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

Study Overview
=================
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.

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

Conditions
-----------------
Hepatitis B

Intervention / Treatment
-----------------
* Drug: Entecavir (ETV)
* Drug: Adefovir (ADV)


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hepatic decompensation