  ( 19 to 71 )   		  43.0  
  ( 16 to 74 )   		  45.0  
  ( 16 to 74 )  
Gender  
[units: participants]
 		       
Female     47     52     40     139  
Male     91     88     97     276  
Race/Ethnicity, Customized  
[units: participants]
 		       
Asian     132     131     126     389  
White     6     9     11     26  
Region of Enrollment  
[units: participants]
 		       
Australia     0     1     1     2  
Canada     1     0     0     1  
Hong Kong     5     7     5     17  
India     4     3     5     12  
Indonesia     0     1     0     1  
Italy     1     0     0     1  
Korea, Republic of     108     105     102     315  
Malaysia     3     0     2     5  
Philippines     0     1     1     2  
Poland     5     9     9     23  
Russian Federation     0     0     2     2  
Singapore     1     1     0     2  
Taiwan     8     9     9     26  
Thailand     1     3     1     5  
Turkey     1     0     0     1  
Hepatitis B surface antigen (HBsAg) status at baseline  
[units: participants]
 		       
Positive     138     140     137     415  
Negative     0     0     0     0  
Hepatitis B e antigen (HBeAg) status at baseline  
[units: participants]
 		       
Positive     138     139     135     412  
Negative     0     1     2     3  
Hepatitis B e antibody (HBeAb) at baseline  
[units: participants]
 		       
Positive     0     1     2     3  
Negative     138     139     135     412  
Alanine Aminotransferase (ALT)  
[units: U/L]
Median ( Full Range ) 		  49  
  ( 10 to 480 )   		  50  
  ( 12 to 367 )   		  45  
  ( 14 to 1300 )   		  47  
  ( 10 to 1300 )  
LVD-Resistance Substitution [1]
[units: participants]
 		       
Present     136     137     134     407  
Absent     2     3     3     8  
log10 HBV DNA by PCR  
[units: IU/mL]
Median ( Full Range ) 		  7.6  
  ( 4.2 to 9.5 )   		  7.5  
  ( 3.0 to 9.7 )   		  7.6  
  ( 3.2 to 10.0 )   		  7.6  
  ( 3.0 to 10.0 )  
International Normalization Ratio  
[units: ratio]
Median ( Full Range ) 		  1.07  
  ( 0.80 to 1.97 )   		  1.07  
  ( 0.87 to 2.48 )   		  1.05  
  ( 0.82 to 7.24 )   		  1.07  
  ( 0.80 to 7.24 )  
Albumin  
[units: g/dL]
Median ( Full Range ) 		  4.4  
  ( 3.1 to 5.1 )   		  4.5  
  ( 3.5 to 5.1 )   		  4.5  
  ( 3.5 to 5.1 )   		  4.5  
  ( 3.1 to 5.1 )  
Total Bilirubin  
[units: mg/dL]
Median ( Full Range ) 		  0.6  
  ( 0.2 to 1.8 )   		  0.6  
  ( 0.2 to 2.4 )   		  0.6  
  ( 0.2 to 2.6 )   		  0.6  
  ( 0.2 to 2.6 )  
[1] LVD resistance (LVDr) substitution at reverse transcription codon 204 (M240V/I/S). The participants who did not have LVDr substitution mutations at baseline (day 1) were distributed equally among the 3 study groups (2 with ETV+ADV combination therapy and 3 each with ETV monotherapy and ADV+LVD combination therapy).



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With HBV Deoxyribonucleic Acid (DNA) < 50 IU/mL (Approximately 300 Copies/mL) by Polymerase Chain Reaction (PCR) at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 1

2.  Secondary:   Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 2

3.  Secondary:   Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 3

4.  Secondary:   Percentage of Participants With HBV DNA by PCR Category at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 4

5.  Secondary:   Change in Mean log10 From Baseline in HBV DNA at Week 48   [ Time Frame: Baseline, Week 48 ]
  Show Outcome Measure 5

6.  Secondary:   Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 6

7.  Secondary:   Percentage of Participants With Confirmed HBeAg Loss at Week 48 (Treated HBeAg Positive Participants)   [ Time Frame: Week 48 ]
  Show Outcome Measure 7

8.  Secondary:   Percentage of Participants With HBeAg Seroconversion at Week 48 (for HBeAg-positive Participants Only)   [ Time Frame: Week 48 ]
  Show Outcome Measure 8

9.  Secondary:   Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 9

10.  Secondary:   Percentage of Participants With HBsAg Seroconversion at Week 48   [ Time Frame: Week 48 ]
  Show Outcome Measure 10

11.  Secondary:   Cumulative Probability of Emergent Genotypic Resistance at Year 1   [ Time Frame: year 1 ]
  Show Outcome Measure 11

12.  Secondary:   Participants With Adverse Events (AE), Serious Adverse Events (SAE), and Discontinuations Due to Adverse Events or Laboratory Abnormalities During Treatment   [ Time Frame: From start of study therapy through Week 100 + 5 days ]
  Show Outcome Measure 12

13.  Secondary:   Number of Participants With Laboratory Abnormalities: Hematology   [ Time Frame: From start of study through Week 100 + 5 days ]
  Show Outcome Measure 13

14.  Secondary:   Number of Participants With Laboratory Abnormalities: Serum Chemistry   [ Time Frame: On treatment (OT): From start of study through Week 100 + 5 days; Offtreatment (OF) = End of OT period through 24 weeks ]
  Show Outcome Measure 14

15.  Secondary:   Percentage of Participants With HBV DNA < 50 IU/mL (Approximately 300 Copies/mL) by PCR at Week 96   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

16.  Secondary:   Percentage of Participants Who Achieve HBV DNA < Lower Limit of Quantitation (LOQ = 29 IU/mL [Approximately 169 Copies/mL]) at Week 96   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

17.  Secondary:   Percentage of Participants Who Achieve HBV DNA < Lower Limit of Detection (LOD = 10 IU/mL [Approximately 58 Copies/mL]) at Week 96   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

18.  Secondary:   Percentage of Participants With HBV DNA by PCR Category at Week 96   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

19.  Secondary:   Mean log10 Reduction From Baseline in HBV DNA at Week 96   [ Time Frame: week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

20.  Secondary:   Percentage of Participants With Alanine Aminotransferase (ALT) > 1 x Upper Limit of Normal (ULN) at Baseline Who Achieve ALT Normalization at Week 96   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

21.  Secondary:   Percentage of Participants With Confirmed HBeAg Loss at Week 96 (Treated HBeAg Positive Participants)   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

22.  Secondary:   Percentage of Participants With HBeAg Seroconversion at Week 96 (for HBeAg-positive Participants Only)   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

23.  Secondary:   Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 96   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

24.  Secondary:   Percentage of Participants With HBsAg Seroconversion at Week 96   [ Time Frame: Week 96 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No

25.  Secondary:   Cumulative Probability of Emergent Genotypic Resistance at Year 2   [ Time Frame: year 2 ]
Results not yet posted.   Anticipated Posting Date:   04/2013   Safety Issue:   No


  Serious Adverse Events
  Show Serious Adverse Events


  Other Adverse Events
  Show Other Adverse Events


  More Information
  Hide More Information

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: BMS Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00410202     History of Changes
Other Study ID Numbers: AI463-111
Study First Received: December 11, 2006
Results First Received: April 24, 2012
Last Updated: April 23, 2013
Health Authority: United States: Food and Drug Administration