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

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT01438424
Collaborator
(none)
1,053
Enrollment
1
Arm
122.9
Duration (Months)

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
1053 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Study Start Date :
Jan 1, 2001
Actual Primary Completion Date :
Dec 1, 2009
Actual Study Completion Date :
Apr 1, 2011

Arms and Interventions

Arm Intervention/Treatment
Experimental: Entecavir, 1.0 mg, with or without lamivudine

Drug: Entecavir
Tablets, Oral, 1.0 mg, once daily
Other Names:
  • Baraclude

    • Drug: Lamivudine
    Oral, 100 mg, daily

    Outcome Measures

    Primary Outcome Measures

    1. 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 [Continuously from Day 1 through Week 240]

      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.

    2. Overall Study: Number of Participants With Normal Hematology Values at Baseline and Abnormalities in Hematology Laboratory Test Results Through Week 240 [Day 1 of treatment 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. .

    3. 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 [Day 1 of treatment through Week 240]

      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.

    4. 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 [Day 1 of treatment through Week 240]

      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.

    5. 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 [Continuously from Day 1 through Week 144]

      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.

    6. 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 [Continuously from Day 1 through Week 192]

      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.

    7. 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) [End of dosing to Week 48 off-treatment follow-up]

      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.

    Secondary Outcome Measures

    1. Overall Study: Percentage of Participants With Sustained HBV DNA Level <300 Copies/mL by PCR Assay [Study entry to Week 192]

    2. Overall Study: Percentage of Participants With Sustained HBV DNA <10^4 Copies/mL by PCR Assay [Study entry to Week 192]

    3. Overall Study: Percentage of Participants by HBV DNA Category by PCR Assay [Baseline to Week 192]

      Observed values.

    4. Overall Study: Mean HBV DNA Level by PCR Assay [Study entry to Week 216]

    5. Overall Study: Percentage of Participants Who Achieved a Loss of Hepatitis B e Antigen (HBeAg) [Study entry to Week 216]

      Observed values.

    6. Overall Study: Percentage of Participants With HBeAg Seroconversion [Study entry to Week 216]

      Observed values. Seroconversion=negative HBeAg with detectable anti-HBe antibody.

    7. Overall Study: Mean Alanine Transaminase (ALT) Levels [Study entry to Week 216]

      Observed values.

    8. Overall Study: Percentage of Participants Who Achieved ALT Normalization [Study entry to Week 216]

      ULN=upper limit of normal. ALT normalization=ALT levels ≤1.0*ULN.

    9. Week 192: Percentage of Participants With Histologic Improvement (Efficacy Evaluable Cohort) [Baseline to Week 192]

      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.

    10. Week 192: Percentage of Participants With Improvement in Fibrosis (Efficacy Evaluable Cohort) [Baseline to Week 192]

      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.

    11. Overall Study: Percentage of Participants With a Confirmed ≥1 log10 Increase From Nadir in HBV DNA by PCR Assay [Baseline to Week 144]

    12. 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) [Baseline to Weeks 48, 96, 144, 192, and 240]

      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.

    13. 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) [Baseline to Weeks 48, 96, and 144]

      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.

    14. 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) [Baseline to Week 96]

      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.

    15. Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Continuous Switch Cohort) [Baseline to Week 144]

      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.

    16. Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort) [Baseline to Week 96]

      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.

    17. Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort) [Baseline to Week 144]

      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.

    18. 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) [End of dosing to Weeks 48 and 96 off-treatment follow-up]

      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.

    19. Off-treatment Follow-up: Mean Change in HBV DNA (Amendment 11 Cohort) [End of dosing to Weeks 48 and 96 off-treatment follow-up]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    16 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Bristol-Myers Squibb

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01438424
    Other Study ID Numbers:
    • AI463-901
    First Posted:
    Sep 22, 2011
    Last Update Posted:
    Aug 23, 2012
    Last Verified:
    Jul 1, 2012
    Additional relevant MeSH terms:
    Hepatitis A
    Hepatitis B
    Hepatitis B, Chronic
    Hepatitis
    Lamivudine
    Entecavir

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Of 1053 participants enrolled, 1051 received treatment.
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir once daily (QD) with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Period Title: Overall Study
    STARTED 1051
    COMPLETED 634
    NOT COMPLETED 417

    Baseline Characteristics

    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir once daily (QD) with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Overall Participants 1051
    Age, Customized (Years) [Median (Standard Deviation) ]
    Median (Standard Deviation) [Years]
    41
    (13)
    Sex: Female, Male (Count of Participants)
    Female
    241
    22.9%
    Male
    810
    77.1%
    Race/Ethnicity, Customized (Number) [Number]
    Asian/Pacific Islander
    544
    51.8%
    White
    481
    45.8%
    Black/African American
    18
    1.7%
    Missing
    2
    0.2%
    Native Hawaiian/Other Pacific Islander
    2
    0.2%
    Other
    2
    0.2%
    Filipino
    1
    0.1%
    Hispanic/Latino
    1
    0.1%
    Region: Continent (Number) [Number]
    Asia
    451
    42.9%
    Europe
    334
    31.8%
    North America
    141
    13.4%
    South America
    125
    11.9%
    Age (Years) [Mean (Full Range) ]
    Mean (Full Range) [Years]
    41

    Outcome Measures

    1. Secondary Outcome
    Title Overall Study: Percentage of Participants With Sustained HBV DNA Level <300 Copies/mL by PCR Assay
    Description
    Time Frame Study entry to Week 192

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    At study entry (n=1051)
    17
    1.6%
    Week 48 (n=905)
    63
    6%
    Week 96 (n=691)
    67
    6.4%
    Week 144 (n=597)
    73
    6.9%
    Week 192 (n=485)
    78
    7.4%
    2. Secondary Outcome
    Title Overall Study: Percentage of Participants With Sustained HBV DNA <10^4 Copies/mL by PCR Assay
    Description
    Time Frame Study entry to Week 192

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    At study entry (n=1051)
    28
    2.7%
    Week 48 (n=905)
    76
    7.2%
    Week 96 (n=691)
    77
    7.3%
    Week 144 (n=597)
    81
    7.7%
    Week 192 (n=485)
    85
    8.1%
    3. Secondary Outcome
    Title Overall Study: Percentage of Participants by HBV DNA Category by PCR Assay
    Description Observed values.
    Time Frame Baseline to Week 192

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants received 1 mg of entecavir QD with or without lamivudine.
    Measure Participants 1051
    Baseline: <300 copies/mL (n=1051)
    17
    (4) 1.6%
    Baseline: 300 - <1.0E3 copies/mL (n=1051)
    4
    (8) 0.4%
    Baseline: 1.0E3 - <1.0E4 copies/mL (n=1051)
    8
    (13) 0.8%
    Baseline: 1.0E4 - <1.0E5 copies/mL (n=1051)
    8
    (11) 0.8%
    Baseline: 1.0E5 - <1.0E6 copies/mL (n=1051)
    12
    1.1%
    Baseline: 1.0E6 - <1.0E7 copies/mL (n=1051)
    13
    1.2%
    Baseline: 1.0E7 - <1.0E8 copies/mL (n=1051)
    8
    0.8%
    Baseline: 1.0E8 - <1.0E9 copies/mL (n=1051)
    11
    1%
    Baseline: 1.0E9 - <1.0E10 copies/mL (n=1051)
    13
    1.2%
    Baseline: >= 1.0E10 copies/mL (n=1051)
    6
    0.6%
    Week 192: < 300 copies/mL (n=485)
    78
    7.4%
    Week 192: 300 - <1.0E3 copies/mL (n=485)
    3
    0.3%
    Week 192: 1.0E3 - <1.0E4 copies/mL (n=485)
    3
    0.3%
    Week 192: 1.0E4 - <1.0E5 copies/mL (n=485)
    4
    0.4%
    Week 192: 1.0E5 - <1.0E6 copies/mL (n=485)
    2
    0.2%
    Week 192: 1.0E6 - <1.0E7 copies/mL (n=485)
    2
    0.2%
    Week 192: 1.0E7 - <1.0E8 copies/mL (n=485)
    1
    0.1%
    Week 192: 1.0E8 - <1.0E9 copies/mL (n=485)
    5
    0.5%
    Week 192: 1.0E9 - <1.0E10 copies/mL (n=485)
    2
    0.2%
    Week 192: >= 1.0E10 copies/mL (n=485)
    0
    0%
    4. Primary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study drug in the current study.
    Arm/Group Title Entecavir, 0.5 or 1.0 mg QD, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir once daily (QD) with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine. All participants, regardless of dosing or regimen, included in these safety analyses.
    Measure Participants 1051
    Deaths on treatment
    18
    1.7%
    Deaths off treatment
    9
    0.9%
    SAEs on treatment
    169
    16.1%
    Discontinuations due to AEs on treatment
    14
    1.3%
    Any AE on treatment
    900
    85.6%
    Grade 3 and 4 AEs on treatment
    203
    19.3%
    Malignancies on and off treatment
    35
    3.3%
    ALT flares (ALT>2*entry and >10*ULN) on treatment
    32
    3%
    Hepatic disease progression on and off treatment
    33
    3.1%
    5. Secondary Outcome
    Title Overall Study: Mean HBV DNA Level by PCR Assay
    Description
    Time Frame Study entry to Week 216

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    At study entry (n=1051)
    6.14
    (2.667)
    Week 12 (n=1017)
    3.87
    (1.749)
    Week 24 (n=1010)
    3.62
    (1.684)
    Week 48 (n=905)
    3.37
    (1.543)
    Week 72 (n=769)
    3.31
    (1.549)
    Week 96 (n=691)
    3.34
    (1.592)
    Week 120 (n=629)
    3.32
    (1.665)
    Week 144 (n=597)
    3.34
    (1.826)
    Week 168 (n=514)
    3.18
    (1.663)
    Week 192 (n=485)
    3.19
    (1.757)
    Week 216 (n=455)
    3.20
    (1.789)
    6. Secondary Outcome
    Title Overall Study: Percentage of Participants Who Achieved a Loss of Hepatitis B e Antigen (HBeAg)
    Description Observed values.
    Time Frame Study entry to Week 216

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants received 1 mg of entecavir QD with or without lamivudine.
    Measure Participants 1051
    At study entry (n=1051)
    34
    3.2%
    Week 12 (n=935)
    40
    3.8%
    Week 24 (n=939)
    42
    4%
    Week 48 (n=864)
    46
    4.4%
    Week 72 (n=752)
    45
    4.3%
    Week 96 (n=679)
    50
    4.8%
    Week 120 (n=609)
    51
    4.9%
    Week 144 (n=587)
    53
    5%
    Week 168 (n=518)
    58
    5.5%
    Week 192 (n=491)
    60
    5.7%
    Week 216 (n=436)
    59
    5.6%
    7. Secondary Outcome
    Title Overall Study: Percentage of Participants With HBeAg Seroconversion
    Description Observed values. Seroconversion=negative HBeAg with detectable anti-HBe antibody.
    Time Frame Study entry to Week 216

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants received 1 mg of entecavir QD with or without lamivudine.
    Measure Participants 1051
    At study entry (n=1051)
    30
    2.9%
    Week 12 (n=931)
    33
    3.1%
    Week 24 (n=934)
    34
    3.2%
    Week 48 (n=862)
    36
    3.4%
    Week 72 (n=755)
    32
    3%
    Week 96 (n=678)
    34
    3.2%
    Week 120 (n=607)
    36
    3.4%
    Week 144 (n=587)
    37
    3.5%
    Week 168 (n=517)
    39
    3.7%
    Week 192 (n=491)
    42
    4%
    Week 216 (n=434)
    40
    3.8%
    8. Secondary Outcome
    Title Overall Study: Mean Alanine Transaminase (ALT) Levels
    Description Observed values.
    Time Frame Study entry to Week 216

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants received 1 mg of entecavir QD with or without lamivudine.
    Measure Participants 1051
    At study entry (n=1051)
    109.4
    (170.5)
    Week 12 (n=1049)
    48.77
    (48.68)
    Week 24 (n=1029)
    42.10
    (36.83)
    Week 48 (n=942)
    37.06
    (34.20)
    Week 72 (n=835)
    38.10
    (41.90)
    Week 96 (n=740)
    39.30
    (46.35)
    Week 120 (n=675)
    37.43
    (28.97)
    Week 144 (n=627)
    38.51
    (38.95)
    Week 168 (n=563)
    36.80
    (29.06)
    Week 192 (n=528)
    37.36
    (30.44)
    Week 216 (n=482)
    38.43
    (55.09)
    9. Secondary Outcome
    Title Overall Study: Percentage of Participants Who Achieved ALT Normalization
    Description ULN=upper limit of normal. ALT normalization=ALT levels ≤1.0*ULN.
    Time Frame Study entry to Week 216

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    At study entry (n=1019)
    40
    3.8%
    Week 48 (n=942)
    75
    7.1%
    Week 144 (n=627)
    74
    7%
    Week 216 (n=482)
    78
    7.4%
    10. Secondary Outcome
    Title Week 192: Percentage of Participants With Histologic Improvement (Efficacy Evaluable Cohort)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Subset of participants who who had evaluable paired liver biopsy results at Phase 3 study baseline and on their last observed biopsies performed in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 57
    Histologic improvement (n=56) (Week 48)
    73
    6.9%
    Histologic improvement (n=57) (Long-term biopsy)
    96
    9.1%
    11. Secondary Outcome
    Title Week 192: Percentage of Participants With Improvement in Fibrosis (Efficacy Evaluable Cohort)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Subset of participants who who had evaluable paired liver biopsy results at Phase 3 study baseline and on their last observed biopsies performed in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 57
    Improvement in fibrosis (n=56) (Week 48)
    32
    3%
    Improvement in fibrosis (n=57) (Long-term biopsy)
    88
    8.4%
    12. Primary Outcome
    Title Overall Study: Number of Participants With Normal Hematology Values at Baseline and Abnormalities in Hematology Laboratory Test Results Through Week 240
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    Hemoglobin (All grades) (n=1007)
    49
    4.7%
    White blood cells (All grades) (n=950)
    226
    21.5%
    Neutrophils (All grades) (n=1002)
    109
    10.4%
    Platelets (All grades) (n=979)
    51
    4.9%
    Protrombin time (All grades) (n=746)
    226
    21.5%
    INR (All grades)(n=746)
    214
    20.4%
    Hemoglobin (Grades 3-4) (n=1007)
    2
    0.2%
    White blood cells (Grades 3-4) (n=950)
    1
    0.1%
    Neutrophils (Grades 3-4) (n=1002)
    21
    2%
    Platelets (Grades 3-4) (n=979)
    1
    0.1%
    Prothrombin time (Grades 3-4) (n=746)
    21
    2%
    INR (Grades 3-4) (n=746)
    12
    1.1%
    13. Primary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    Amylase (All grades) (n=875)
    179
    17%
    Lipase (All grades) (n=390)
    126
    12%
    Amylase (Grades 3-4) (n=875)
    13
    1.2%
    Lipase (Grades 3-4) (n=390)
    38
    3.6%
    BUN/Urea (All grades) (n=998)
    57
    5.4%
    Creatinine (All grades) (n=1000)
    61
    5.8%
    BUN/Urea (Grades 3-4) (n=998)
    0
    0%
    Creatinine (Grades 3-4) (n=1000)
    2
    0.2%
    14. Primary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    Hypochloremia (mEq/L) (All grades) (n=982)
    44
    4.2%
    Hyperchloremia (mEq/L) (All grades) (n=982)
    76
    7.2%
    Hypocarbia (mEq/L) (All grades) (n=831)
    285
    27.1%
    Hypercarbia (mEq/L) (All grades) (n=831)
    148
    14.1%
    Hyponatremia (mEq/L) (All grades) (n=1003)
    68
    6.5%
    Hypernatremia (mEq/L) (All grades) (n=1003)
    106
    10.1%
    Hypokalemia (mEq/L) (All grades) (n=993)
    135
    12.8%
    Hyperkalemia (mEq/L) (All grades (n=993)
    42
    4%
    Hypochloremia (mEq/L) (Grades 3-4) (n=982)
    3
    0.3%
    Hyperchloremia (mEq/L) (Grades 3-4) (n=982)
    7
    0.7%
    Hypocarbia (mEq/L) (Grades 3-4) (n=831)
    14
    1.3%
    Hypercarbia (mEq/L) (Grades 3-4) (n=831)
    2
    0.2%
    Hyponatremia (mEq/L)(Grades 3-4) (n=1003)
    2
    0.2%
    Hypernatremia (mEq/L) (Grades 3-4) (n=1003)
    5
    0.5%
    Hypokalemia (mEq/L) (Grades 3-4) (n=993)
    1
    0.1%
    Hyperkalemia (mEq/L) (Grades 3-4) (n=993)
    6
    0.6%
    Hypoglycemia (mg/dL) (All grades) (n=521)
    47
    4.5%
    Hyperglycemia (mg/dL) (All grades) (n=521)
    150
    14.3%
    Hypoglycemia (mg/dL) (Grades 3-4) (n=521)
    3
    0.3%
    Hyperglycemia (mg/dL) (Grades 3-4) (n=521)
    4
    0.4%
    15. Secondary Outcome
    Title Overall Study: Percentage of Participants With a Confirmed ≥1 log10 Increase From Nadir in HBV DNA by PCR Assay
    Description
    Time Frame Baseline to Week 144

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 1051
    Number [Percentage of participants]
    18
    1.7%
    16. Primary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled up to Week 144 who received at least 1 dose of study drug in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg QD, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine. All participants, regardless of dosing or regimen, included in these safety analyses.
    Measure Participants 996
    Deaths on study
    13
    1.2%
    Malignant neoplasms
    17
    1.6%
    SAEs
    107
    10.2%
    Discontinuations due to AEs
    13
    1.2%
    Any AE
    842
    80.1%
    Grade 3 and 4 AEs
    156
    14.8%
    ALT flares (ALT>2*entry and >10*ULN)
    29
    2.8%
    ALT >5.0*ULN
    93
    8.8%
    AST >5.0*ULN
    53
    5%
    Total bilirubin >2.5*ULN
    22
    2.1%
    Lipase >2.0*ULN
    71
    6.8%
    Creatinine ≥0.5 mg/dL from baseline
    6
    0.6%
    Hypocarbia
    4
    0.4%
    17. Secondary Outcome
    Title 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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled from study AI463-022 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 study and were evaluable. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 146
    Week 48: HBV DNA <300 copies/mL (n=146)
    55
    5.2%
    Week 96: HBV DNA <300 copies/mL (n=140)
    83
    7.9%
    Week 144: HBV DNA <10^4 copies/mL (n=131)
    89
    8.5%
    Week 192: HBV DNA < 10^4 copies/mL (n=108)
    91
    8.7%
    Week 240: HBV DNA <300 copies/mL (n=94)
    94
    8.9%
    Week 48: Loss of HBeAg (n=146)
    1
    0.1%
    Week 96: Loss of HBeAg (n=140)
    4
    0.4%
    Week 144: Loss of HBeAg (n=132)
    30
    2.9%
    Week 192: Loss of HBeAg (n=111)
    39
    3.7%
    Week 240: Loss of HBeAg (n=95)
    41
    3.9%
    Week 48: Seroconversion (n=146)
    1
    0.1%
    Week 96: Seroconversion (n=140)
    3
    0.3%
    Week 144: Seroconversion (n=133)
    17
    1.6%
    Week 192: Seroconversion (n=111)
    16
    1.5%
    Week 240: Seroconversion (n=95)
    17
    1.6%
    Week 48: ALT ≤1.0*ULN (n=146)
    65
    6.2%
    Week 96: ALT ≤1.0*ULN (n=140)
    78
    7.4%
    Week 144: ALT ≤1.0*ULN (n=134)
    77
    7.3%
    Week 192: ALT ≤1.0*ULN (n=112)
    86
    8.2%
    Week 240: ALT ≤1.0*ULN (n=98)
    80
    7.6%
    18. Secondary Outcome
    Title 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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled from study AI463-027 who were nucleoside-naive, HBeAg-negative and had >60 days off treatment between the last dose in AI463-027 and the first dose in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 99
    Week 48: HBV DNA <300 copies/mL (n=119)
    88
    8.4%
    Week 48: HBV DNA <10^4 copies/mL (n=88)
    87
    8.3%
    Week: 48: ALT ≤1.0*ULN (n=95)
    83
    7.9%
    Week 96: HBV DNA <300 copies/mL (n=74)
    91
    8.7%
    Week: 96: ALT ≤1.0*ULN (n=76)
    79
    7.5%
    Week 144: HBV DNA <300 copies/mL (n=57)
    95
    9%
    Week 144: ALT ≤1.0*ULN (n=66)
    86
    8.2%
    19. Secondary Outcome
    Title 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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled from AI463-022 who received lamivudine, were nucleoside-naive HBeAg-positive, and had ≤35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 183
    HBV DNA <300 copies/mL (n=147)
    58
    5.5%
    Achieved loss of HbeAg (n=129)
    25
    2.4%
    Achieved HBeAg seroconversion (n=129)
    8
    0.8%
    Achieved ALT ≤1.0*ULN (n=154)
    76
    7.2%
    20. Secondary Outcome
    Title Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Continuous Switch Cohort)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled from AI463-022 who received lamivudine, were nucleoside-naive HBeAg-positive, and had ≤35 days off treatment between end of dosing in AI463-022 and the switch to entecavir in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 183
    HBV DNA <300 copies/mL (n=130)
    65
    6.2%
    Achieved ALT ≤1.0*ULN (n=135)
    68
    6.5%
    21. Primary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants who enrolled from Phase 3 studies of nucleoside-naive HBeAg-positive (AI463-022) and HBeAg-negative (AI463-027) participants and received at least 1 dose of study drug in the current study up to Week 192. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg QD, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine. All participants, regardless of dosing or regimen, included in these safety analyses.
    Measure Participants 1006
    Deaths on study
    18
    1.7%
    Malignant neoplasms
    27
    2.6%
    SAEs
    135
    12.8%
    Discontinuations due to AEs
    11
    1%
    Any AE
    862
    82%
    Grade 3 and 4 AEs
    174
    16.6%
    ALT flares (ALT>2*entry and >10*ULN)
    30
    2.9%
    ALT >5.0*ULN
    175
    16.7%
    Total bilirubin >2.5*ULN
    32
    3%
    Lipase >2.0*ULN
    81
    7.7%
    Creatinine ≥0.3 mg/dL from baseline
    80
    7.6%
    Hypocarbia Grades 3-4
    5
    0.5%
    22. Secondary Outcome
    Title Week 96: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled from AI463-027 who were nucleoside-naive HBeAg-negative, received lamivudine, and had >60 days between end of dosing in AI463-027 and the switch to entecavir in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 123
    HBV DNA <300 copies/mL (n=69)
    97
    9.2%
    ALT ≤1.0*ULN (n=81)
    81
    7.7%
    23. Secondary Outcome
    Title Week 144: Percentage of Participants Who Achieved HBV DNA <300 Copies/mL by PCR Assay and ALT ≤1.0*ULN (Lamivudine Retreatment Switch Cohort)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled from study AI463-027 who were nucleoside-naive HBeAg-negative and had >60 days off treatment between the last dose in AI463-027 and the first dose in the current study. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 123
    HBV DNA <300 copies/mL (n=67)
    99
    9.4%
    Achieved ALT ≤1.0*ULN (n=73)
    85
    8.1%
    24. Primary Outcome
    Title 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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 29
    End of dosing current study
    100
    9.5%
    Off-treatment Week 48
    21
    2%
    25. Secondary Outcome
    Title 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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants who were HBeAg negative and who had liver disease, a minimum of 192 weeks of entecavir treatment, HBV DNA <300 copies/mL by PCR assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks before end of dosing, and serum ALT levels ≤1.0*ULN at the end of study drug dosing. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 29
    Off-treatment Week 48 <1000 copies/mL
    10
    1%
    Off-treatment Week 96 <1000 copies/mL
    10
    1%
    Off-treatment Week 48 <300 copies/mL
    7
    0.7%
    Off-treatment Week 96 <300 copies/mL
    3
    0.3%
    Off treatment Week 96 <10,000 copies/mL
    14
    1.3%
    Off treatment Week 48: ALT ≤1*ULN
    31
    2.9%
    Off treatment Week 96: ALT ≤1*ULN
    24
    2.3%
    26. Secondary Outcome
    Title Off-treatment Follow-up: Mean Change in HBV DNA (Amendment 11 Cohort)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Participants who were HBeAg negative and who had liver disease, a minimum of 192 weeks of entecavir treatment, HBV DNA <300 copies/mL by PCR assay for ≥48 weeks before end of dosing and on the last observed result ≤24 weeks before end of dosing, and had serum ALT levels ≤1.0*ULN at the end of study drug dosing. (n=number of evaluable participants)
    Arm/Group Title Entecavir, 0.5 or 1.0 mg, With or Without Lamivudine
    Arm/Group Description Participants originally received 0.5 mg of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine.
    Measure Participants 29
    Off-treatment Week 48
    1.54
    (0.336)
    Off-treatment Week 96
    1.18
    (0.326)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Adefovir, 10 mg Entecavir, 0.02588 mg Entecavir, 0.1 mg Entecavir, 0.5 mg Entecavir, 1.0 mg Lamovidine, 100 mg Missing Placebo
    Arm/Group Description Participants who received adefovir concomitantly at postdosing follow-up Participants originally received lower doses of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine. Participants originally received lower doses of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine. Participants received entecavir QD with lamovidine Participants originally received lower doses of entecavir QD with lamivudine, but protocol later amended to 1.0 mg of entecavir QD without lamivudine. Participants originally received lamovidine with entecavir Category missing Participants originally assigned to placebo before protocol change to study drug.
    All Cause Mortality
    Adefovir, 10 mg Entecavir, 0.02588 mg Entecavir, 0.1 mg Entecavir, 0.5 mg Entecavir, 1.0 mg Lamovidine, 100 mg Missing Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Adefovir, 10 mg Entecavir, 0.02588 mg Entecavir, 0.1 mg Entecavir, 0.5 mg Entecavir, 1.0 mg Lamovidine, 100 mg Missing Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 7/35 (20%) 0/1 (0%) 3/29 (10.3%) 57/336 (17%) 15/123 (12.2%) 87/523 (16.6%) 0/2 (0%) 0/2 (0%)
    Blood and lymphatic system disorders
    HAEMOLYTIC ANAEMIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    THROMBOCYTOPENIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    AUTOIMMUNE THROMBOCYTOPENIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Cardiac disorders
    MYOCARDIAL ISCHAEMIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    VENTRICULAR EXTRASYSTOLES 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ARRHYTHMIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CARDIAC FAILURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ATRIAL FIBRILLATION 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    CORONARY ARTERY STENOSIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Congenital, familial and genetic disorders
    MALFORMATION VENOUS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Ear and labyrinth disorders
    VERTIGO POSITIONAL 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Endocrine disorders
    ADRENAL MASS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Eye disorders
    MACULAR OEDEMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    DIPLOPIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Gastrointestinal disorders
    ASCITES 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CONSTIPATION 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ABDOMINAL PAIN 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    INGUINAL HERNIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    INTESTINAL OBSTRUCTION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    PERITONITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HAEMATOCHEZIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    ABDOMINAL PAIN UPPER 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 2/523 (0.4%) 0/2 (0%) 0/2 (0%)
    OESOPHAGEAL VARICES HAEMORRHAGE 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    ANAL FISTULA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    DYSPEPSIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    FOOD POISONING 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    GASTRIC VARICES HAEMORRHAGE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    PANCREATITIS ACUTE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ABDOMINAL PAIN LOWER 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    OESOPHAGEAL ULCER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    VOMITING 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 2/523 (0.4%) 0/2 (0%) 0/2 (0%)
    HAEMATEMESIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HAEMORRHOIDS 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    VARICES OESOPHAGEAL 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    General disorders
    INFLAMMATION 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    OEDEMA PERIPHERAL 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    PYREXIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PAIN 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 2/523 (0.4%) 0/2 (0%) 0/2 (0%)
    CHEST PAIN 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Hepatobiliary disorders
    CHOLECYSTITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CHRONIC HEPATITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CHOLECYSTITIS ACUTE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CHOLELITHIASIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 2/523 (0.4%) 0/2 (0%) 0/2 (0%)
    LIVER DISORDER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    JAUNDICE 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEPATIC FAILURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEPATITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Infections and infestations
    VESTIBULAR NEURONITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CELLULITIS 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    DEVICE RELATED INFECTION 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HAEMORRHAGIC FEVER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    UPPER RESPIRATORY TRACT INFECTION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    AMOEBIASIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    BILIARY TRACT INFECTION 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEPATITIS B 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    SEPSIS 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    SIALOADENITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    STREPTOCOCCAL SEPSIS 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    SUBCUTANEOUS ABSCESS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    APPENDICITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 3/523 (0.6%) 0/2 (0%) 0/2 (0%)
    HEPATITIS INFECTIOUS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    PYELONEPHRITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    URINARY TRACT INFECTION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    GASTROENTERITIS 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    KLEBSIELLA SEPSIS 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ANAL ABSCESS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 3/523 (0.6%) 0/2 (0%) 0/2 (0%)
    CHRONIC SINUSITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    DENGUE FEVER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    SOFT TISSUE INFECTION 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    TYPHOID FEVER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    LIVER ABSCESS 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PERITONITIS BACTERIAL 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PERITONSILLAR ABSCESS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PNEUMONIA 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    VIRAL INFECTION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    BRONCHOPNEUMONIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    DIARRHOEA INFECTIOUS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    EAR INFECTION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HERPES ZOSTER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    ABSCESS 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Injury, poisoning and procedural complications
    ANKLE FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEPATIC HAEMATOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    SPINAL COLUMN INJURY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    CLAVICLE FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    MEDICATION ERROR 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    BURN OESOPHAGEAL 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    EYE PENETRATION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HUMERUS FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    SPINAL CORD INJURY CERVICAL 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ELECTRICAL BURN 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    FALL 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HEAD INJURY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    SPINAL FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    TOXICITY TO VARIOUS AGENTS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    GENITAL INJURY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    POST PROCEDURAL HAEMORRHAGE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    WRIST FRACTURE 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    FEMORAL NECK FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    JOINT DISLOCATION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    RIB FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CONTUSION 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HAND FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HIP FRACTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    JOINT INJURY 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    OVERDOSE 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 1/123 (0.8%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Investigations
    BLOOD BILIRUBIN INCREASED 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ALANINE AMINOTRANSFERASE INCREASED 0/35 (0%) 0/1 (0%) 0/29 (0%) 6/336 (1.8%) 3/123 (2.4%) 16/523 (3.1%) 0/2 (0%) 0/2 (0%)
    TRANSAMINASES INCREASED 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    TUBERCULIN TEST POSITIVE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    ASPARTATE AMINOTRANSFERASE INCREASED 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 6/523 (1.1%) 0/2 (0%) 0/2 (0%)
    BLOOD AMYLASE INCREASED 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    LIPASE INCREASED 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    LABORATORY TEST ABNORMAL 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    INVESTIGATION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Metabolism and nutrition disorders
    DEHYDRATION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    OBESITY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    DIABETES MELLITUS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 2/523 (0.4%) 0/2 (0%) 0/2 (0%)
    Musculoskeletal and connective tissue disorders
    BACK PAIN 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    SJOGREN'S SYNDROME 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    CHONDROPATHY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    OSTEOARTHRITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    INTERVERTEBRAL DISC PROTRUSION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    FLANK PAIN 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    INTERVERTEBRAL DISC DEGENERATION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    LUNG NEOPLASM 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    MYOLIPOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PANCREATIC CARCINOMA METASTATIC 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PROSTATE CANCER 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEPATIC NEOPLASM 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    BASAL CELL CARCINOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    BENIGN BREAST NEOPLASM 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    OSTEOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    THYROID ADENOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEPATIC NEOPLASM MALIGNANT RECURRENT 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    MULTIPLE MYELOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    SQUAMOUS CELL CARCINOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    LYMPHOPROLIFERATIVE DISORDER 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    BREAST CANCER 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    TRANSITIONAL CELL CARCINOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEPATIC NEOPLASM MALIGNANT 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 4/336 (1.2%) 0/123 (0%) 8/523 (1.5%) 0/2 (0%) 0/2 (0%)
    LYMPHOMA CUTIS 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    MALIGNANT PERITONEAL NEOPLASM 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    METASTASES TO BONE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    ADENOMA BENIGN 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    BILE DUCT CANCER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CEREBRAL HAEMANGIOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    GASTRIC CANCER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    SQUAMOUS CELL CARCINOMA OF SKIN 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    COLON CANCER 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    UTERINE LEIOMYOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Nervous system disorders
    HEPATIC ENCEPHALOPATHY 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    VASCULAR ENCEPHALOPATHY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    RESTLESS LEGS SYNDROME 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    POLYNEUROPATHY 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    CEREBRAL HAEMATOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    EPILEPSY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    INTRACRANIAL HAEMATOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    LOSS OF CONSCIOUSNESS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HEADACHE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    IIIRD NERVE PARESIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PARAESTHESIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    CEREBRAL HAEMORRHAGE 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    DIZZINESS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HAEMORRHAGE INTRACRANIAL 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Psychiatric disorders
    MANIA 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    COMPLETED SUICIDE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Renal and urinary disorders
    NEPHROLITHIASIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    OBSTRUCTIVE UROPATHY 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    URINARY INCONTINENCE 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    URETHRAL DISORDER 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    CALCULUS URETERIC 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HYDRONEPHROSIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    NEPHROPATHY 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Reproductive system and breast disorders
    OVARIAN CYST 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 2/523 (0.4%) 0/2 (0%) 0/2 (0%)
    MENORRHAGIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    UTERINE POLYP 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    BENIGN PROSTATIC HYPERPLASIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    OVARIAN CYST RUPTURED 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Respiratory, thoracic and mediastinal disorders
    NASAL SEPTUM DEVIATION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    PULMONARY EMBOLISM 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    SLEEP APNOEA SYNDROME 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    DYSPNOEA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ACUTE RESPIRATORY FAILURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    ASTHMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    PULMONARY MASS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    TONSILLAR DISORDER 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HAEMOTHORAX 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    PLEURAL EFFUSION 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    Surgical and medical procedures
    ELECTIVE SURGERY 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    SKIN NEOPLASM EXCISION 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Vascular disorders
    DEEP VEIN THROMBOSIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    HYPERTENSION 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    HAEMATOMA 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    VARICOSE VEIN 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    Other (Not Including Serious) Adverse Events
    Adefovir, 10 mg Entecavir, 0.02588 mg Entecavir, 0.1 mg Entecavir, 0.5 mg Entecavir, 1.0 mg Lamovidine, 100 mg Missing Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 27/35 (77.1%) 0/1 (0%) 25/29 (86.2%) 274/336 (81.5%) 94/123 (76.4%) 439/523 (83.9%) 2/2 (100%) 1/2 (50%)
    Cardiac disorders
    TACHYCARDIA 0/35 (0%) 0/1 (0%) 0/29 (0%) 3/336 (0.9%) 0/123 (0%) 3/523 (0.6%) 1/2 (50%) 0/2 (0%)
    PALPITATIONS 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 9/336 (2.7%) 0/123 (0%) 12/523 (2.3%) 0/2 (0%) 0/2 (0%)
    Eye disorders
    CONJUNCTIVITIS 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 8/336 (2.4%) 1/123 (0.8%) 5/523 (1%) 1/2 (50%) 0/2 (0%)
    Gastrointestinal disorders
    ABDOMINAL PAIN 1/35 (2.9%) 0/1 (0%) 0/29 (0%) 23/336 (6.8%) 5/123 (4.1%) 52/523 (9.9%) 0/2 (0%) 0/2 (0%)
    ASCITES 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 2/523 (0.4%) 0/2 (0%) 0/2 (0%)
    DUODENAL ULCER 3/35 (8.6%) 0/1 (0%) 0/29 (0%) 6/336 (1.8%) 0/123 (0%) 5/523 (1%) 0/2 (0%) 0/2 (0%)
    GASTRIC ULCER 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 5/336 (1.5%) 2/123 (1.6%) 6/523 (1.1%) 0/2 (0%) 0/2 (0%)
    NAUSEA 2/35 (5.7%) 0/1 (0%) 4/29 (13.8%) 12/336 (3.6%) 2/123 (1.6%) 37/523 (7.1%) 1/2 (50%) 0/2 (0%)
    ABDOMINAL PAIN UPPER 1/35 (2.9%) 0/1 (0%) 7/29 (24.1%) 42/336 (12.5%) 7/123 (5.7%) 67/523 (12.8%) 0/2 (0%) 0/2 (0%)
    TOOTHACHE 2/35 (5.7%) 0/1 (0%) 1/29 (3.4%) 16/336 (4.8%) 4/123 (3.3%) 38/523 (7.3%) 0/2 (0%) 0/2 (0%)
    DYSPEPSIA 3/35 (8.6%) 0/1 (0%) 8/29 (27.6%) 25/336 (7.4%) 10/123 (8.1%) 44/523 (8.4%) 1/2 (50%) 0/2 (0%)
    FOOD POISONING 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 2/523 (0.4%) 1/2 (50%) 0/2 (0%)
    DIARRHOEA 5/35 (14.3%) 0/1 (0%) 1/29 (3.4%) 44/336 (13.1%) 12/123 (9.8%) 69/523 (13.2%) 1/2 (50%) 0/2 (0%)
    HAEMORRHOIDS 3/35 (8.6%) 0/1 (0%) 0/29 (0%) 6/336 (1.8%) 2/123 (1.6%) 14/523 (2.7%) 0/2 (0%) 0/2 (0%)
    General disorders
    ASTHENIA 2/35 (5.7%) 0/1 (0%) 1/29 (3.4%) 13/336 (3.9%) 4/123 (3.3%) 25/523 (4.8%) 0/2 (0%) 0/2 (0%)
    FATIGUE 2/35 (5.7%) 0/1 (0%) 7/29 (24.1%) 36/336 (10.7%) 13/123 (10.6%) 63/523 (12%) 0/2 (0%) 0/2 (0%)
    INFLUENZA LIKE ILLNESS 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 10/336 (3%) 3/123 (2.4%) 18/523 (3.4%) 1/2 (50%) 0/2 (0%)
    OEDEMA PERIPHERAL 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 1/123 (0.8%) 13/523 (2.5%) 0/2 (0%) 0/2 (0%)
    PYREXIA 7/35 (20%) 0/1 (0%) 7/29 (24.1%) 38/336 (11.3%) 10/123 (8.1%) 43/523 (8.2%) 0/2 (0%) 0/2 (0%)
    MALAISE 2/35 (5.7%) 0/1 (0%) 2/29 (6.9%) 5/336 (1.5%) 1/123 (0.8%) 20/523 (3.8%) 0/2 (0%) 0/2 (0%)
    PAIN 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 2/336 (0.6%) 1/123 (0.8%) 11/523 (2.1%) 0/2 (0%) 0/2 (0%)
    CHEST PAIN 2/35 (5.7%) 0/1 (0%) 3/29 (10.3%) 8/336 (2.4%) 6/123 (4.9%) 20/523 (3.8%) 0/2 (0%) 0/2 (0%)
    Hepatobiliary disorders
    GALLBLADDER POLYP 2/35 (5.7%) 0/1 (0%) 1/29 (3.4%) 9/336 (2.7%) 1/123 (0.8%) 13/523 (2.5%) 0/2 (0%) 0/2 (0%)
    HEPATIC STEATOSIS 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 14/336 (4.2%) 8/123 (6.5%) 21/523 (4%) 0/2 (0%) 0/2 (0%)
    CHOLELITHIASIS 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 3/336 (0.9%) 1/123 (0.8%) 14/523 (2.7%) 0/2 (0%) 0/2 (0%)
    Immune system disorders
    SEASONAL ALLERGY 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 7/336 (2.1%) 3/123 (2.4%) 19/523 (3.6%) 1/2 (50%) 0/2 (0%)
    HYPERSENSITIVITY 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 11/523 (2.1%) 0/2 (0%) 0/2 (0%)
    Infections and infestations
    UPPER RESPIRATORY TRACT INFECTION 9/35 (25.7%) 0/1 (0%) 5/29 (17.2%) 89/336 (26.5%) 27/123 (22%) 154/523 (29.4%) 0/2 (0%) 0/2 (0%)
    NASOPHARYNGITIS 8/35 (22.9%) 0/1 (0%) 5/29 (17.2%) 60/336 (17.9%) 18/123 (14.6%) 83/523 (15.9%) 0/2 (0%) 0/2 (0%)
    URINARY TRACT INFECTION 3/35 (8.6%) 0/1 (0%) 0/29 (0%) 18/336 (5.4%) 3/123 (2.4%) 29/523 (5.5%) 1/2 (50%) 0/2 (0%)
    BRONCHITIS 1/35 (2.9%) 0/1 (0%) 2/29 (6.9%) 17/336 (5.1%) 4/123 (3.3%) 20/523 (3.8%) 0/2 (0%) 0/2 (0%)
    INFLUENZA 4/35 (11.4%) 0/1 (0%) 4/29 (13.8%) 45/336 (13.4%) 13/123 (10.6%) 53/523 (10.1%) 1/2 (50%) 0/2 (0%)
    RHINITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 11/336 (3.3%) 3/123 (2.4%) 15/523 (2.9%) 1/2 (50%) 0/2 (0%)
    TONSILLITIS 2/35 (5.7%) 0/1 (0%) 1/29 (3.4%) 11/336 (3.3%) 1/123 (0.8%) 11/523 (2.1%) 0/2 (0%) 0/2 (0%)
    HERPES ZOSTER 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 1/336 (0.3%) 0/123 (0%) 7/523 (1.3%) 0/2 (0%) 0/2 (0%)
    Injury, poisoning and procedural complications
    LACERATION 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 4/336 (1.2%) 3/123 (2.4%) 7/523 (1.3%) 0/2 (0%) 0/2 (0%)
    MUSCLE RUPTURE 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 1/2 (50%)
    Investigations
    BLOOD BILIRUBIN INCREASED 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 16/336 (4.8%) 2/123 (1.6%) 14/523 (2.7%) 0/2 (0%) 0/2 (0%)
    ALANINE AMINOTRANSFERASE INCREASED 1/35 (2.9%) 0/1 (0%) 6/29 (20.7%) 33/336 (9.8%) 11/123 (8.9%) 86/523 (16.4%) 0/2 (0%) 0/2 (0%)
    ASPARTATE AMINOTRANSFERASE INCREASED 0/35 (0%) 0/1 (0%) 5/29 (17.2%) 22/336 (6.5%) 9/123 (7.3%) 44/523 (8.4%) 0/2 (0%) 0/2 (0%)
    Metabolism and nutrition disorders
    DIABETES MELLITUS 2/35 (5.7%) 0/1 (0%) 3/29 (10.3%) 16/336 (4.8%) 4/123 (3.3%) 31/523 (5.9%) 0/2 (0%) 0/2 (0%)
    Musculoskeletal and connective tissue disorders
    PAIN IN EXTREMITY 0/35 (0%) 0/1 (0%) 1/29 (3.4%) 15/336 (4.5%) 4/123 (3.3%) 31/523 (5.9%) 0/2 (0%) 0/2 (0%)
    ARTHRALGIA 2/35 (5.7%) 0/1 (0%) 5/29 (17.2%) 35/336 (10.4%) 5/123 (4.1%) 59/523 (11.3%) 0/2 (0%) 0/2 (0%)
    MYALGIA 2/35 (5.7%) 0/1 (0%) 3/29 (10.3%) 13/336 (3.9%) 7/123 (5.7%) 36/523 (6.9%) 0/2 (0%) 0/2 (0%)
    BACK PAIN 1/35 (2.9%) 0/1 (0%) 5/29 (17.2%) 46/336 (13.7%) 12/123 (9.8%) 84/523 (16.1%) 0/2 (0%) 0/2 (0%)
    GROIN PAIN 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 1/523 (0.2%) 1/2 (50%) 0/2 (0%)
    MUSCULOSKELETAL PAIN 0/35 (0%) 0/1 (0%) 5/29 (17.2%) 12/336 (3.6%) 2/123 (1.6%) 26/523 (5%) 0/2 (0%) 0/2 (0%)
    NECK PAIN 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 7/336 (2.1%) 2/123 (1.6%) 20/523 (3.8%) 0/2 (0%) 0/2 (0%)
    Nervous system disorders
    HEPATIC ENCEPHALOPATHY 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 0/123 (0%) 0/523 (0%) 0/2 (0%) 0/2 (0%)
    RESTLESS LEGS SYNDROME 0/35 (0%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 0/523 (0%) 1/2 (50%) 0/2 (0%)
    SCIATICA 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 2/336 (0.6%) 0/123 (0%) 3/523 (0.6%) 0/2 (0%) 0/2 (0%)
    HEADACHE 3/35 (8.6%) 0/1 (0%) 13/29 (44.8%) 69/336 (20.5%) 16/123 (13%) 131/523 (25%) 1/2 (50%) 0/2 (0%)
    DIZZINESS 2/35 (5.7%) 0/1 (0%) 2/29 (6.9%) 24/336 (7.1%) 5/123 (4.1%) 44/523 (8.4%) 1/2 (50%) 0/2 (0%)
    Psychiatric disorders
    INSOMNIA 2/35 (5.7%) 0/1 (0%) 4/29 (13.8%) 26/336 (7.7%) 6/123 (4.9%) 49/523 (9.4%) 0/2 (0%) 0/2 (0%)
    Renal and urinary disorders
    HAEMATURIA 1/35 (2.9%) 0/1 (0%) 1/29 (3.4%) 21/336 (6.3%) 4/123 (3.3%) 29/523 (5.5%) 0/2 (0%) 0/2 (0%)
    Reproductive system and breast disorders
    PROSTATITIS 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 1/336 (0.3%) 0/123 (0%) 3/523 (0.6%) 0/2 (0%) 0/2 (0%)
    Respiratory, thoracic and mediastinal disorders
    ASTHMA 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 7/336 (2.1%) 2/123 (1.6%) 7/523 (1.3%) 0/2 (0%) 0/2 (0%)
    UPPER RESPIRATORY TRACT CONGESTION 2/35 (5.7%) 0/1 (0%) 0/29 (0%) 1/336 (0.3%) 0/123 (0%) 1/523 (0.2%) 0/2 (0%) 0/2 (0%)
    COUGH 5/35 (14.3%) 0/1 (0%) 4/29 (13.8%) 48/336 (14.3%) 15/123 (12.2%) 77/523 (14.7%) 0/2 (0%) 0/2 (0%)
    NASAL CONGESTION 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 5/336 (1.5%) 2/123 (1.6%) 7/523 (1.3%) 0/2 (0%) 0/2 (0%)
    OROPHARYNGEAL PAIN 1/35 (2.9%) 0/1 (0%) 1/29 (3.4%) 28/336 (8.3%) 7/123 (5.7%) 37/523 (7.1%) 1/2 (50%) 0/2 (0%)
    Skin and subcutaneous tissue disorders
    LIPODYSTROPHY ACQUIRED 0/35 (0%) 0/1 (0%) 0/29 (0%) 0/336 (0%) 1/123 (0.8%) 0/523 (0%) 0/2 (0%) 1/2 (50%)
    DERMATITIS 0/35 (0%) 0/1 (0%) 0/29 (0%) 2/336 (0.6%) 1/123 (0.8%) 4/523 (0.8%) 1/2 (50%) 0/2 (0%)
    DERMATITIS CONTACT 0/35 (0%) 0/1 (0%) 2/29 (6.9%) 3/336 (0.9%) 1/123 (0.8%) 3/523 (0.6%) 0/2 (0%) 0/2 (0%)
    RASH 2/35 (5.7%) 0/1 (0%) 2/29 (6.9%) 11/336 (3.3%) 7/123 (5.7%) 14/523 (2.7%) 0/2 (0%) 0/2 (0%)
    ECZEMA 1/35 (2.9%) 0/1 (0%) 4/29 (13.8%) 8/336 (2.4%) 3/123 (2.4%) 11/523 (2.1%) 0/2 (0%) 0/2 (0%)
    PRURITUS 0/35 (0%) 0/1 (0%) 4/29 (13.8%) 16/336 (4.8%) 5/123 (4.1%) 13/523 (2.5%) 0/2 (0%) 0/2 (0%)
    Vascular disorders
    HYPERTENSION 1/35 (2.9%) 0/1 (0%) 4/29 (13.8%) 44/336 (13.1%) 13/123 (10.6%) 63/523 (12%) 0/2 (0%) 0/2 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

    Results Point of Contact

    Name/Title BMS Study Director
    Organization Bristol-Myers Squibb
    Phone
    Email Clinical.Trials@bms.com
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT01438424
    Other Study ID Numbers:
    • AI463-901
    First Posted:
    Sep 22, 2011
    Last Update Posted:
    Aug 23, 2012
    Last Verified:
    Jul 1, 2012