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

Hepatitis B Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00065507
• Other study ID #: AI463-048
• Status: Completed
• Phase: Phase 3
• First received: July 28, 2003
• Last updated: June 17, 2013
• Start date: August 2003
• Est. completion date: May 2013

Study information

• Verified date: June 2013
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 195
• Est. completion date: May 2013
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B

Intervention

Drug:
• Entecavir (ETV)
Tablets, Oral, 1 mg once daily, 96 weeks from the time the last patient is randomized
• Adefovir (ADV)
Tablets, Oral, 10 mg, once daily, 96 weeks from the time the last patient is randomized

Locations

Country	Name	City	State
Brazil	Local Institution	Porto Alegre - Rs	Rio Grande Do Sul
Brazil	Local institution	Sao Paulo
Brazil	Local Institution	Sao Paulo
Brazil	Local Institution	Sao Paulo - Sp	Sao Paulo
Canada	Local Institution	Calgary	Alberta
Canada	Local Institution	Vancouver	British Columbia
France	Local Institution	Clichy Cedex
France	Local Institution	Strasbourg
Greece	Local institution	Athens
Greece	Local Institution	Athens
Greece	Local Institution	Athens
Greece	Local Instituition	Thessaloniki
Greece	Local Institution	Thessaloniki
Hong Kong	Local Institution	Tai Po
India	Local Institution	Hyderabad	Andhra Pradesh
India	Local Institution	Kolkata
India	Local Institution	Lucknow
India	Local Institution	New Delhi
Indonesia	Local Institution	Jakarta
Philippines	Local Institution	Cebu
Philippines	Local Institution	Manila
Poland	Local Institution	Bydgoszcz
Poland	Local Institution	Chorzow
Poland	Local Institution	Krakow
Poland	Local Institution	Lodz
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Smolensk
Singapore	Local Institution	Singapore
Singapore	Local Institution	Singapore
Singapore	Local Institution	Singapore
Singapore	Local Institution	Singapore
South Africa	Local Institution	Observatory	Western Cape
South Africa	Local Institution	Paarl	Western Cape
Taiwan	Local Institution	Changhua
Taiwan	Local Institution	Taichung
Taiwan	Local Institution	Taipei
Taiwan	Local Institution	Taoyuan
Taiwan	Local Institution	Tianan
Thailand	Local Institution	Bangkok
Thailand	Local Institution	Bangkok
Thailand	Local Institution	Hatyai
Turkey	Local Institution	Adana
Turkey	Local Institution	Izmir
United Kingdom	Local Institution	London	Greater London
United States	Pediatric Gasteroenterology	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Baylor University Medical Center	Dallas	Texas
United States	Ut Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Health System Irb	Detroit	Michigan
United States	Hawaii Medical Center East	Honolulu	Hawaii
United States	Indiana University Med Center	Indianapolis	Indiana
United States	The Cht Liver Research Center	Louisville	Kentucky
United States	University Of Miami School Of Medicine	Miami	Florida
United States	Yale University School Of Medicine	New Haven	Connecticut
United States	Columbia Presbyterian Medical Center (Cpmc)	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	Integris Baptist Medical Center	Oklahoma City	Oklahoma
United States	Mcguire Dvamc	Richmond	Virginia
United States	Research And Education, Inc.	San Diego	California
United States	California Pacific Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  France,  Greece,  Hong Kong,  India,  Indonesia,  Philippines,  Poland,  Russian Federation,  Singapore,  South Africa,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	Number of Participants With HBV DNA < 300 Copies/mL by PCR At Week 24		Week 24	No
Secondary	Number of Participants With HBV DNA < 300 Copies/mL by PCR At Week 48		Week 48	No
Secondary	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	No
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		Baseline, Week 4, Week 8, Week 12, Week 24, Week 48	No
Secondary	>=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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
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	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.	Yes
Secondary	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.	Yes
Secondary	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.	Yes
Secondary	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.	Yes
Secondary	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.	Yes

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