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    Clinical Trial Results:
    A Randomized, Double-Blind Evaluation of the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate Versus Placebo in Adolescents With Chronic Hepatitis B Infection

    Summary
    EudraCT number
    		 2007-003704-35
    Trial protocol
    		 GB   BE   FR   ES   BG   DE   GR   Outside EU/EEA  
    Global end of trial date
    02 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jun 2016
    First version publication date
    17 Jun 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-174-0115
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00734162
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000533-PIP01-08
    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
    02 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the antiviral efficacy, safety, and tolerability of tenofovir disoproxil fumarate (TDF) 300 mg once daily versus placebo once daily in adolescents (aged 12 to 17 years) with chronic hepatitis B infection.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 74
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Turkey: 2
    Worldwide total number of subjects
    106
    EEA total number of subjects
    99
    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)
    0
    Adolescents (12-17 years)
    106
    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
    		 Participants were enrolled at 3 sites in the United States, 8 sites in Poland, 3 sites in Romania, 2 sites in Bulgaria, 2 sites in France, 2 sites in Spain, and 1 site in Turkey. The first participant was screened on 03 December 2008. The last study visit occurred on 02 December 2015.

    Pre-assignment
    Screening details
    		 149 participants were screened.

    Period 1
    Period 1 title
    Randomized Phase (Through Week 72)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TDF 12-14 years
    Arm description
    		 TDF in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tenofovir disoproxil fumarate (TDF) 300 mg once daily

    Arm title
    		 Placebo 12-14 years
    Arm description
    		 TDF placebo in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF placebo once daily

    Arm title
    		 Placebo 15-17 years
    Arm description
    		 TDF placebo in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF placebo once daily

    Arm title
    		 TDF 15-17 years
    Arm description
    		 TDF in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg once daily

    Number of subjects in period 1
    		TDF 12-14 years Placebo 12-14 years Placebo 15-17 years TDF 15-17 years
    Started
    10
    13
    41
    42
    Completed
    10
    13
    37
    41
    Not completed
    0
    0
    4
    1
         Per protocol ALT elevation
    -
    -
    2
    -
         Investigator's Discretion
    -
    -
    2
    1
    Period 2
    Period 2 title
    Open-Label Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TDF 12-14 years
    Arm description
    		 TDF in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg once daily

    Arm title
    		 TDF 15-17 years
    Arm description
    		 TDF in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg once daily

    Arm title
    		 Placebo 12-14 years
    Arm description
    		 TDF placebo in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Placebo

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg once daily

    Arm title
    		 Placebo 15-17 years
    Arm description
    		 TDF placebo in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg once daily

    Number of subjects in period 2
    		TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years
    Started
    10
    41
    13
    37
    Completed
    7
    39
    12
    36
    Not completed
    3
    2
    1
    3
         Withdrew Consent
    1
    -
    1
    1
         Did Not Meet Entrance Criteria
    -
    -
    -
    1
         Safety, Tolerability or Efficacy Reasons
    1
    -
    -
    -
         Lost to follow-up
    1
    2
    -
    1
    Joined
    0
    0
    0
    2
         Switched prior to completing double-blind period
    -
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TDF 12-14 years
    Reporting group description
    		 TDF in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    TDF 15-17 years
    Reporting group description
    		 TDF in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    Placebo 12-14 years
    Reporting group description
    		 TDF placebo in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    Placebo 15-17 years
    Reporting group description
    		 TDF placebo in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total
    Number of subjects
    		 10 42 13 41 106
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 13.3 ± 0.82 16.1 ± 0.75 13.2 ± 0.69 15.9 ± 0.82 -
    Gender, Male/Female
    Units: participants
        Female
    		 3 11 4 15 33
        Male
    		 7 31 9 26 73
    Race
    Units: Subjects
        Asian
    		 0 1 1 0 2
        Black
    		 0 1 0 0 1
        White
    		 10 39 12 37 98
        Other
    		 0 1 0 4 5
    Alanine aminotransferase (ALT) normal at baseline
    The upper limit of normal (ULN) was 43 U/L for males and 34 U/L for females.
    Units: Subjects
        Normal
    		 3 14 4 8 29
        Abnormal
    		 7 28 9 33 77
    HBV Genotype
    Units: Subjects
        Genotype A
    		 5 30 5 29 69
        Genotype B
    		 0 1 1 1 3
        Genotype C
    		 0 1 0 0 1
        Genotype D
    		 5 10 7 11 33
    Hepatitis B e Antigen (HBeAg) status at baseline
    Units: Subjects
        Negative
    		 1 3 0 6 10
        Positive
    		 9 39 13 35 96
    ALT level at baseline
    Units: U/L
        arithmetic mean (standard deviation)
    		 77 ± 54.8 106 ± 116.4 101 ± 95.4 101 ± 89.5 -
    HBV DNA level at baseline
    Units: Log_10 copies/mL
        arithmetic mean (standard deviation)
    		 8.26 ± 1.455 7.95 ± 1.421 8.61 ± 1.166 8.12 ± 1.451 -

    End points

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    End points reporting groups
    Reporting group title
    TDF 12-14 years
    Reporting group description
    		 TDF in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    Placebo 12-14 years
    Reporting group description
    		 TDF placebo in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    Placebo 15-17 years
    Reporting group description
    		 TDF placebo in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    TDF 15-17 years
    Reporting group description
    		 TDF in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase
    Reporting group title
    TDF 12-14 years
    Reporting group description
    		 TDF in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    TDF 15-17 years
    Reporting group description
    		 TDF in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    Placebo 12-14 years
    Reporting group description
    		 TDF placebo in participants 12-14 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Reporting group title
    Placebo 15-17 years
    Reporting group description
    		 TDF placebo in participants 15-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Subject analysis set title
    Total TDF 12-17 Years
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    TDF in participants 12-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Subject analysis set title
    Total Placebo 12-17 Years
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    TDF in participants 12-17 years of age in the Randomized Phase, followed by TDF in the Open-Label Phase

    Primary: Percentage of Participants With HBV DNA < 400 Copies/mL at Week 72

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    End point title
    		 Percentage of Participants With HBV DNA < 400 Copies/mL at Week 72
    End point description
    The percentage of participants with HBV DNA < 400 copies/mL at Week 72 was summarized by treatment and age group (grouped by baseline age for analysis), using the missing = failure (M = F) analysis with the double-blind efficacy evaluation (DBEE) algorithm. In the M = F analysis method, all missing data were considered as failure to meet the outcome measure threshold. This method was combined with the DBEE algorithm, which included all available data for the double-blind period, and any data for the open-label period were not included; data generated during treatment-free follow-up from subjects who achieved HBsAg loss and entered treatment-free follow-up during double-blind treatment period were included. Full Analysis Set: participants who were randomized and received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 72
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
        number (not applicable)
    90
    88.1
    0
    0
    88.5
    0
    Statistical analysis title
    		 Difference between treatment arms
    Statistical analysis description
    Analysis is the difference between treatment groups in the proportion of participants who met the outcome measure criterion, controlling for randomization age group.
    Comparison groups
    TDF 12-14 years v TDF 15-17 years v Placebo 12-14 years v Placebo 15-17 years
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - A p-value of < 0.05 was considered statistically significant.

    Primary: Percentage of Participants With at Least a 6% Decrease From Baseline in Bone Mineral Density (BMD) of the Spine at Week 72

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    End point title
    		 Percentage of Participants With at Least a 6% Decrease From Baseline in Bone Mineral Density (BMD) of the Spine at Week 72 [2]
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). In contrast with what was previously reported in the interim Week 72 CSR, 1 participant met the primary safety endpoint of at least a 6% decrease from baseline in spine BMD at Week 72, based on the final BMD data analysis. The apparent discrepancy was due to the correction factor applied to the subject-specific BMD calculations performed at the time of the Interim Week 72 clinical study report that could not take into account the actual Week 72 phantom data (ie, calibration test used in longitudinal clinical trials to monitor and adjust for shifts in the DXA scanner calibration over time), which were not provided by the site at that time. The correction factor applied to the final analysis has been properly based on all phantom data through the end of Week 72, as well as through the end of Week 192. Safety Analysis Set: participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to Week 72
    Notes
    [2] - 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: No statistical comparison was planned or performed.
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
        number (not applicable)
    0
    2.4
    0
    0
    1.9
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 96, 144, and 192

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    End point title
    		 Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 48, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Full Analysis Set
    End point type
    Secondary
    End point timeframe
    Weeks 48, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    90
    85.7
    0
    0
    86.5
    0
        Week 96
    90
    88.1
    53.8
    68.3
    88.5
    64.8
        Week 144
    100
    90.5
    69.2
    85.4
    92.3
    81.5
        Week 192
    90
    85.7
    76.9
    73.2
    86.5
    74.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Full Analysis Set
    End point type
    Secondary
    End point timeframe
    Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    70
    76.2
    30.8
    26.8
    75
    27.8
        Week 72
    80
    76.2
    30.8
    41.5
    76.9
    38.9
        Week 96
    80
    76.2
    69.2
    65.9
    76.9
    66.7
        Week 144
    60
    71.4
    69.2
    75.6
    69.2
    74.1
        Week 192
    80
    71.4
    84.6
    75.6
    73.1
    77.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA < 400 Copies/mL and Normal ALT at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With HBV DNA < 400 Copies/mL and Normal ALT at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Full Analysis Set
    End point type
    Secondary
    End point timeframe
    Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    70
    69
    0
    0
    69.2
    0
        Week 72
    80
    69
    0
    0
    71.2
    0
        Week 96
    80
    73.8
    46.2
    51.2
    75
    50
        Week 144
    60
    69
    53.8
    68.3
    67.3
    64.8
        Week 192
    80
    64.3
    69.2
    63.4
    67.3
    64.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With HBV DNA < 169 Copies/mL at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Full Analysis Set
    End point type
    Secondary
    End point timeframe
    Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    80
    81
    0
    0
    80.8
    0
        Week 72
    90
    83.3
    0
    0
    84.6
    0
        Week 96
    90
    88.1
    53.8
    63.4
    88.5
    61.1
        Week 144
    90
    88.1
    69.2
    82.9
    88.5
    79.6
        Week 192
    90
    83.3
    76.9
    73.2
    84.6
    74.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis), using the M = F. Full Analysis Set
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    0
    0
    0
    0
    0
    0
        Week 72
    0
    2.4
    0
    0
    1.9
    0
        Week 96
    0
    2.4
    0
    0
    1.9
    0
        Week 144
    0
    2.4
    0
    0
    1.9
    0
        Week 192
    0
    2.4
    0
    0
    1.9
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBsAg Seroconversion at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With HBsAg Seroconversion at Weeks 48, 72, 96, 144, and 192
    End point description
    HBsAg seroconversion was defined as change of detectable antibody to HBsAg from negative to positive. Data were summarized by treatment and age group (grouped by baseline age for analysis), using the M = F. Full Analysis Set
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    0
    0
    0
    0
    0
    0
        Week 72
    0
    2.4
    0
    0
    1.9
    0
        Week 96
    0
    2.4
    0
    0
    1.9
    0
        Week 144
    0
    2.4
    0
    0
    1.9
    0
        Week 192
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least a 6% Decrease From Baseline in Spine BMD at Weeks 48, 96, 144, and 192

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    End point title
    		 Percentage of Participants With at Least a 6% Decrease From Baseline in Spine BMD at Weeks 48, 96, 144, and 192
    End point description
    The percentage of participants reported is the cumulative incidence from baseline to the respective time point. Data were summarized by treatment and age group (grouped by baseline age for analysis). Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    0
    0
    0
    0
    0
    0
        Week 96
    0
    2.4
    0
    0
    1.9
    0
        Week 144
    0
    2.4
    0
    0
    1.9
    0
        Week 192
    0
    4.8
    0
    4.9
    3.8
    3.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least a 6% Decrease From Baseline in Whole Body BMD at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With at Least a 6% Decrease From Baseline in Whole Body BMD at Weeks 48, 72, 96, 144, and 192
    End point description
    The percentage of participants reported is the cumulative incidence from baseline to the respective time point. Data were summarized by treatment and age group (grouped by baseline age for analysis). Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    42
    13
    41
    52
    54
    Units: percentage of participants
    number (not applicable)
        Week 48
    0
    0
    0
    0
    0
    0
        Week 72
    0
    0
    0
    0
    0
    0
        Week 96
    0
    0
    0
    0
    0
    0
        Week 144
    0
    0
    0
    2.4
    0
    1.9
        Week 192
    0
    0
    0
    2.4
    0
    1.9
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spine Bone Mineral Density (BMD) at Week 48

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    End point title
    		 Percent Change From Baseline in Spine Bone Mineral Density (BMD) at Week 48
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    39
    10
    38
    51
    49
    Units: percentage change
        arithmetic mean (standard deviation)
    9.234 ± 3.4782
    2.114 ± 3.6023
    9.038 ± 6.6575
    4.435 ± 4.9091
    3.51 ± 4.5507
    5.562 ± 5.6772
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spine BMD at Week 72

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    End point title
    		 Percent Change From Baseline in Spine BMD at Week 72
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 72
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    41
    12
    37
    51
    49
    Units: percentage change
        arithmetic mean (standard deviation)
    11.516 ± 3.8818
    3.589 ± 4.5633
    14.131 ± 9.9563
    6.117 ± 6.0624
    5.144 ± 5.4291
    8.08 ± 7.8996
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spine BMD at Week 96

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    End point title
    		 Percent Change From Baseline in Spine BMD at Week 96
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    40
    11
    39
    50
    50
    Units: percentage change
        arithmetic mean (standard deviation)
    13.811 ± 4.6712
    4.196 ± 4.8021
    16.687 ± 10.4359
    4.272 ± 7.0463
    6.119 ± 6.12
    7.003 ± 9.3658
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spine BMD at Week 144

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    End point title
    		 Percent Change From Baseline in Spine BMD at Week 144
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 144
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    39
    10
    38
    49
    48
    Units: percentage change
        arithmetic mean (standard deviation)
    19.224 ± 8.7594
    5.289 ± 5.8084
    21.346 ± 13.4709
    6.144 ± 8.3286
    8.133 ± 8.5611
    9.311 ± 11.3262
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Spine BMD at Week 192

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    End point title
    		 Percent Change From Baseline in Spine BMD at Week 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    37
    11
    35
    46
    46
    Units: percentage change
        arithmetic mean (standard deviation)
    23.933 ± 8.5166
    6.673 ± 7.287
    25.036 ± 14.2346
    6.867 ± 9.3736
    10.05 ± 10.1637
    11.212 ± 13.1459
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Whole Body BMD at Week 48

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    End point title
    		 Percent Change From Baseline in Whole Body BMD at Week 48
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    39
    13
    37
    48
    50
    Units: percentage change
        arithmetic mean (standard deviation)
    5.123 ± 3.8309
    1.339 ± 1.9324
    5.47 ± 3.4958
    3.236 ± 2.8573
    2.048 ± 2.783
    3.817 ± 3.1576
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Whole Body BMD at Week 72

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    End point title
    		 Percent Change From Baseline in Whole Body BMD at Week 72
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 72
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    41
    13
    38
    50
    51
    Units: percentage change
        arithmetic mean (standard deviation)
    7.282 ± 3.9156
    2.141 ± 2.6284
    8.48 ± 4.477
    4.335 ± 3.4073
    3.067 ± 3.4819
    5.391 ± 4.0902
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Whole Body BMD at Week 96

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    End point title
    		 Percent Change From Baseline in Whole Body BMD at Week 96
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    40
    12
    38
    49
    50
    Units: percentage change
        arithmetic mean (standard deviation)
    8.034 ± 3.4973
    3.023 ± 3.2063
    10.056 ± 5.4296
    4.291 ± 4.3195
    3.943 ± 3.773
    5.675 ± 5.1858
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Whole Body BMD at Week 144

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    End point title
    		 Percent Change From Baseline in Whole Body BMD at Week 144
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 144
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    38
    11
    38
    47
    49
    Units: percentage change
        arithmetic mean (standard deviation)
    10.94 ± 4.8819
    3.529 ± 3.1734
    12.638 ± 5.9973
    4.73 ± 5.2213
    4.949 ± 4.5753
    6.505 ± 6.2944
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Whole Body BMD at Week 192

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    End point title
    		 Percent Change From Baseline in Whole Body BMD at Week 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    8
    35
    12
    34
    43
    46
    Units: percentage change
        arithmetic mean (standard deviation)
    13.923 ± 4.6139
    4.295 ± 3.7318
    14.797 ± 6.4993
    4.549 ± 5.4494
    6.086 ± 5.4029
    7.223 ± 7.2666
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Spine BMD at Week 48

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    End point title
    		 Change From Baseline in Z-score for Spine BMD at Week 48
    End point description
    To assess any effect of treatment on growth, Z-scores were used to express the deviation from a reference population for lumbar spine BMD. A Z-score of 0 indicated that a subject was typical of the population for their age, ethnicity, and gender. A negative Z-score indicated that the subject’s recorded value was lower than typical for their age, ethnicity, and gender. A positive Z-score indicates that the subject’s recorded value was higher than typical for their age, ethnicity, and gender. Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    41
    12
    37
    51
    49
    Units: z-score
        arithmetic mean (standard deviation)
    0.02 ± 0.247
    -0.1 ± 0.255
    0.04 ± 0.393
    0.05 ± 0.322
    -0.08 ± 0.256
    0.05 ± 0.337
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Spine BMD at Week 72

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    End point title
    		 Change From Baseline in Z-score for Spine BMD at Week 72
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 72
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    41
    12
    37
    51
    49
    Units: z-scores
        arithmetic mean (standard deviation)
    -0.1 ± 0.312
    -0.05 ± 0.325
    0.09 ± 0.498
    0.1 ± 0.339
    -0.06 ± 0.32
    0.1 ± 0.378
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Spine BMD at Week 96

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    End point title
    		 Change From Baseline in Z-score for Spine BMD at Week 96
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    40
    11
    39
    50
    50
    Units: z-score
        arithmetic mean (standard deviation)
    -0.19 ± 0.365
    -0.07 ± 0.356
    -0.02 ± 0.498
    -0.13 ± 0.414
    -0.1 ± 0.357
    -0.11 ± 0.431
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Spine BMD at Week 144

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    End point title
    		 Change From Baseline in Z-score for Spine BMD at Week 144
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 144
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    10
    39
    10
    38
    49
    48
    Units: z-score
        arithmetic mean (standard deviation)
    -0.2 ± 0.56
    -0.05 ± 0.417
    -0.16 ± 0.625
    -0.04 ± 0.405
    -0.08 ± 0.447
    -0.06 ± 0.455
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Spine BMD at Week 192

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    End point title
    		 Change From Baseline in Z-score for Spine BMD at Week 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    37
    11
    35
    46
    46
    Units: z-score
        arithmetic mean (standard deviation)
    -0.24 ± 0.518
    0.08 ± 0.544
    -0.26 ± 0.654
    -0.05 ± 0.504
    0.02 ± 0.548
    -0.1 ± 0.543
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Whole Body BMD at Week 48

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    End point title
    		 Change From Baseline in Z-score for Whole Body BMD at Week 48
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    39
    13
    37
    48
    50
    Units: z-score
        arithmetic mean (standard deviation)
    0.02 ± 0.426
    -0.15 ± 0.257
    0.1 ± 0.37
    0.04 ± 0.308
    -0.12 ± 0.298
    0.05 ± 0.322
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Whole Body BMD at Week 72

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    End point title
    		 Change From Baseline in Z-score for Whole Body BMD at Week 72
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 72
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    41
    13
    38
    50
    51
    Units: z-score
        arithmetic mean (standard deviation)
    0.02 ± 0.398
    -0.19 ± 0.338
    0.2 ± 0.45
    0.06 ± 0.306
    -0.16 ± 0.355
    0.09 ± 0.349
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Whole Body BMD at Week 96

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    End point title
    		 Change From Baseline in Z-score for Whole Body BMD at Week 96
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    40
    12
    38
    49
    50
    Units: z-score
        arithmetic mean (standard deviation)
    -0.12 ± 0.294
    -0.19 ± 0.451
    0.09 ± 0.528
    -0.06 ± 0.432
    -0.18 ± 0.424
    -0.03 ± 0.456
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Whole Body BMD at Week 144

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    End point title
    		 Change From Baseline in Z-score for Whole Body BMD at Week 144
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 144
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    38
    11
    38
    47
    49
    Units: z-score
        arithmetic mean (standard deviation)
    -0.27 ± 0.431
    -0.21 ± 0.473
    -0.06 ± 0.554
    -0.16 ± 0.468
    -0.22 ± 0.462
    -0.14 ± 0.484
    No statistical analyses for this end point

    Secondary: Change From Baseline in Z-score for Whole Body BMD at Week 192

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    End point title
    		 Change From Baseline in Z-score for Whole Body BMD at Week 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis). Participants in the Safety Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    8
    35
    12
    34
    43
    46
    Units: z-score
        arithmetic mean (standard deviation)
    -0.34 ± 0.499
    -0.11 ± 0.524
    -0.21 ± 0.486
    -0.19 ± 0.517
    -0.16 ± 0.521
    -0.19 ± 0.504
    No statistical analyses for this end point

    Secondary: Number of Participants With Changes in Drug-Resistant Mutations During the Study

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    End point title
    		 Number of Participants With Changes in Drug-Resistant Mutations During the Study
    End point description
    The number of participants with changes in drug-resistant mutations during the study was summarized.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 192
    End point values
    		 Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    52
    54
    Units: participants
        New TDF Drug-Resistant Mutations
    0
    0
        Enrichment of TDF Drug-Resistant Mutations
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Loss at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Loss at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Participants in the Full Analysis Set who were HBeAg-positive at baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    39
    13
    35
    48
    48
    Units: percentage of participants
    number (not applicable)
        Week 48
    11.1
    17.9
    7.7
    8.6
    16.7
    8.3
        Week 72
    11.1
    23.1
    23.1
    11.4
    20.8
    14.6
        Week 96
    44.4
    30.8
    38.5
    28.6
    33.3
    31.3
        Week 144
    44.4
    38.5
    53.8
    34.3
    39.6
    39.6
        Week 192
    33.3
    43.6
    53.8
    37.1
    41.7
    41.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Seroconversion at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants Who Were HBeAg-Positive at Baseline and Who Had HBeAg Seroconversion at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Participants in the Full Analysis Set who were HBeAg-positive at baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    39
    13
    35
    48
    48
    Units: percentage of participants
    number (not applicable)
        Week 48
    11.1
    15.4
    7.7
    8.6
    14.6
    8.3
        Week 72
    11.1
    23.1
    23.1
    11.4
    20.8
    14.6
        Week 96
    44.4
    30.8
    38.5
    25.7
    33.3
    29.2
        Week 144
    33.3
    38.5
    53.8
    34.3
    37.5
    39.6
        Week 192
    33.3
    38.5
    53.8
    37.1
    37.5
    41.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Were HBeAg-Positive at Baseline Who Had HBV DNA < 400 Copies/mL, Normal ALT, and HBeAg Loss/Seroconversion at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants Who Were HBeAg-Positive at Baseline Who Had HBV DNA < 400 Copies/mL, Normal ALT, and HBeAg Loss/Seroconversion at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Participants in the Full Analysis Set who were HBeAg-positive at baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    9
    39
    13
    35
    48
    48
    Units: percentage of participants
    number (not applicable)
        Week 48
    11.1
    12.8
    0
    0
    12.5
    0
        Week 72
    11.1
    15.4
    0
    0
    14.6
    0
        Week 96
    44.4
    28.2
    30.8
    22.9
    31.3
    25
        Week 144
    22.2
    30.8
    46.2
    25.7
    29.2
    31.3
        Week 192
    33.3
    28.2
    46.2
    25.7
    29.2
    31.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Abnormal ALT at Baseline Who Had Normalized ALT at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With Abnormal ALT at Baseline Who Had Normalized ALT at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Participants in the Full Analysis Set with abnormal ALT at baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    7
    28
    9
    33
    35
    42
    Units: percentage of participants
    number (not applicable)
        Week 48
    85.7
    71.4
    11.1
    21.2
    74.3
    19
        Week 72
    85.7
    71.4
    22.2
    33.3
    74.3
    31
        Week 96
    85.7
    78.6
    66.7
    63.6
    80
    64.3
        Week 144
    57.1
    71.4
    66.7
    72.7
    68.6
    71.4
        Week 192
    85.7
    75
    77.8
    69.7
    77.1
    71.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Abnormal ALT at Baseline Who Had HBV DNA < 400 Copies/mL and Normalized ALT at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants With Abnormal ALT at Baseline Who Had HBV DNA < 400 Copies/mL and Normalized ALT at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Participants in the Full Analysis Set with abnormal ALT at baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    7
    28
    9
    33
    35
    42
    Units: percentage of participants
    number (not applicable)
        Week 48
    85.7
    71.4
    0
    0
    74.3
    0
        Week 72
    85.7
    71.4
    0
    0
    74.3
    0
        Week 96
    85.7
    78.6
    55.6
    54.5
    80
    54.8
        Week 144
    57.1
    71.4
    66.7
    69.7
    68.6
    69
        Week 192
    85.7
    67.9
    77.8
    57.6
    71.4
    61.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Were HBeAg-Positive With Abnormal ALT at Baseline Who Had HBV DNA < 400 Copies/mL, Normalized ALT, and HBeAg Loss/Seroconversion at Weeks 48, 72, 96, 144, and 192

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    End point title
    		 Percentage of Participants Who Were HBeAg-Positive With Abnormal ALT at Baseline Who Had HBV DNA < 400 Copies/mL, Normalized ALT, and HBeAg Loss/Seroconversion at Weeks 48, 72, 96, 144, and 192
    End point description
    Data were summarized by treatment and age group (grouped by baseline age for analysis) using the missing = failure method. Participants in the Full Analysis Set who were HBeAg-Positive with abnormal ALT at baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Weeks 48, 72, 96, 144, and 192
    End point values
    		 TDF 12-14 years TDF 15-17 years Placebo 12-14 years Placebo 15-17 years Total TDF 12-17 Years Total Placebo 12-17 Years
    Number of subjects analysed
    6
    27
    9
    33
    33
    42
    Units: percentage of participants
    number (not applicable)
        Week 48
    16.7
    18.5
    0
    0
    18.2
    0
        Week 72
    16.7
    22.2
    0
    0
    21.2
    0
        Week 96
    50
    33.3
    33.3
    24.2
    36.4
    26.2
        Week 144
    33.3
    29.6
    55.6
    27.3
    30.3
    33.3
        Week 192
    50
    29.6
    55.6
    27.3
    33.3
    33.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through end of the Open-Label Phase (up to 4 years)
    Adverse event reporting additional description
    Safety Analysis Set
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Double-Blind TDF
    Reporting group description
    		 Adverse events reported in this group occurred during the Randomized Phase (+7 days for participants who did not continue to the Open-Label Phase) and includes all participants who received double-blind TDF during the Randomized Phase of the study.

    Reporting group title
    Double-Blind Placebo
    Reporting group description
    		 Adverse events reported in this group occurred during the Randomized Phase (+7 days for participants who did not continue to the Open-Label Phase) and includes all participants who received placebo during the Randomized Phase of the study.

    Reporting group title
    Open-Label TDF-TDF
    Reporting group description
    		 Adverse events reported in this group occurred during the Open-Label Phase and includes all participants who received double-blind TDF during the Randomized Phase of the study and continued to the Open-Label Phase.

    Reporting group title
    Open-Label Placebo-TDF
    Reporting group description
    		 Adverse events reported in this group occurred during the Open-Label Phase and includes all participants who received placebo during the Randomized Phase of the study and continued to the Open-Label Phase.

    Serious adverse events
    		 Double-Blind TDF Double-Blind Placebo Open-Label TDF-TDF Open-Label Placebo-TDF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 52 (9.62%)
    11 / 54 (20.37%)
    8 / 51 (15.69%)
    10 / 52 (19.23%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menstrual disorder
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glucose urine present
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Protein urine present
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase abnormal
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer perforation
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 52 (1.92%)
    7 / 54 (12.96%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 7
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double-Blind TDF Double-Blind Placebo Open-Label TDF-TDF Open-Label Placebo-TDF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 52 (65.38%)
    40 / 54 (74.07%)
    30 / 51 (58.82%)
    31 / 52 (59.62%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 52 (3.85%)
    5 / 54 (9.26%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    2
    5
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 54 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
         occurrences all number
    3
    0
    2
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 54 (5.56%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 52 (3.85%)
    9 / 54 (16.67%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
         occurrences all number
    2
    18
    1
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 52 (0.00%)
    5 / 54 (9.26%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences all number
    0
    5
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 54 (1.85%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
         occurrences all number
    6
    2
    1
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 52 (5.77%)
    7 / 54 (12.96%)
    1 / 51 (1.96%)
    9 / 52 (17.31%)
         occurrences all number
    3
    12
    2
    13
    Diarrhoea
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 54 (1.85%)
    3 / 51 (5.88%)
    2 / 52 (3.85%)
         occurrences all number
    4
    1
    4
    3
    Nausea
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 54 (5.56%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences all number
    2
    4
    0
    2
    Toothache
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 54 (5.56%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences all number
    1
    5
    3
    1
    Constipation
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 54 (5.56%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 54 (5.56%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 54 (7.41%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    15
    0
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 54 (5.56%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    3
    3
    0
    1
    Epistaxis
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 54 (3.70%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    5 / 54 (9.26%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences all number
    0
    5
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 52 (3.85%)
    10 / 54 (18.52%)
    2 / 51 (3.92%)
    6 / 52 (11.54%)
         occurrences all number
    2
    10
    2
    6
    Nail disorder
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 54 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    15 / 52 (28.85%)
    11 / 54 (20.37%)
    9 / 51 (17.65%)
    13 / 52 (25.00%)
         occurrences all number
    16
    17
    12
    14
    Nasopharyngitis
         subjects affected / exposed
    5 / 52 (9.62%)
    12 / 54 (22.22%)
    6 / 51 (11.76%)
    12 / 52 (23.08%)
         occurrences all number
    8
    21
    11
    20
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 52 (9.62%)
    7 / 54 (12.96%)
    3 / 51 (5.88%)
    7 / 52 (13.46%)
         occurrences all number
    6
    9
    3
    9
    Bronchitis
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 54 (1.85%)
    6 / 51 (11.76%)
    4 / 52 (7.69%)
         occurrences all number
    2
    1
    7
    7
    Rhinitis
         subjects affected / exposed
    5 / 52 (9.62%)
    3 / 54 (5.56%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
         occurrences all number
    5
    3
    4
    2
    Tonsillitis
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 54 (7.41%)
    2 / 51 (3.92%)
    4 / 52 (7.69%)
         occurrences all number
    3
    4
    2
    4
    Gastroenteritis
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 54 (3.70%)
    0 / 51 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    2
    2
    0
    5
    Respiratory tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 54 (3.70%)
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences all number
    1
    2
    1
    3
    Viral infection
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
    4 / 51 (7.84%)
    2 / 52 (3.85%)
         occurrences all number
    0
    0
    5
    2
    Herpes zoster
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 54 (5.56%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
         occurrences all number
    0
    3
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2008
    • The requirement for daily multivitamin to contain 100% of RDA for vitamin D was changed to require 100% of country-specific RDA for vitamin D. • The study phase (Phase 3) was added to the protocol. • Given the pediatric age range of study participants, the absolute requirement for contraception was changed to apply to sexually-active males and females of reproductive potential. • The drug dispensing schedule was corrected to reflect that subjects were provided with sufficient supplies for 4 to 8 weeks of dosing during Weeks 1 to 96. Thereafter, subjects were provided with sufficient supplies for 12 weeks of dosing. • The definition of overdose was corrected to match the text for definition of overdose in the existing approved Gilead Drug Safety and Public Health Standard Operating Procedure (SOP), effective date 07 January 2008.
    17 Feb 2009
    • The primary endpoint was changed from a composite of HBV DNA < 400 copies/mL and ALT normal at Week 72 to the single endpoint of HBV DNA < 400 copies/mL. This was done because the protocol permitted entry based upon historical ALT in the event that ALT was not > 2 x the upper limit of normal at screening. Thus, some subjects may have been enrolled who had intermittent ALT elevations but a normal ALT at the time of baseline such that the composite endpoint would not be fully evaluable. • The requirement for protocol-specified unblinding of treatment assignment in relation to persistent Grade 4 ALT was removed. Additionally, in the event where Grade 4 ALT was maintained for 16 weeks and in the case of ALT flare, both considered situations of medical need, serial HBV DNA values from Screen through time of event were made available to the investigator. This protected the blind of the study but permitted the investigator to use HBV DNA to make a medical management decision regarding the subjects with Grade 4 ALT. • The inclusion criteria were modified to permit up to 50% of subjects enrolled to be HBeAg-negative. It was originally felt there would be a paucity of such subjects due to the natural course of chronic HBV infection in children and adolescents (ie, most in the “immune tolerant” phase). However, initial screening indicated that approximately 50% of potential subjects have HBeAg-negative disease.
    01 Jun 2012
    • Analysis of the primary endpoint was planned to occur at Week 72. Additional efficacy and safety analyses to be conducted after Week 72 were considered secondary. • A Treatment Extension period was added instead of a separate rollover study. Subjects who were 17 years of age or younger at the last visit (Week 192) were offered the opportunity to continue in an extension of the study, where they would receive open-label TDF 300 mg until they reached 18 years of age or until standard of care therapy was initiated. • Safety contact information was updated and reporting procedures were updated to include the process for special situations. • The DXA window was increased to ± 15 days for visits occurring after Week 72. Visit window through Week 72 remained unchanged at ± 1 week (7 days).

    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.
    There were no limitations affecting the analysis or results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/22544804
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