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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00065507
First received: July 28, 2003
Last updated: June 17, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Hepatitis B
Drug: Entecavir (ETV)
Drug: Adefovir (ADV)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Change From Baseline in Hepatitis B Virus (HBV) DNA by Polymerase Chain Reaction (PCR) at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    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:
  • Change From Baseline in HBV DNA by PCR at Week 48 [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  • Number of Participants With HBV DNA < 300 Copies/mL by PCR At Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 48 ] [ Designated as safety issue: No ]
  • >=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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 24, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 48 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 24, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: on-treatment events obtained after the start of therapy and no more than 5 days after the last dose of study therapy. ] [ Designated as safety issue: Yes ]
    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 [ 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. ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: On-treatment=up to Week 48 (Day 336); if discontinued early, all data up to 5 days after discontinuation date. ] [ Designated as safety issue: Yes ]
    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 [ 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. ] [ Designated as safety issue: Yes ]
    Data includes type of malignant neoplasm.

  • 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. ] [ Designated as safety issue: Yes ]

Enrollment: 195
Study Start Date: August 2003
Study Completion Date: May 2013
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Active Comparator: A2 Drug: Adefovir (ADV)
Tablets, Oral, 10 mg, once daily, 96 weeks from the time the last patient is randomized

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00065507

  Show 61 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
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: June 17, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Bristol-Myers Squibb:
hepatic decompensation

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis B
DNA Virus Infections
Digestive System Diseases
Enterovirus Infections
Hepadnaviridae Infections
Hepatitis, Viral, Human
Liver Diseases
Picornaviridae Infections
RNA Virus Infections
Virus Diseases
Adefovir
Adefovir dipivoxil
Entecavir
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014