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

Comparison of the Efficacy and Safety of Entecavir Versus Adefovir in Subjects Chronically Infected With Hepatitis B Virus and Evidence of Hepatic Decompensation

This is a phase IIIb comparative study of entecavir 1.0 mg once daily (QD) vs. adefovir 10 mg QD in patients who have chronic hepatitis B infection and hepatic decompensation. The patients are treated for 96 weeks after the last subject is randomized.

Study Overview

• Status: Completed
• Conditions: Hepatitis B
• Intervention / Treatment: Drug: Entecavir (ETV); Drug: Adefovir (ADV)

• Study Type: Interventional
• Enrollment (Actual): 195
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 01246-000
    • Local Institution
  • Sao Paulo, Brazil, 01246-903
    • Local Institution
  • Rio Grande Do Sul
    • Porto Alegre - Rs, Rio Grande Do Sul, Brazil, 90035-003
      • Local Institution
  • Sao Paulo
    • Sao Paulo - Sp, Sao Paulo, Brazil, 05403-900
      • Local Institution
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Local Institution
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1H2
      • Local Institution
• France
  • Clichy Cedex, France, 92118
    • Local Institution
  • Strasbourg, France, 67100
    • Local Institution
• Greece
  • Athens, Greece, 11527
    • Local Institution
  • Athens, Greece, 11522
    • Local Institution
  • Athens, Greece, 15127
    • Local Institution
  • Thessaloniki, Greece, 54006
    • Local Instituition
  • Thessaloniki, Greece, 570 10
    • Local Institution
• Hong Kong
  • Tai Po, Hong Kong
    • Local Institution
• India
  • Kolkata, India, 700020
    • Local Institution
  • Lucknow, India, 226014
    • Local Institution
  • New Delhi, India, 110002
    • Local Institution
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500082
      • Local Institution
• Indonesia
  • Jakarta, Indonesia, 10430
    • Local Institution
• Philippines
  • Cebu, Philippines, 6000
    • Local Institution
  • Manila, Philippines, 1008
    • Local Institution
• Poland
  • Bydgoszcz, Poland, 85-030
    • Local Institution
  • Chorzow, Poland, 41-500
    • Local Institution
  • Krakow, Poland, 31-202
    • Local Institution
  • Lodz, Poland, 91-347
    • Local Institution
• Russian Federation
  • Moscow, Russian Federation, 115446
    • Local Institution
  • Moscow, Russian Federation, 117333
    • Local Institution
  • Smolensk, Russian Federation, 214018
    • Local Institution
• Singapore
  • Singapore, Singapore, 308433
    • Local Institution
  • Singapore, Singapore, 529889
    • Local Institution
  • Singapore, Singapore, 169608
    • Local Institution
  • Singapore, Singapore, 119228
    • Local Institution
• South Africa
  • Western Cape
    • Observatory, Western Cape, South Africa, 7925
      • Local Institution
    • Paarl, Western Cape, South Africa, 7620
      • Local Institution
• Taiwan
  • Changhua, Taiwan, 500
    • Local Institution
  • Taichung, Taiwan, 404
    • Local Institution
  • Taipei, Taiwan, 100
    • Local Institution
  • Taoyuan, Taiwan, 333
    • Local Institution
  • Tianan, Taiwan, 704
    • Local Institution
• Thailand
  • Bangkok, Thailand, 10400
    • Local Institution
  • Bangkok, Thailand, 10700
    • Local Institution
  • Hatyai, Thailand, 90110
    • Local Institution
• Turkey
  • Adana, Turkey, 01330
    • Local Institution
  • Izmir, Turkey, 35100
    • Local Institution
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, NW3 2QG
      • Local Institution
• United States
  • California
    • San Diego, California, United States, 92115
      • Research and Education, Inc.
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Pediatric Gasteroenterology
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Medical Center East
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5121
      • Indiana University Med Center
  • Kentucky
    • Louisville, Kentucky, United States, 40292
      • The Cht Liver Research Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System Irb
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10032
      • Columbia Presbyterian Medical Center (Cpmc)
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • INTEGRIS Baptist Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75390-9151
      • UT Southwestern Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23249
      • McGuire DVAMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion

• Child-Pugh (CP) score >= 7
• Hepatitis B virus (HBV) viremia

Exclusion

• Alanine aminotransferase (ALT) > 15 x upper limit of normal (ULN)
• Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)/hepatitis D virus (HDV) coinfection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A2	Drug: Adefovir (ADV); Tablets, Oral, 10 mg, once daily, 96 weeks from the time the last patient is randomized
Experimental: A1	Drug: Entecavir (ETV); Tablets, Oral, 1 mg once daily, 96 weeks from the time the last patient is randomized; Other Names: Baraclude; BMS-200475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hepatitis B Virus (HBV) DNA by Polymerase Chain Reaction (PCR) at Week 24	Mean reduction in serum HBV DNA determined by PCR assay (log10 copies/mL) at Week 24 adjusted for baseline HBV DNA and lamivudine resistance (LVDr) status, based on linear regression analysis.	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HBV DNA by PCR at Week 48	Mean change from baseline in HBV DNA by PCR at Week 48, adjusted for baseline HBV DNA and LVDr Status.	Baseline, Week 48
Number of Participants With HBV DNA < 300 Copies/mL by PCR At Week 24		Week 24
Number of Participants With HBV DNA < 300 Copies/mL by PCR At Week 48		Week 48
Number of Participants Achieving Alanine Transaminase (ALT) Normalization (≤1.0 x Upper Limit of Normal [ULN]) at Weeks 24 and 48	Number of participants in each group who achieved ALT normalization (≤1.0 x upper limit of normal [ULN]) among those with baseline ALT >1.0 x ULN at Weeks 24 and 48	Week 24, Week 48
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		Baseline, Week 4, Week 8, Week 12, Week 24, Week 48
>=2-Point Reduction From Baseline in Child-Pugh Score Through Week 48	Child-Pugh classification assesses the prognosis of chronic liver disease by 5 clinical measures, scored 1-3 each (most severe derangement=3). Score range: 5 (best prognosis) to 15 (worst prognosis).	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Number of Participants With Improvement or No Worsening in Child-Pugh Score From Baseline to Week 48	Number of participants in each group with improvement or no worsening in Child-Pugh score from baseline to Week 48 as measured by improvement or no worsening in Child-Pugh score. Child-Pugh classification assesses the prognosis of chronic liver disease by 5 clinical measures, scored 1-3 each (most severe derangement=3). Score range: 5 (best prognosis) to 15 (worst prognosis).	Baseline, Week 4, Week 8, Week 12, Week 24, Week 48
Change From Baseline in Child-Pugh Score Through Week 48	Mean change from baseline in Child-Pugh score through week 48. Child-Pugh classification assesses the prognosis of chronic liver disease by 5 clinical measures, scored 1-3 each (most severe derangement=3). Score range: 5 (best prognosis) to 15 (worst prognosis).	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Number of Participants With Improvement in Child-Pugh Class at Week 24 and Week 48	Number of Participants in each group with improvement in Child-Pugh score from baseline to Week 48 as measured by improvement in Child-Pugh class. Improvement in Child-Pugh Class is defined as change from B to A or C to A. Evaluable subjects are subjects with Child-Pugh Class B or C at Baseline. Child-Pugh classification assesses the prognosis of chronic liver disease by 5 clinical measures, scored 1-3 each (most severe derangement=3). Score range: 5 (best prognosis) to 15 (worst prognosis). Child-Pugh class A to C employs the added score from above: 5-6=Class A; 7-9=Class B; 10-15=Class C.	Week 24, Week 48
Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores From Baseline Through Week 48	Adjusted mean change from baseline in MELD score through Week 48 (adjusted for baseline value). 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.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Improvement or No Worsening in MELD Score Through Week 48	Participants with improvement or no worsening (any decrease or no change from baseline in score) in MELD score through Week 48. 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.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 48
Mean Changes From Baseline in Quality of Life as Measured by the Short Form 36 (SF-36)	Scoring for the SF-36 will be done using the algorithm developed by the Research ANd Development(RAND) Corporation (a scale of 0-100). Higher scores represent better quality of life. Coding for items with 2-category responses=0 and 100; 3-category=0/50/100; 5-category=0/25/50/75/100; 6-category=0/20/40/60/80/100. Scores of items in the same scale are combined to create the 8 scale scores (physical functioning, role-physical, bodily-pain, general health, vitality, social functioning, role-emotional, mental health). Physical and mental health composite scores will be computed for the group.	Baseline, Week 24, Week 48
Mean Changes From Baseline in Quality of Life, as Measured by EuroQol-5D (EQ-5D) at Weeks 24 and 48	The EQ-5D has 5 attributes (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression), each with 3 levels (no problem, some problems, and major problems). This algorithm gives valuation (weights) to each of the 15 responses on the form. Each valuation is a negative number, subtracted from the maximum score of 1 (perfect well being). The overall health index score ranges from 0 (dead) to 1 (perfect health) value scale, and the visual analog scale ranges from 0 to 100. Item weights will be obtained from the EuroQol group.	Baseline, Week 24, Week 48
Change From Baseline in Albumin Through Week 48	Mean albumin levels, and mean change from baseline in albumin, a measure of synthetic liver function. Normal range for albumin = 3.5 - 5.3 g/dL.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Mean Change From Baseline in Prothrombin Time Through Week 48	Mean prothrombin time, and mean change from baseline in prothrombin time, a measure of synthetic liver function. Prothrombin time is the time it takes (in seconds) for a sample of blood to clot. Normal range for prothrombin time (PT) = 10-13 seconds.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Mean Change From Baseline in Total Bilirubin Through Week 48	Mean total bilirubin levels, and mean change from baseline in total bilirubin, a measure of liver secretory function.Normal range for total bilirubin = 0.2 - 1.2 mg/dL.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Change From Baseline in Platelet Count Through Week 48	Mean baseline platelet count and mean change from baseline in platelet count at specific timepoints. Platelets are the smallest particles found in the blood, which play a major role in forming blood clots. Normal range for platelets = 140 - 450 X 10*9 c/L.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Participants Achieving Albumin Normalization Through Week 48	Number of participants who achieved normalization of albumin (>= 1 x lower limit of normal [LLN]), a measure of liver function, at specific timepoints.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Participants Achieving Prothrombin Time Normalization Through Week 48	Number of participants who achieved normalization of prothrombin time (<= 1 x ULN), a measure of liver function, at specific timepoints.	Baseline, Week4, Week 8, Week 12, Week 24, Week 36, Week 48
Participants Achieving Total Bilirubin Normalization Through Week 48	Number of participants who achieved normalization of total bilirubin (<= 1 x ULN), a measure of liver function, at specific timepoints.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Participants Achieving Platelet Count Normalization Through Week 48	Number of participants who achieved normalization of platelet count (>= 1 x lower limit of normal [LLN]), a measure of liver function, at specific timepoints.	Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48
Number of Hepatocellular Carcinoma (HCC) Events at Different Time Points Through Week 48	HCC-free survival was analyzed using life tables. Measured values show the number of HCC events among treated participants at given time points.	Week 48
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	AE=any new untoward medical occurrence/worsening of a pre-existing medical condition regardless of causal relationship. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires/prolongs inpatient hospitalization; results in persistent/significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event. Grades:1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death. Confirmed increase in serum creatinine=values ≥0.5 mg/dL compared with baseline on 2 sequential measures.	on-treatment events obtained after the start of therapy and no more than 5 days after the last dose of study therapy.
Number of Participants With Treatment-Emergent Grade 3/4 Laboratory Abnormalities - Week 48 and Cumulative Data	Grade 3/4 laboratory abnormalities (hematology, electrolyte, lipase, liver function, metabolic, renal function, urinalysis). The Week 48 data set was used to evaluate the Week-48 on-treatment safety. The cumulative data set was used to evaluate the safety while on treatment. Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Grades:1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death.	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.
Number of Participants With Alanine Aminotransferase (ALT) Flares - On Treatment	ALT flare=ALT > 2 x baseline and > 10 x upper limit of normal (ULN) by clinical laboratory evaluation. Table includes number of participants with selected clinical events and/or laboratory abnormalities during ALT flares. Selected clinical events during ALT flares=ascites, hepatic encephalopathy, jaundice, bacterial peritonitis. Selected Laboratory abnormalities during ALT flares=international normalized ratio > 1.5 or prothrombin time >= 1.2 x ULN and total bilirubin >2.5 mg/dL and > 1 mg/dL increase from baseline.	On-treatment=up to Week 48 (Day 336); if discontinued early, all data up to 5 days after discontinuation date.
Number of Participants With Malignant Neoplasms - On Treatment or During 24-Week Follow-up Period	Data includes type of malignant neoplasm.	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.
Number of Participants Undergoing Liver Transplant - On-Treatment or 24-Week Follow-Up		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.

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: August 1, 2003
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: July 28, 2003
• First Submitted That Met QC Criteria: July 28, 2003
• First Posted (Estimate): July 29, 2003

Study Record Updates

• Last Update Posted (Estimate): June 24, 2013
• Last Update Submitted That Met QC Criteria: June 17, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: hepatic decompensation
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Entecavir; Adefovir
• Other Study ID Numbers: AI463-048