The purpose of this study is to provide entecavir to participants who have completed another entecavir trial without achieving virologic response or who relapsed during postdosing follow-up.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
1,053
Tablets, Oral, 1.0 mg, once daily
Oral, 100 mg, daily
Overall Study: Number of Participants With Death As Outcome, Any Adverse Event (AE), Grade 3-4 AEs, Serious Adverse Events (SAEs), and Discontinuations Due to AEs
An AE is a new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not be causally related to treatment. An SAE is an unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. ALT=alanine transaminase; ULN=upper limit of normal.
Time frame: Continuously from Day 1 through Week 240
Overall Study: Number of Participants With Normal Hematology Values at Baseline and Abnormalities in Hematology Laboratory Test Results Through Week 240
Hemoglobin (g/dL): Grade (Gr) 1=9.5-11.0; Gr 2=8.0-\<9.5; Gr 3=6.5-\<8.0; Gr 4=\<6.5 White blood cells (cells/mm\^3): Gr 1=2,500-\<4,000; Gr 2=1,000-\<2,500; Gr 3=800-\<1,000; Gr 4=\<800. Neutrophils (cells/mm\^3): Gr 1=1000-\<1500; Gr 2=750-\<1000; Gr 3=500-\<750; Gr 4=\<500. Platelets (cells/mm\^3): Gr 1=75,000-99,000; Gr 2=50,000-\<75,000; Gr 3=20,000-\<50,000; Gr 4=\<20,000. Prothrombin time (seconds): Gr 1=1.01-\<1.26\*ULN; Gr 2=1.26-\<1.51 \*ULN; Gr 3=1.51-3\*ULN; Gr 4=\>3\*ULN. INR: Gr 1=1.24-1.5; Gr 2=1.5-2; Gr 3=2-3; Gr 4=\>3. INR=international normalized ratio; ULN=upper limit of normal. .
Time frame: Day 1 of treatment through Week 240
Overall Study: Number of Participants With Normal Pancreatic Enzyme and Renal Function Values at Baseline and Abnormalities in Pancreatic Enzyme and Renal Function Laboratory Test Results at End of Dosing
Amylase: Grade 1=1.10-\<1.40\*ULN; Grade 2=1.40-\< 2.10\*ULN; Grade 3=2.10-5.00\*ULN; Grade 4=\>5.00\*ULN. Lipase: Grade 1.1-\<1.4\*ULN; Grade 2=1.4-\<2.1\*ULN; Grade 3=2.1-5.0\*ULN; Grade 4=\>5.0\*ULN. Creatinine: Grade 1=1.10-\< 1.60\*ULN; Grade 2=1.60-\<3.10\*ULN; Grade 3=3.10-6.00\*ULN; Grade 4=\>6.00\*ULN. Blood urea nitrogen (BUN): Grade 1=1.25-\<2.60\*ULN; Grade 2=2.60-\<5.10\*ULN; Grade 3=5.10-10\*ULN; Grade 4=\>10\*ULN. ULN=upper limit of normal.
Time frame: Day 1 of treatment through Week 240
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Overall Study: Number of Participants With Normal Electrolyte and Fasting Glucose Values at Baseline and Abnormalities in Electrolyte and Fasting Glucose Laboratory Test Results at End of Dosing
Hypochloremia: Grade (Gr) 1=90-93; Gr 2=85-\<90; Gr 3=80-\<85; Gr 4=40-\<80. Hyperchloremia: Gr 1=113-\<117; Gr 2=117-\<121; Gr 3=121-125; Gr 4\>125. Hypocarbia: Gr 1=19-21; Gr 2=15-\<19; Gr 3=41-45; Gr 4=\>45. Hypercarbia: Gr 1=31-36; Gr 2=37-40; Gr 3=41-45; Gr 4=\>45. Hyponatremia: Gr 1=130-132; Gr 2=123-\<130; Gr 3=116-\<123; Gr 4\<116. Hypernatremia: Gr 1=148-\<151; Gr 2=151-\<158; Gr 3=158-165; Gr 4=\>165. Hypokalemia: Gr 1=3-3.4; Gr 2=2.5-\<3; Gr 3=2-\<2.5; Gr 4=\<2. Hyperkalemia: Gr 1=5.6-\<6.1; G2=6.1-\<6.6; Gr 3=6.6-7; Gr 4=\>7. Hypoglycemia: Gr 1=55-64; Gr 2=40-\<55; Gr 3=30-\< 40; G4=-\<30. Hyperglycemia: Gr 1=116-\<161; Gr 2=161-\<251; Gr 3=251-500; Gr 4\>500.
Time frame: Day 1 of treatment through Week 240
Week 144: Number of Participants With Death As Outcome, Any AE, Grade 3-4 AEs, SAEs, Discontinuations Due to AEs, and Abnormalities in Selected Laboratory Test Results
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. AST=aspartate aminotransferase; ULN=upper limit of normal.
Time frame: Continuously from Day 1 through Week 144
Week 192: Number of Participants With Death As Outcome, Any AE, Grade 3-4 AEs, SAEs, Discontinuations Due to AEs, and Abnormalities in Selected Laboratory Test Results
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. CTC Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling. ALT=alanine aminotransferase; ULN=upper limit of normal.
Time frame: Continuously from Day 1 through Week 192
Off-treatment Follow-up: Percentage of Participants With Sustained Hepatitis B Virus (HBV) DNA <10,000 Copies by Polymerase Chain Reaction (PCR) Assay (Amendment 11 Cohort)
The Amendment 11 Cohort consisted of participants who were hepatitis B e antigen (HBeAg) negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA \<300 copies/mL by PCR assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks prior to end of dosing, and serum ALT levels ≤1.0\*ULN at the end of study drug dosing.ALT=alanine aminotransferase; ULN=upper limit of normal.
Time frame: End of dosing to Week 48 off-treatment follow-up
Overall Study: Percentage of Participants With Sustained HBV DNA Level <300 Copies/mL by PCR Assay
Time frame: Study entry to Week 192
Overall Study: Percentage of Participants With Sustained HBV DNA <10^4 Copies/mL by PCR Assay
Time frame: Study entry to Week 192
Overall Study: Percentage of Participants by HBV DNA Category by PCR Assay
Observed values.
Time frame: Baseline to Week 192
Overall Study: Mean HBV DNA Level by PCR Assay
Time frame: Study entry to Week 216
Overall Study: Percentage of Participants Who Achieved a Loss of Hepatitis B e Antigen (HBeAg)
Observed values.
Time frame: Study entry to Week 216
Overall Study: Percentage of Participants With HBeAg Seroconversion
Observed values. Seroconversion=negative HBeAg with detectable anti-HBe antibody.
Time frame: Study entry to Week 216
Overall Study: Mean Alanine Transaminase (ALT) Levels
Observed values.
Time frame: Study entry to Week 216
Overall Study: Percentage of Participants Who Achieved ALT Normalization
ULN=upper limit of normal. ALT normalization=ALT levels ≤1.0\*ULN.
Time frame: Study entry to Week 216
Week 192: Percentage of Participants With Histologic Improvement (Efficacy Evaluable Cohort)
The Knodell Histologic Activity Index scores stage of necrosis and grade of inflammation in liver biopsies. Components are necrosis near the portal vein, intralobular degeneration and focal necrosis, portal inflammation, and fibrosis. The 4 components are scored from 1 to 4 and 1 to 10 (necrosis near the portal vein) and combined for a total score, with 22 being the highest possible score. Higher the score for each component=greater liver damage. Histologic improvement=a ≥2-point reduction in total Knodell score and no worsening in fibrosis. Cohort participants had to have adequate baseline and long-term biopsy samples and baseline Knodell necroinflammatory scores ≥2.
Time frame: Baseline to Week 192
Week 192: Percentage of Participants With Improvement in Fibrosis (Efficacy Evaluable Cohort)
The Ishak Modification for Hepatic Activity Index (HAI) scores necroinflammatory activity in chronic hepatitis. 0=no fibrosis, 1=fibrosis expansion of some portal areas, 2=fibrosis expansion of most portal areas, 3=fibrosis expansion of most portal areas with occasional bridging, 4=fibrosis expansion of portal areas with marked bridging, 5=incomplete cirrhosis, 6=probable or definite cirrhosis. Higher score=more severe necrosis. Improvement in fibrosis=≥1-point reduction in HAI score. Cohort participants had to have adequate baseline and long-term biopsy samples and baseline Knodell scores ≥2.
Time frame: Baseline to Week 192
Overall Study: Percentage of Participants With a Confirmed ≥1 log10 Increase From Nadir in HBV DNA by PCR Assay
Time frame: Baseline to Week 144
Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay, Loss of HBeAG, Seroconversion, and ALT ≤1.0*Upper Limit of Normal (ULN) (Entecavir Continuous Treatment Cohort)
The Entecavir Continuous Treatment Cohort consisted of participants from study AI463-022 (NCT00035633) who were nucleoside-naive HBeAg-positive and enrolled in the current study with ≤35 days off treatment between the last dose in AI463-022 and the first dose in the current. This cohort is considered to be on continuous entecavir treatment and permitted assessment of continuous administration of entecavir in AI463-022 and the current study.
Time frame: Baseline to Weeks 48, 96, 144, 192, and 240
Percentage of Participants Who Achieved HBV DNA <300 and <10^4 Copies/mL by PCR Assay and ALT ≤1.0*Upper Limit of Normal (ULN) (Entecavir Retreatment Cohort)
The Entecavir Retreatment Cohort consisted of participants who were nucleoside-naive, HBeAg-negative and enrolled from BMS study AI463-027 with \>60 days off treatment between the last dose in AI463-027 and the first dose in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as retreatment in the current study.
Time frame: Baseline to Weeks 48, 96, and 144
Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay, Loss of HBeAg, HBeAg Seroconversion, and ALT ≤1.0*ULN (Lamivudine Continuous Switch Cohort)
The Lamivudine Continuous Switch Cohort consisted of participants who were nucleoside-naive, HBeAg-positive and received lamivudine in BMS study AI463-022 (NCT00035633) and enrolled in the current study with ≤35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.
Time frame: Baseline to Week 96
Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Continuous Switch Cohort)
The Lamivudine Continuous Switch Cohort consisted of participants who were nucleoside-naive, HBeAg-positive and received lamivudine in BMS study AI463-022 (NCT00035633) and enrolled in the current study with ≤35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.
Time frame: Baseline to Week 144
Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort)
The Lamivudine Retreatment Switch Cohort consisted of participants who were nucleoside-naive HBeAg negative and enrolled from BMS study AI463-027 (NCT00035789) with \>60 days between end of dosing in AI463-027 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.
Time frame: Baseline to Week 96
Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort)
The Lamivudine Retreatment Switch Cohort consisted of participants who were nucleoside-naive HBeAg negative and enrolled from BMS study AI463-027 (NCT00035789) with \>60 days between end of dosing in AI463-027 and the switch to entecavir in the current study. This cohort permitted assessment of entecavir, 1.0 mg, provided as switch therapy in the current study.
Time frame: Baseline to Week 144
Off-treatment Follow-up: Percentage of Participants With Sustained HBV DNA <1,000, <300, and <10,000 Copies/mL by PCR Assay and With ALT ≤1*ULN (Amendment 11 Cohort)
The Amendment 11 Cohort consisted of participants who were HBeAg negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA \<300 copies/mL by PCR Assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks prior to end of dosing, and serum ALT levels ≤1.0\*ULN at the end of study drug dosing. ULN=upper limit of normal.
Time frame: End of dosing to Weeks 48 and 96 off-treatment follow-up
Off-treatment Follow-up: Mean Change in HBV DNA (Amendment 11 Cohort)
The Amendment 11 Cohort consisted of participants who were HBeAg negative and who had compensated liver disease, a minimum of 192 weeks (4 years) of treatment with entecavir, HBV DNA \<300 copies/mL by PCR assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks prior to end of dosing, and serum ALT levels ≤1.0\*ULN at the end of study drug dosing.
Time frame: End of dosing to Weeks 48 and 96 off-treatment follow-up