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    Clinical Trial Results:
    Evaluation of the Pharmacokinetics, Safety, Tolerability and Efficacy of Entecavir (ETV) in Pediatric Subjects with Chronic Hepatitis B Virus (HBV) Infection who are HBeAg-Positive

    Summary
    EudraCT number
    		 2005-005816-26
    Trial protocol
    		 GB   BE   Outside EU/EEA  
    Global end of trial date
    04 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2018
    First version publication date
    16 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AI463-028
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000339-PIP02-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of study AI463028 was (1) to evaluate the pharmacokinetic (PK) profile of entecavir (ETV) in children and adolescents in order to identify doses that produce drug exposures comparable to those observed in adults receiving the currently approved 0.5 mg and 1.0 doses; and (2) to describe the safety, tolerability and preliminary efficacy of ETV in pediatric subjects ≥2 to ≤ 18 years of age who had chronic hepatitis B virus (HBV) infection and were hepatitis B e antigen (HBeAg)-positive.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jun 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    64
    EEA total number of subjects
    6
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    39
    Adolescents (12-17 years)
    25
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study started June 2007, currently ongoing. Cohort 1: age ≥ 2 to ≤ 6 years; Cohort 2: >6 to ≤ 12 years; Cohort 3: age >12 to ≤18 years. Groups A and B: lamivudine-naive and experienced participants, respectively. Nucleoside/tide analog - treatment-experienced participants (Group C) added September 2011 via country-specific amendment to protocol.

    Pre-assignment
    Screening details
    		 64 enrolled. 48 treated. Participants received a minimum of 48 weeks study drug but depending on response to drug, could remain on treatment for up to a total of 120 weeks. Participants were to receive post dosing follow up after last dose, for a total of 5 years on-study (on and off study drug).

    Period 1
    Period 1 title
    Enrolled
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lamivudine (LVD)-naive (Group A)
    Arm description
    		 Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Lamivudine (LVD)-experienced (Group B)
    Arm description
    		 Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Nucleoside/tide analog (NA) - experienced (Group C)
    Arm description
    		 Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Started
    35
    21
    8
    Completed
    24
    19
    5
    Not completed
    11
    2
    3
         Consent withdrawn by subject
    -
    -
    1
         Lost to follow-up
    -
    -
    1
         No longer met criteria
    11
    2
    1
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lamivudine (LVD)-naive (Group A)
    Arm description
    		 Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entecavir
    Investigational medicinal product code
    Other name
    BMS-200475
    Pharmaceutical forms
    Tablet, Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Entecavir (ETV) 0.015 mg/kg up to 0.5 mg, once a day (QD)

    Arm title
    		 Lamivudine (LVD)-experienced (Group B)
    Arm description
    		 Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entecavir
    Investigational medicinal product code
    Other name
    BMS-200475
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Entecavir (ETV) 0.030 mg/kg up to 1.0 mg, once a day (QD)

    Arm title
    		 Nucleoside/tide analog (NA) - experienced (Group C)
    Arm description
    		 Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entecavir
    Investigational medicinal product code
    Other name
    BMS-200475
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Entecavir (ETV) 0.030 mg/kg up to 1.0 mg, once a day (QD)

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics were calculated only for treated subjects (Period 2).
    Number of subjects in period 2 [2]
    		Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Started
    24
    19
    5
    Completed
    22
    19
    5
    Not completed
    2
    0
    0
         Consent withdrawn by subject
    1
    -
    -
         Lost to follow-up
    1
    -
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 64 enrolled. 48 treated. Participants received a minimum of 48 weeks study drug but depending on response to drug, could remain on treatment for up to a total of 120 weeks. Participants were to receive post dosing follow up after last dose, for a total of 5 years on-study (on and off study drug).
    Period 3
    Period 3 title
    Post-Dosing Follow Up
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lamivudine (LVD)-naive (Group A)
    Arm description
    		 Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Lamivudine (LVD)-experienced (Group B)
    Arm description
    		 Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Nucleoside/tide analog (NA) - experienced (Group C)
    Arm description
    		 Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [3]
    		Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Started
    22
    18
    5
    Completed
    20
    15
    3
    Not completed
    2
    3
    2
         Consent withdrawn by subject
    -
    3
    2
         Lost to follow-up
    2
    -
    -
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One subject in Group B did not enter the follow-up period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lamivudine (LVD)-naive (Group A)
    Reporting group description
    		 Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Lamivudine (LVD)-experienced (Group B)
    Reporting group description
    		 Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Nucleoside/tide analog (NA) - experienced (Group C)
    Reporting group description
    		 Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.

    Reporting group values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C) Total
    Number of subjects
    		 24 19 5 48
    Age, Customized
    Units: Subjects
        ≥ 2 years to ≤ 6 years|
    		 7 3 2 12
        >6 years to ≤ 12 years|
    		 9 7 2 18
        >12 years to ≤18 years|
    		 8 9 1 18
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.2 ( 5.41 ) 11.0 ( 4.42 ) 8.8 ( 5.02 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 14 7 2 23
        Male
    		 10 12 3 25
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 17 10 5 32
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Black or African American
    		 0 2 0 2
        White
    		 5 6 0 11
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 2 0 0 2
    Region of Enrollment
    Units: Subjects
        United States|
    		 10 5 1 16
        Taiwan|
    		 3 0 0 3
        Canada|
    		 1 0 0 1
        Argentina|
    		 3 0 0 3
        Belgium|
    		 1 1 0 2
        Brazil|
    		 1 3 0 4
        United Kingdom|
    		 2 1 0 3
        Korea, Republic of|
    		 3 9 4 16
    Alanine Aminotransferase (ALT)
    The normal range for serum ALT as established by the study's central laboratory was 5 - 45 units per liter (U/L). The inclusion criteria for Groups A and B was >= 2 X ULN to <= 10 X ULN, while only the upper range applied to Group C (<= 10 X ULN).
    Units: U/L
        arithmetic mean (standard deviation)
    		 142.8 ( 85.18 ) 125.7 ( 67.96 ) 44.6 ( 22.96 ) -
    Hepatitis B virus (HBV) deoxyribonucleic acid (DNA)
    Hepatitis B virus DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS TaqMan - high pure system (HPS) assay and was reported in international units per milliliter (IU/mL).
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 7.92 ( 0.864 ) 7.74 ( 0.856 ) 7.96 ( 0.238 ) -

    End points

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    End points reporting groups
    Reporting group title
    Lamivudine (LVD)-naive (Group A)
    Reporting group description
    		 Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Lamivudine (LVD)-experienced (Group B)
    Reporting group description
    		 Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Nucleoside/tide analog (NA) - experienced (Group C)
    Reporting group description
    		 Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.
    Reporting group title
    Lamivudine (LVD)-naive (Group A)
    Reporting group description
    		 Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Lamivudine (LVD)-experienced (Group B)
    Reporting group description
    		 Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Nucleoside/tide analog (NA) - experienced (Group C)
    Reporting group description
    		 Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.
    Reporting group title
    Lamivudine (LVD)-naive (Group A)
    Reporting group description
    		 Participants with less than (<) 1 week of prior LVD therapy and with no LVD therapy within 24 weeks prior to enrollment were included in Group A. Prior to Pharmacokinetic (PK) assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (>6 years to ≤ 12 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, once a day (QD) and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.015 mg/kg up to 0.5 mg, or ETV tablets, 0.5 mg, QD. Following PK analysis, those who met the specified dosing requirements (at least 0.5 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Lamivudine (LVD)-experienced (Group B)
    Reporting group description
    		 Participants with greater than (>) 12 weeks of prior LVD therapy were included in Group B. Prior to PK assessment, Cohort 1 (age ≥ 2 years to ≤ 6 years) and Cohort 2 (> 6 years to ≤ 12 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, QD and Cohort 3 (age >12 years to ≤18 years) received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg QD. Following PK analysis, those who met the specified dosing requirements (at least 1.0 mg/day) and could tolerate swallowing ETV tablets were allowed to choose either formulation. Entecavir (ETV) was administered for a maximum of 120 weeks.

    Reporting group title
    Nucleoside/tide analog (NA) - experienced (Group C)
    Reporting group description
    		 Participants who failed previous treatment with any non-ETV nucleoside/tide analog (NA) were included in Group C, starting in 2011. PK assessment was optional to participants in Group C. All participants received ETV oral solution, 0.030 mg/kg up to 1.0 mg, or ETV tablets, 1.0 mg, QD. Participants who met the specified dosing requirements (at least 1.0 mg/day for NA-experienced participants) and could tolerate swallowing ETV tablets were allowed to choose either formulation. ETV was administered for a maximum of 120 weeks.

    Primary: Number of Subjects with Serious Adverse Events (SAE) and Discontinuations Due to Adverse Events (AEs) - On Treatment

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    End point title
    		 Number of Subjects with Serious Adverse Events (SAE) and Discontinuations Due to Adverse Events (AEs) - On Treatment [1]
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Medical Dictionary for Regulatory Activities (MedDRA) version 16.0 was used.
    End point type
    Primary
    End point timeframe
    Day 1 to Week 120
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Serious Adverse Events (n=24, 19, 5)|
    2
    0
    0
        Discontinuations Due to AEs (n=24,19,5)|
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Maximum Observed Plasma Concentration (Cmax) and Mean Trough Observed Plasma Concentration (Cmin) of Entecavir in LVD-naive and LVD-experienced Subjects, by Age Cohort

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    End point title
    		 Mean Maximum Observed Plasma Concentration (Cmax) and Mean Trough Observed Plasma Concentration (Cmin) of Entecavir in LVD-naive and LVD-experienced Subjects, by Age Cohort
    End point description
    Cmax and Cmin were derived from plasma concentration of ETV versus time and measured in nanograms per milliliters (ng/mL). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. Note: PK parameters were summarized for only Groups A and B. PK assessment was optional for Group C subjects (NA-experienced subjects who were included with the September 2011 country-specific protocol amendment). No Group C subjects chose to participate in the PK assessment.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B)
    Number of subjects analysed
    24
    19
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cmax of ETV (≥ 2 yrs to ≤ 6 yrs), (n=7, 3)|
    8.07 ( 24 )
    16.03 ( 8 )
        Cmax of ETV (> 6 yrs to ≤ 12 yrs), (n=9, 7)|
    6.29 ( 25 )
    19.01 ( 15 )
        Cmax of ETV (> 12 yrs to ≤ 18 yrs), (n=8,9)|
    5.11 ( 27 )
    11.32 ( 37 )
        Cmin of ETV (≥ 2 yrs to ≤ 6 yrs), (n=7, 3)|
    0.244 ( 32 )
    0.468 ( 17 )
        Cmin of ETV (> 6 yrs to ≤ 12 yrs), (n=9, 7)|
    0.320 ( 22 )
    0.497 ( 32 )
        Cmin of ETV (> 12 yrs to ≤ 18 yrs), (n=8,9)|
    0.271 ( 25 )
    0.455 ( 25 )
    No statistical analyses for this end point

    Secondary: Median Time of Maximum Observed Plasma Concentration (Tmax) in LVD-naive and LVD-experienced Subjects, by Age Cohort

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    End point title
    		 Median Time of Maximum Observed Plasma Concentration (Tmax) in LVD-naive and LVD-experienced Subjects, by Age Cohort
    End point description
    Tmax was derived from plasma concentration of ETV versus time and measured in hours (h). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. Age categories presented below: subjects age as of first day of dosing. PK assessment was optional for Group C subjects (NA-experienced subjects who were included with the September 2011 country-specific protocol amendment). No Group C subjects chose to participate in the PK assessment.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B)
    Number of subjects analysed
    24
    19
    Units: hr
    median (full range (min-max))
        Tmax of ETV (≥ 2 yrs to ≤ 6 yrs), (n=7, 3)|
    0.50 (0.5 to 1.0)
    1.00 (0.5 to 1.5)
        Tmax of ETV (> 6 yrs to ≤ 12 yrs), (n=9, 7)|
    0.57 (0.5 to 2.0)
    0.72 (0.5 to 1.0)
        Tmax of ETV (> 12 yrs to ≤ 18 yrs), (n=8,9)|
    0.78 (0.5 to 1.0)
    0.52 (0.5 to 1.0)
    No statistical analyses for this end point

    Secondary: Mean Area Under the Concentration-Time Curve in One Dosing Interval [AUC(TAU)] of Entecavir in LVD-naive and LVD-experienced Subjects, by Age Cohort

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    End point title
    		 Mean Area Under the Concentration-Time Curve in One Dosing Interval [AUC(TAU)] of Entecavir in LVD-naive and LVD-experienced Subjects, by Age Cohort
    End point description
    Area under the Curve (AUC) was derived from plasma concentration of ETV versus time. AUC(TAU) was calculated by log- and linear trapezoidal summations, TAU = 24 hours, and was measured in nanograms*hours per milliliter (ng*h/mL). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. PK assessment was optional for Group C subjects (NA-experienced subjects who were included with the September 2011 country-specific protocol amendment). No Group C subjects chose to participate in the PK assessment.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B)
    Number of subjects analysed
    24
    19
    Units: ng*h/mL
    geometric mean (geometric coefficient of variation)
        AUC(TAU) of ETV (≥ 2 yrs to ≤ 6 yrs), (n=7, 3)|
    18.69 ( 21 )
    42.26 ( 27 )
        AUC(TAU) of ETV (> 6 yrs to ≤ 12 yrs), (n=9, 7)|
    20.42 ( 20 )
    41.50 ( 21 )
        AUC(TAU) of ETV (> 12 yrs to ≤ 18 yrs), (n=8,9)|
    15.96 ( 22 )
    35.36 ( 24 )
    No statistical analyses for this end point

    Secondary: Mean Apparent Total Body Clearance (CLT/F) of Entecavir in LVD-naive and LVD-experienced Subjects, by Age Cohort

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    End point title
    		 Mean Apparent Total Body Clearance (CLT/F) of Entecavir in LVD-naive and LVD-experienced Subjects, by Age Cohort
    End point description
    CLT/F was calculated by dividing the dose of ETV by AUC(TAU) of ETV and was measured in liters per hour (L/h). Blood samples were obtained before study drug administration and at 0.5, 1, 2, 4, 8, and 24 hours after study drug administration on Day 14 (+/- 4 days) for the PK assessment. Plasma samples were analyzed for ETV with a validated method using liquid chromatography-tandem mass spectrometry detection. PK assessment was optional for Group C subjects (NA-experienced subjects who were included with the September 2011 country-specific protocol amendment). No Group C subjects chose to participate in the PK assessment.
    End point type
    Secondary
    End point timeframe
    At 2 weeks
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B)
    Number of subjects analysed
    24
    19
    Units: L/h
    arithmetic mean (standard deviation)
        CLT/F of ETV (≥ 2 yrs to ≤ 6 yrs), (n=7, 3)|
    11.40 ( 2.564 )
    12.31 ( 3.102 )
        CLT/F of ETV (> 6 yrs to ≤ 12 yrs), (n=9, 7)|
    22.66 ( 6.134 )
    21.67 ( 6.940 )
        CLT/F of ETV (> 12 yrs to ≤ 18 yrs), (n=8,9)|
    31.92 ( 6.429 )
    28.95 ( 6.496 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with HBV DNA Less than 50 IU/mL through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with HBV DNA Less than 50 IU/mL through Week 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by polymerase chain reaction (PCR) was measured using the Roche COBAS TaqMan - high pure system (HPS) assay and was reported in international units per milliliter (IU/mL). Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    1
    0
    0
        Week 24 (n=24,19,5)
    10
    3
    0
        Week 36 (n=24,19,5)
    11
    6
    0
        Week 48 (n=24,19,5)
    14
    9
    0
        Week 96 (n=12,13,4)
    8
    11
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with Hepatitis B e antigen (HBeAg) Loss through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with Hepatitis B e antigen (HBeAg) Loss through Week 96 in Treated Subjects
    End point description
    HBeAg loss: HBeAg negative. The method used for the detection of HBe Ag was the DiaSorin - Anti HBe enzyme immunoassay kit. Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    3
    0
    0
        Week 24 (n=24,19,5)
    4
    1
    0
        Week 36 (n=23,19,5)
    5
    1
    0
        Week 48 (n=24,19,5)
    10
    3
    0
        Week 96 (n=12,13,4)
    5
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Hepatitis B s antigen (HBsAg) Loss through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with Hepatitis B s antigen (HBsAg) Loss through Week 96 in Treated Subjects
    End point description
    HBsAg loss: HBsAg negative. The method used for detection of HBsAg was the ADVIA Centaur iImmunoassay system. Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    0
    0
    0
        Week 24 (n=24,19,5)
    0
    0
    0
        Week 36 (n=24,19,5)
    1
    0
    0
        Week 48 (n=24,19,5)
    1
    0
    0
        Week 96 (n=12,13,4)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Hepatitis B e antigen Seroconversion through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with Hepatitis B e antigen Seroconversion through Week 96 in Treated Subjects
    End point description
    HBe seroconversion: loss of HBeAg (HBeAg negative) with positive HB e antibodies (HBeAb), ie both the presence of HBeAb and the absence of HBeAg. The method used for the detection HBeAg seroconversion was the DiaSorin - Anti HBe enzyme immunoassay kit. Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    3
    0
    0
        Week 24 (n=24,19,5)
    4
    1
    0
        Week 36 (n=24,19,5)
    5
    1
    0
        Week 48 (n=24,19,5)
    10
    3
    0
        Week 96 (n=12,13,4)
    5
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with HBV DNA Less than Lower Limit of Detection (LLD) for the Roche COBAS TaqMan - HPS assay at Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with HBV DNA Less than Lower Limit of Detection (LLD) for the Roche COBAS TaqMan - HPS assay at Week 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. LLD = 6 IU/mL). Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    1
    0
    0
        Week 24 (n=24,19,5)
    6
    1
    0
        Week 36 (n=24,19,5)
    7
    5
    0
        Week 48 (n=24,19,5)
    13
    6
    0
        Week 96 (n=12,13,4)
    8
    8
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With HBV DNA Less Than Lower Limit of Quantification (LLQ) for the Roche COBAS TaqMan - HPS Assay through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects With HBV DNA Less Than Lower Limit of Quantification (LLQ) for the Roche COBAS TaqMan - HPS Assay through Week 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. LLQ = 29 IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    1
    0
    0
        Week 24 (n=24,19,5)
    9
    2
    0
        Week 36 (n=24,19,5)
    10
    5
    0
        Week 48 (n=24,19,5)
    14
    7
    0
        Week 96 (n=12,13,4)
    8
    8
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with HB s Antigen (HBsAg) Seroconversion through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with HB s Antigen (HBsAg) Seroconversion through Week 96 in Treated Subjects
    End point description
    HB s Ag seroconversion: loss of HBsAg (HBsAg negative) and presence of HB s antibodies (HBsAb). The method used for the detection of HBsAg seroconversion was the ADVIA Centaur iImmunoassay system. Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    0
    0
    0
        Week 24 (n=24,19,5)
    0
    0
    0
        Week 36 (n=24,19,5)
    0
    0
    0
        Week 48 (n=24,19,5)
    0
    0
    0
        Week 96 (n=12,13,4)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects who had a Protocol Defined Response (PDR) through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects who had a Protocol Defined Response (PDR) through Week 96 in Treated Subjects
    End point description
    PDR was defined as confirmed HBV DNA < 50 IU/mL plus confirmed HBeAg seroconversion on 2 sequential measurements at least 14 days apart. Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Week 12 (n=24,19,5)
    0
    0
    0
        Week 24 (n=24,19,5)
    4
    0
    0
        Week 36 (n=24,19,5)
    4
    1
    0
        Week 48 (n=24,19,5)
    7
    3
    0
        Week 96 (n=12,13,4)
    3
    1
    0
    No statistical analyses for this end point

    Secondary: Mean Log10 Change from Baseline in HBV DNA using Roche COBAS TaqMan - HPS through Week 96 in Treated Subjects

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    End point title
    		 Mean Log10 Change from Baseline in HBV DNA using Roche COBAS TaqMan - HPS through Week 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. HBV DNA log10 changes from baseline were summarized over time.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: IU/mL
    arithmetic mean (standard error)
        Week 12 (n=22,17,5)
    -4.45 ( 0.2418 )
    -3.89 ( 0.1592 )
    -3.80 ( 0.4657 )
        Week 24 (n=24,18,5)
    -5.30 ( 0.2744 )
    -4.85 ( 0.2900 )
    -3.89 ( 0.5440 )
        Week 36 (n=21,19,5)
    -5.61 ( 0.2580 )
    -5.14 ( 0.2604 )
    -3.90 ( 0.2499 )
        Week 48 (n=22,18,5)
    -5.86 ( 0.2176 )
    -5.36 ( 0.3032 )
    -4.32 ( 0.4794 )
        Week 96 (n=12,13,4)
    -6.30 ( 0.2576 )
    -5.86 ( 0.2222 )
    -5.79 ( 0.5308 )
    No statistical analyses for this end point

    Secondary: Alanine aminotransferase (ALT) Normalization from Baseline through Week 96 in Treated Subjects

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    End point title
    		 Alanine aminotransferase (ALT) Normalization from Baseline through Week 96 in Treated Subjects
    End point description
    Normalization in ALT= ALT ≤ 1.0*upper limit of normal (ULN). Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    1
    2
        Week 4 (n=24,19,5)
    1
    1
    2
        Week 8 (n=24,19,5)
    3
    2
    2
        Week 12 (n=24,19,5)
    5
    7
    3
        Week 18 (n=24,19,5)
    15
    10
    5
        Week 24 (n=24,19,5)
    15
    12
    5
        Week 30 (n=24,19,5)
    16
    13
    5
        Week 36 (n=24,19,5)
    16
    16
    5
        Week 42 (n=24,19,5)
    16
    15
    5
        Week 48 (n=24,19,5)
    20
    18
    4
        Week 96 (n=11,13,4)
    10
    13
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects with HBV DNA by PCR Categories at Weeks 48 and 96 in Treated Subjects

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    End point title
    		 Number of Subjects with HBV DNA by PCR Categories at Weeks 48 and 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. LLQ = 29 IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48, Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline >=17,200 IU/mL (n=24,19,5)
    24
    19
    5
        Week 48: < 50 IU/mL (n=22,19,5)
    14
    9
    0
        Week 48: 50 - < 172 IU/mL (n=22,19,5)
    1
    2
    0
        Week 48: 172 - < 1720 IU/mL (n=22,19,5)
    3
    3
    1
        Week 48: 1720 - < 17,200 IU/mL (n=22,19,5)
    3
    1
    3
        Week 48: > = 17,200 IU/mL (n=22,19,5)
    1
    3
    1
        Week 96: < 50 IU/mL (n=12,13,4)
    8
    11
    2
        Week 96: 50 - < 172 IU/mL (n=12,13,4)
    1
    1
    0
        Week 96: 172 - < 1720 IU/mL (n=12,13,4)
    3
    0
    1
        Week 96: 1720 - < 17,200 IU/mL (n=12,13,4)
    0
    1
    1
        Week 96: > = 17,200 IU/mL (n=12,13,4)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with a Combination of ALT Normalization and HBV DNA Less than 50 IU/mL Through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with a Combination of ALT Normalization and HBV DNA Less than 50 IU/mL Through Week 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. Normalization in ALT= ALT ≤ 1.0*ULN. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24, 19, 5)
    0
    0
    0
        Week 24 (n=24, 19, 5)
    10
    3
    0
        Week 36 (n=24, 19, 5)
    11
    4
    0
        Week 48 (n=24, 19, 5)
    13
    9
    0
        Week 96 (n=12,13,4)
    7
    11
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with a Combination of ALT Normalization and HBV DNA Less than 50 IU/mL, plus HBeAg Seroconversion Through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with a Combination of ALT Normalization and HBV DNA Less than 50 IU/mL, plus HBeAg Seroconversion Through Week 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. Normalization in ALT= ALT ≤ 1.0*ULN. HBe seroconversion was determination of presence of HBeAb and loss of HBeAg. The method used for the detection of HBeAg seroconversion was the DiaSorin - Anti HBe enzyme immunoassay kit. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    0
    0
    0
        Week 24 (n=24,19,5)
    4
    0
    0
        Week 36 (n=24,19,5)
    4
    1
    0
        Week 48 (n=24,19,5)
    8
    3
    0
        Week 96 (n=11,13,4)
    3
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with a Combination of ALT Normalization and HBV DNA Less than 50 IU/mL, without HBeAg Seroconversion, Through Week 96 in Treated Subjects

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    End point title
    		 Number of Subjects with a Combination of ALT Normalization and HBV DNA Less than 50 IU/mL, without HBeAg Seroconversion, Through Week 96 in Treated Subjects
    End point description
    Hepatitis B virus DNA by PCR was measured using the Roche COBAS TaqMan - HPS assay and was reported in IU/mL. Baseline was the last value measured prior to or on the date of the first dose of study therapy. Normalization in ALT= ALT ≤ 1.0*ULN. HBe seroconversion: loss of HBeAg (HBeAg negative) with positive HBeAb. The method used for the detection of HBeAg/Ab serologies was the DiaSorin enzyme immunoassay kit. The intent-to-treat method of Non-Completer = Failure was used through Week 48 in which all treated subjects were analyzed, and participants with missing data at the analysis week were considered failures. After Week 48, the method of Non-Completer = Missing was used, in which subjects with missing data at the analysis week were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Baseline (n=24,19,5)
    0
    0
    0
        Week 12 (n=24,19,5)
    0
    0
    0
        Week 24 (n=24,19,5)
    6
    3
    0
        Week 36 (n=24,19,5)
    7
    3
    0
        Week 48 (n=24,19,5)
    5
    6
    0
        Week 96 (n=12,13,4)
    4
    10
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects with Hematology Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Subjects

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    End point title
    		 Number of Subjects with Hematology Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Subjects
    End point description
    Toxicity Scale: Division of AIDs (DAIDS) grades Version 1.0. Upper limit of normal (ULN); lower limit of normal (LLN); Cells per Liter (c/L); cells per microliter (c/µL); grams per deciliter (g/dL); milliequivalents per liter (mEq/L); cells per microliter (c/µL): Grade (Gr). Hemoglobin g/dL: Gr1:10.0-10.9;Gr2: 9.0-9.9; Gr3:7.0-8.9; Gr4: <7.0. International normalization ratio (INR): Gr1:1.1-<1.5*ULN; Gr2: 1.6-<2.0*ULN; Gr3: 2.1-3.0*ULN;Gr4: >3.0*ULN. Neutrophils/bands c/µL: Gr1;1.0-1.3*10^3; Gr2: 0.75-0.99*10^3; Gr 3: 0.50-0.749*10^3; Gr4: <0.5*10^3.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 120
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Hemoglobin
    1
    0
    1
        International normalization ratio
    4
    3
    0
        Neutrophils (absolute) + bands
    3
    3
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Chemistry Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Subjects

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    End point title
    		 Number of Subjects with Chemistry Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Subjects
    End point description
    Toxicity Scale: DAIDS Version 1.0 and modified World Health Organization (WHO). Grade (Gr). ALT: Gr1:1.25-<2.5*ULN; Gr2: 2.6-<5.0 *ULN; Gr3: 5.1-10.0*ULN; Gr4:>10.0*ULN. Aspartate aminotransferase (AST): Gr1: 1.25-<2.5*ULN; Gr2:2.6-<5.0*ULN; Gr 3: 5.1-10.0*ULN; Gr4>10.0*ULN. Alkaline phosphatase: Gr1:1.25-<2.5*ULN; Gr2: 2.6-<5.0*ULN; Gr3: 5.1-10.0*ULN; Gr4: >10.0*ULN. Lipase: Gr1:1.1-<1.5*ULN;Gr2:1.6-<3.0*ULN; Gr3: 3.1-5.0*ULN; Gr4: >5.0*ULN. Creatinine: Gr1: 1.1-1.3*ULN; Gr2: 1.4-<1.8*ULN; Gr3: 1.9 - <3.4*ULN; Gr4: >=3.5*ULN. Glucose mg/dL (high): Gr1:110-<125 (Fasting)/116-<160;Gr2:126-<250 (F)/161-<250; Gr3: 251-500; Gr4: >500.Glucose (low): Gr1: 55-64; Gr2: 40 - <54; Gr3: 30-39; Gr4: <30 mg/dL.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 120
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        ALT
    23
    17
    4
        AST
    14
    9
    1
        Alkaline Phosphatase
    3
    3
    0
        Lipase
    5
    12
    3
        Creatinine
    1
    1
    0
        Glucose, high
    3
    4
    1
        Glucose, low
    3
    4
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects with Electrolyte Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Subjects

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    End point title
    		 Number of Subjects with Electrolyte Laboratory Abnormalities (Grades 1 - 4) - On Treatment - Treated Subjects
    End point description
    Toxicity Scale: DAIDS Version 1.0 and modified World Health Organization (WHO) for chloride. Milliequivalents per liter (mEq/L); Grade (Gr). Chloride high (mEq/L): Gr1: 113-<117; Gr2: 117-<121; Gr3: 121-125; Gr4: >125. Potassium low (mEq/L): Gr1: 3.0-3.4; Gr2: 2.5-2.9; Gr3:2.0-<2.4; Gr4: <2.0. Potassium high: Gr1; 5.6- <6.0; Gr2: 6.1-<6.5; Gr3: 6.6-7.0; Gr4: >7.0. Sodium high (mEq/L): Gr1; 146-<150; Gr2: 151-<154; Gr3: 155-<159; Gr4: >=160.
    End point type
    Secondary
    End point timeframe
    Day 1 Week 120
    End point values
    		 Lamivudine (LVD)-naive (Group A) Lamivudine (LVD)-experienced (Group B) Nucleoside/tide analog (NA) - experienced (Group C)
    Number of subjects analysed
    24
    19
    5
    Units: Subjects
        Chloride, high
    3
    0
    0
        Potassium, low
    1
    0
    0
        Potassium, high
    1
    1
    0
        Sodium, high
    4
    3
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study initiation to study completion (June 2007 to September 2017, approximately 118 months)
    Adverse event reporting additional description
    From first dose to date of last dose plus 5 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    LVD-naive
    Reporting group description
    		 Subjects who have not received LVD therapy within 24 weeks were treated with age stratified oral dose of Entecavir (ETV) 0.015 milligram (mg) per kilogram (kg) up to a maximum dose of 0.5 mg once daily (QD). Subjects with age ranging 2-6 years received treatment as solution, while subjects ranging from 6-12 and 12-18 years received treatment as either solution or tablet based on subject's convenience for up to maximum of 120 weeks.

    Reporting group title
    NA-experienced
    Reporting group description
    		 Subjects who had failed previous treatment with any non-ETV NA therapy were treated with age stratified oral dose of ETV 0.030 mg/kg up to a maximum of 1.0 mg QD. Subjects with age ranging 2-6 years received treatment as solution, while subjects ranging from 6-12 and 12-18 years received treatment as either solution or tablet based on subject's convenience for up to maximum of 120 weeks.

    Reporting group title
    LVD-experienced
    Reporting group description
    		 Subjects who have received LVD therapy before 12 weeks were treated with age stratified oral dose of ETV 0.030 mg/kg up to a maximum of 1.0 mg QD. Subjects with age ranging 2-6 years received treatment as solution, while subjects ranging from 6-12 and 12-18 years received treatment as either solution or tablet based on subject's convenience for up to maximum of 120 weeks.

    Serious adverse events
    		 LVD-naive NA-experienced LVD-experienced
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LVD-naive NA-experienced LVD-experienced
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 24 (87.50%)
    4 / 5 (80.00%)
    17 / 19 (89.47%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    3
    0
    Fatigue
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Influenza like illness
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Pyrexia
         subjects affected / exposed
    10 / 24 (41.67%)
    1 / 5 (20.00%)
    5 / 19 (26.32%)
         occurrences all number
    16
    1
    6
    Product taste abnormal
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Cough
         subjects affected / exposed
    7 / 24 (29.17%)
    1 / 5 (20.00%)
    5 / 19 (26.32%)
         occurrences all number
    8
    2
    5
    Epistaxis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    1
    Nasal congestion
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    3
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    3
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 5 (20.00%)
    1 / 19 (5.26%)
         occurrences all number
    3
    2
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Mood swings
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Limb injury
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Headache
         subjects affected / exposed
    7 / 24 (29.17%)
    0 / 5 (0.00%)
    5 / 19 (26.32%)
         occurrences all number
    9
    0
    9
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Tinnitus
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 5 (20.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    1
    7
    Abdominal pain upper
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    4
    Dental caries
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    5 / 24 (20.83%)
    1 / 5 (20.00%)
    3 / 19 (15.79%)
         occurrences all number
    7
    1
    3
    Enteritis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Soft stool
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Nausea
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Odynophagia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Tooth impacted
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 5 (20.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    2
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis bullous
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 5 (20.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    4
    2
    Rash macular
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    1
    0
    Myalgia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    1
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Impetigo
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    3
    Lyme disease
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Molluscum contagiosum
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 5 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Mumps
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Otitis externa
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Otitis media acute
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 5 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 24 (41.67%)
    2 / 5 (40.00%)
    3 / 19 (15.79%)
         occurrences all number
    21
    2
    4
    Nasopharyngitis
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 5 (20.00%)
    9 / 19 (47.37%)
         occurrences all number
    12
    2
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 5 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2008
    Changes incorporated in this amendment are: 1) Incorporate new information regarding the potential anti-HIV effect of entecavir 2) Recent changes in study personnel 3) Adding that the Schwartz method for calculating estimated creatinine clearance should be used in subjects  17 years of age, and the Cockcroft-Gault equation should be used in subjects 18 years of age 4) Clarify labeling and storage of study drug 5) Extending the period of time between the Screening Visit and Day 1 Visit from 4 weeks to 6 weeks in order to provide greater study visit scheduling flexibility for subjects and their guardians 6) Define Targeted Physical Exam 7) Change address of the PK analytical laboratory 8) Update serious adverse event contact information 9) Clarify reporting of suspected serious adverse events to relevant health authorities 10) Clarify inconsistencies within the protocol with respect to: pregnancy restrictions after study medication has been discontinued, endpoint definitions, efficacy analyses, and which concomitant medications are contraindicated 11) Correct typographical errors and administrative clarifications.
    05 Dec 2008
    To include information regarding the definition of a 'serious breach' of GCP, and to specify the associated reporting requirements including investigator reporting responsibilities.
    18 Oct 2013
    1. Address the potential safety issues associated with extreme elevations of ALT (serum ALT > 1,000 U/L or > 20x ULN and clinical or laboratory findings suggestive of liver dysfunction) due to acute exacerbation of CHB by providing emergency access to study ETV (“rescue ETV”) for subjects who cannot access acceptable alternative anti-HBV therapy; 2. Specify that rescue ETV would be provided by the sponsor at the request of a primary investigator and approval of the Central Medical Monitor; 3. Specify that rescue therapy provided by the sponsor would be ETV only, and would be provided for up to 96 consecutive weeks; 4. Specify that the management of extreme elevations of ALT are at the discretion of the primary investigator; 5. Clarify that non-serious adverse events should be documented for all LTFU subjects receiving rescue ETV; 6. Change the duration of study to, “5 years, or until the last study subject treated with rescue ETV for an extreme elevation of ALT completes 48-weeks of off-treatment follow-up; whichever is later”; 7. Specify that on-treatment efficacy endpoints are based on ETV therapy, and therefore exclude rescue ETV; 8. Specify entecavir tablets should be protected from light during storage; 9. Modify Figure 5.3.2.1-1 to provide guidance to investigators managing significant elevations of ALT due to acute exacerbation of CHB.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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