Comparison of Entecavir to Adefovir in Chronic Hepatitis B Virus (HBV) Patients With Hepatic Decompensation
- Registration Number
- NCT00065507
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 195
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description A1 Entecavir (ETV) - A2 Adefovir (ADV) -
- Primary Outcome Measures
Name Time Method Change From Baseline in Hepatitis B Virus (HBV) DNA by Polymerase Chain Reaction (PCR) at Week 24 Baseline, 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline in HBV DNA by PCR at Week 48 Baseline, Week 48 Mean change from baseline in HBV DNA by PCR at Week 48, adjusted for baseline HBV DNA and LVDr Status.
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 Week 24, Week 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
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 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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).
Number of Participants With Improvement or No Worsening in Child-Pugh Score From Baseline to Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, 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).
Change From Baseline in Child-Pugh Score Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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).
Number of Participants With Improvement in Child-Pugh Class at Week 24 and Week 48 Week 24, 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.
Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores From Baseline Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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.
Improvement or No Worsening in MELD Score Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, 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.
Mean Changes From Baseline in Quality of Life as Measured by the Short Form 36 (SF-36) Baseline, Week 24, Week 48 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.
Mean Changes From Baseline in Quality of Life, as Measured by EuroQol-5D (EQ-5D) at Weeks 24 and 48 Baseline, Week 24, Week 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.
Change From Baseline in Albumin Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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.
Mean Change From Baseline in Prothrombin Time Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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.
Mean Change From Baseline in Total Bilirubin Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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.
Change From Baseline in Platelet Count Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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.
Participants Achieving Albumin Normalization Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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.
Participants Achieving Prothrombin Time Normalization Through Week 48 Baseline, Week4, Week 8, Week 12, Week 24, Week 36, Week 48 Number of participants who achieved normalization of prothrombin time (\<= 1 x ULN), a measure of liver function, at specific timepoints.
Participants Achieving Total Bilirubin Normalization Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 Number of participants who achieved normalization of total bilirubin (\<= 1 x ULN), a measure of liver function, at specific timepoints.
Participants Achieving Platelet Count Normalization Through Week 48 Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, 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.
Number of Hepatocellular Carcinoma (HCC) Events at Different Time Points Through Week 48 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.
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 on-treatment events obtained after the start of therapy and no more than 5 days after the last dose of study therapy. 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.
Number of Participants With Treatment-Emergent Grade 3/4 Laboratory Abnormalities - Week 48 and Cumulative Data 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. 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.
Number of Participants With Alanine Aminotransferase (ALT) Flares - On Treatment On-treatment=up to Week 48 (Day 336); if discontinued early, all data up to 5 days after discontinuation date. 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.
Number of Participants With Malignant Neoplasms - On Treatment or During 24-Week Follow-up Period 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. Data includes type of malignant neoplasm.
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.
Trial Locations
- Locations (19)
California Pacific Medical Center
🇺🇸San Francisco, California, United States
Local institution
🇬🇷Athens, Greece
Mount Sinai Medical Center
🇺🇸New York, New York, United States
Baylor University Medical Center
🇺🇸Dallas, Texas, United States
Mcguire Dvamc
🇺🇸Richmond, Virginia, United States
Pediatric Gasteroenterology
🇺🇸Atlanta, Georgia, United States
Hawaii Medical Center East
🇺🇸Honolulu, Hawaii, United States
Local Institution
🇬🇧London, Greater London, United Kingdom
Ut Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Indiana University Med Center
🇺🇸Indianapolis, Indiana, United States
The Cht Liver Research Center
🇺🇸Louisville, Kentucky, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Integris Baptist Medical Center
🇺🇸Oklahoma City, Oklahoma, United States
Local Instituition
🇬🇷Thessaloniki, Greece
University Of Miami School Of Medicine
🇺🇸Miami, Florida, United States
Columbia Presbyterian Medical Center (Cpmc)
🇺🇸New York, New York, United States
Henry Ford Health System Irb
🇺🇸Detroit, Michigan, United States
Research And Education, Inc.
🇺🇸San Diego, California, United States
Yale University School Of Medicine
🇺🇸New Haven, Connecticut, United States