Safety and Antiviral Activity of Entecavir in Participants With Chronic Hepatitis B Following Monotherapy in Other Entecavir Trials

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
A Preliminary Assessment of Safety and Antiviral Activity of Open-label Entecavir in Subjects With Chronic Hepatitis B Following Monotherapy in Other Entecavir Trials

Conditions
-----------------
HBV, Hepatitis B Virus

Intervention / Treatment
-----------------
* Drug: Entecavir
* Drug: Lamivudine


Participation Criteria
=================
Eligibility Criteria
-----------------
Key inclusion criteria: Age of 16 years and older Receipt of entecavir or lamivudine in a previous entecavir study. Participants who were, based on their response to entecavir: Virologic nonresponders at Week 48 Partial virologic responders who became nonresponders during the second year of treatment Partial virologic responders at Week 96 Complete responders who relapsed during postdosing follow-up Decompensated liver disease in AI463-048 that met 1 or more of the following criteria: Nonresponse to adefovir after at least 24 weeks of treatment Partial response to adefovir after 96 weeks of treatment Complete response to adefovir after relapsing during postdosing follow-up Demonstrated intolerance to adefovir Except for those participants enrolled from AI463-048, compensated liver disease. Key exclusion criteria: HIV coinfection Receiving nephrotoxic or hepatotoxic agents Ongoing opportunistic infections Hemoglobin level <11.0 g/dL except for those enrolled from AI463-048 Platelet count <70,000 mm^3 except for those enrolled from AI463-048 Absolute granulocyte count <1,500 cells/mm^3 Recent history of pancreatitis (within 24 weeks prior to first dose of therapy) Current evidence of ascites requiring paracentesis, hepatic encephalopathy, or variceal bleeding, except for those enrolled from AI463-048 Known history of allergy to nucleoside analogues.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entecavir, 1.0 mg, with or without lamivudine<br> | Drug: Entecavir<br>* Tablets, Oral, 1.0 mg, once daily<br>* Other names: Baraclude;Drug: Lamivudine<br>* Oral, 100 mg, daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. . | 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. | Day 1 of treatment through Week 240 | 
| 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. | 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. | 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. | 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. | End of dosing to Week 48 off-treatment follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Study: Percentage of Participants With Sustained HBV DNA Level <300 Copies/mL by PCR Assay |  | Study entry to Week 192 | 
| Overall Study: Percentage of Participants With Sustained HBV DNA <10^4 Copies/mL by PCR Assay |  | Study entry to Week 192 | 
| Overall Study: Percentage of Participants by HBV DNA Category by PCR Assay | Observed values. | Baseline to Week 192 | 
| Overall Study: Mean HBV DNA Level by PCR Assay |  | Study entry to Week 216 | 
| Overall Study: Percentage of Participants Who Achieved a Loss of Hepatitis B e Antigen (HBeAg) | Observed values. | Study entry to Week 216 | 
| Overall Study: Percentage of Participants With HBeAg Seroconversion | Observed values. Seroconversion=negative HBeAg with detectable anti-HBe antibody. | Study entry to Week 216 | 
| Overall Study: Mean Alanine Transaminase (ALT) Levels | Observed values. | 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. | 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. | 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. | Baseline to Week 192 | 
| Overall Study: Percentage of Participants With a Confirmed ≥1 log10 Increase From Nadir in HBV DNA by PCR Assay |  | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | End of dosing to Weeks 48 and 96 off-treatment follow-up |