Comparison of Entecavir to Adefovir in Chronic Hepatitis B Virus (HBV) Patients With Hepatic Decompensation - Study Results

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
Interventions:	Drug: Entecavir (ETV) Drug: Adefovir (ADV)

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 431 participants were enrolled into the study. 236 were never randomized (213 no longer met study criteria; 6 withdrew consent; 3 died; 1 for administrative reasons by sponsor; 1 for adverse events; 1 lost to follow-up; 11 for other reasons).

Reporting Groups

	Description
Entecavir (ETV) 1.0 mg	Tablets, Oral, 1 mg once daily
Adefovir (ADV) 10 mg	Tablets, Oral, 10 mg once daily

Participant Flow: Overall Study

	Entecavir (ETV) 1.0 mg	Adefovir (ADV) 10 mg
STARTED	100 ^[1]	91 ^[2]
Treated (As-Randomized Population)	100 ^[3]	91 ^[3]
Treated (As-Treated Population)	102 ^[4]	89 ^[4]
Treated, Wk 48 (As-Treated Population)	102 ^[4]	89 ^[4]
Treated, 24-Week Follow-Up Population	25	28
COMPLETED	71 ^[5]	62 ^[5]
NOT COMPLETED	29	29
Death	16	17
Adverse Event	4	3
Lack of Efficacy	0	6
Poor/Non-compliance	3	2
Lost to Follow-up	3	0
Subject Withdrew Consent	2	1
Subject No Longer Meets Study Criteria	1	0

[1]	101 participants were randomized; 1 never treated.
[2]	94 participants were randomized; 3 never treated.
[3]	As-randomized population was used in efficacy analyses, unless otherwise noted.
[4]	2 subjects randomized to ADV were treated with ETV for the entire dosing period and included in ETV.
[5]	Completed first 48 weeks of treatment

Baseline Characteristics

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Reporting Groups

	Description
Entecavir (ETV) 1.0 mg	Tablets, Oral, 1 mg once daily
Adefovir (ADV) 10 mg	Tablets, Oral, 10 mg once daily

Baseline Measures

	Entecavir (ETV) 1.0 mg	Adefovir (ADV) 10 mg	Total
Number of Participants [units: participants]	100	91	191
Age [units: years] Mean ± Standard Deviation	51 ± 12	53 ± 11	52 ± 11
Gender [units: participants]
Female	22	27	49
Male	78	64	142
Race/Ethnicity, Customized ^[1] [units: participants]
Asian	55	49	104
White	35	28	63
Other	5	9	14
Black/African American	5	5	10
Region of Enrollment [units: participants]
United States	12	9	21
Philippines	4	5	9
Taiwan	11	11	22
Hong Kong	5	5	10
Greece	8	5	13
Thailand	10	9	19
Indonesia	2	0	2
Turkey	3	1	4
Russian Federation	1	1	2
India	15	14	29
Canada	5	3	8
Brazil	13	13	26
Poland	3	5	8
Singapore	3	5	8
South Africa	3	4	7
France	2	0	2
United Kingdom	0	1	1
Child-Pugh Class ^[2] [units: Participants]
Class A	7	10	17
Class B	63	61	124
Class C	30	20	50
Alanine Aminotransferase (ALT) ^[3] [units: U/L] Mean ± Standard Deviation	99.2 ± 111.23	100.0 ± 81.68	99.6 ± 98.01
Child-Pugh Score ^[2] [units: units on a scale] Mean ± Standard Deviation	8.81 ± 1.98	8.35 ± 1.82	8.59 ± 1.91
HBV DNA by PCR ^[4] [units: log10 copies/mL] Mean ± Standard Deviation	7.53 ± 1.829	8.16 ± 2.179	7.83 ± 2.023
Mayo End-Stage Liver Disease (MELD) score ^[5] [units: units on a scale] Mean ± Standard Deviation	17.07 ± 5.00	15.30 ± 4.61	16.23 ± 4.89

[1]	Other category includes Asian Indian, South African "color," "mixed ancestry," and "mixed race"
[2]	The Child-Pugh classification is used to assess the prognosis of chronic liver disease. The score employs 5 clinical measures of liver disease; each measure is scored 1-3, with 3 indicating most severe derangement. Total possible score is 15. Chronic liver disease is classified into Child-Pugh class A to C, employing the added score from above: 5-6=Class A; 7-9=Class B; 10-15=Class C. As-Randomized population.
[3]	As-randomized population
[4]	HBV=hepatitis B virus, PCR=polymerase chain reaction. As-Randomized population.
[5]	The Model for End-Stage Liver Disease (MELD), is a scoring system for assessing the severity of chronic liver disease. MELD uses the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival. In interpreting the MELD Score in hospitalized patients, the 3 month mortality is: 40 or more=100% mortality; 30-39=83% mortality; 20-29=76% mortality; 10-19=27% mortality; <10=4% mortality. As-randomized population.

Outcome Measures

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1. Primary:

Change From Baseline in Hepatitis B Virus (HBV) DNA by Polymerase Chain Reaction (PCR) at Week 24 [ Time Frame: Baseline, Week 24 ]

Show Outcome Measure 1

2. Secondary:

Change From Baseline in HBV DNA by PCR at Week 48 [ Time Frame: Baseline, Week 48 ]

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3. Secondary:

Number of Participants With HBV DNA < 300 Copies/mL by PCR At Week 24 [ Time Frame: Week 24 ]

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4. Secondary:

Number of Participants With HBV DNA < 300 Copies/mL by PCR At Week 48 [ Time Frame: Week 48 ]

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5. Secondary:

Number of Participants Achieving Alanine Transaminase (ALT) Normalization (≤1.0 x Upper Limit of Normal [ULN]) at Weeks 24 and 48 [ Time Frame: Week 24, Week 48 ]

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6. Secondary:

Number of Subjects Achieving Composite Endpoint (HBV DNA < 10*4 Copies/mL by PCR Assay and Normal ALT [≤ 1.0 x ULN]) Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 48 ]

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7. Secondary:

>=2-Point Reduction From Baseline in Child-Pugh Score Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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8. Secondary:

Number of Participants With Improvement or No Worsening in Child-Pugh Score From Baseline to Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 48 ]

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9. Secondary:

Change From Baseline in Child-Pugh Score Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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10. Secondary:

Number of Participants With Improvement in Child-Pugh Class at Week 24 and Week 48 [ Time Frame: Week 24, Week 48 ]

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11. Secondary:

Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores From Baseline Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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12. Secondary:

Improvement or No Worsening in MELD Score Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 48 ]

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13. Secondary:

Mean Changes From Baseline in Quality of Life as Measured by the Short Form 36 (SF-36) [ Time Frame: Baseline, Week 24, Week 48 ]

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14. Secondary:

Mean Changes From Baseline in Quality of Life, as Measured by EuroQol-5D (EQ-5D) at Weeks 24 and 48 [ Time Frame: Baseline, Week 24, Week 48 ]

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15. Secondary:

Change From Baseline in Albumin Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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16. Secondary:

Mean Change From Baseline in Prothrombin Time Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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17. Secondary:

Mean Change From Baseline in Total Bilirubin Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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18. Secondary:

Change From Baseline in Platelet Count Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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19. Secondary:

Participants Achieving Albumin Normalization Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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20. Secondary:

Participants Achieving Prothrombin Time Normalization Through Week 48 [ Time Frame: Baseline, Week4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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21. Secondary:

Participants Achieving Total Bilirubin Normalization Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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22. Secondary:

Participants Achieving Platelet Count Normalization Through Week 48 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ]

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23. Secondary:

Number of Hepatocellular Carcinoma (HCC) Events at Different Time Points Through Week 48 [ Time Frame: Week 48 ]

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24. Secondary:

Cumulative Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, HCC, Discontinuations Due to AEs, and Confirmed Creatinine Increase >=0.5 mg/dL [ Time Frame: on-treatment events obtained after the start of therapy and no more than 5 days after the last dose of study therapy. ]

Show Outcome Measure 24

25. Secondary:

Number of Participants With Treatment-Emergent Grade 3/4 Laboratory Abnormalities - Week 48 and Cumulative Data [ Time Frame: Week 48=all on-treatment laboratory measurements up to Week 48. Cumulative data = on-treatment laboratory measurements obtained after the start of therapy and no more than 5 days after the last dose of study therapy. ]

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26. Secondary:

Number of Participants With Alanine Aminotransferase (ALT) Flares - On Treatment [ Time Frame: On-treatment=up to Week 48 (Day 336); if discontinued early, all data up to 5 days after discontinuation date. ]

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27. Secondary:

Number of Participants With Malignant Neoplasms - On Treatment or During 24-Week Follow-up Period [ Time Frame: On-treatment=up to Week 48 (Day 336); if discontinued early, all data up to 5 days after discontinuation date. 24-week follow-up=limited to end-of-dosing values and those from 6 days after last dose of study therapy to end of follow-up. ]

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28. Secondary:

Number of Participants Undergoing Liver Transplant - On-Treatment or 24-Week Follow-Up [ Time Frame: On-treatment=up to Week 48 (Day 336); if discontinued early, all data up to 5 days after discontinuation date. 24-week follow-up=limited to end-of-dosing values and those from 6 days after last dose of study therapy to end of follow-up. ]

Show Outcome Measure 28

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: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

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
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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:	NCT00065507 History of Changes
Other Study ID Numbers:	AI463-048
Study First Received:	July 28, 2003
Results First Received:	February 25, 2010
Last Updated:	February 2, 2012
Health Authority:	United States: Food and Drug Administration