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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 Pediatric Patients With Chronic Hepatitis B Infection

    Summary
    EudraCT number
    		 2012-000586-20
    Trial protocol
    		 PL   BG   Outside EU/EEA   RO  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2021
    First version publication date
    28 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-174-0144
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01651403
    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
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@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
    Interim
    Date of interim/final analysis
    02 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Aug 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the antiviral efficacy of tenofovir disoproxil fumarate (tenofovir DF; TDF) versus placebo in pediatric population (aged 2 to < 12 years at the time of enrollment) with chronic hepatitis B (CHB) 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
    06 Dec 2012
    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
    India: 13
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Romania: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 34
    Country: Number of subjects enrolled
    Bulgaria: 1
    Worldwide total number of subjects
    90
    EEA total number of subjects
    24
    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)
    1
    Children (2-11 years)
    88
    Adolescents (12-17 years)
    1
    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 study sites in the United States, Asia, and Europe.The first participant was screened on 06 December 2012. The last Week 192 study visit occurred on 02 June 2020.

    Pre-assignment
    Screening details
    		 176 participants were screened.

    Period 1
    Period 1 title
    Double-Blind Period (Through Week 48/72)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tenofovir Disoproxil Fumarate
    Arm description
    		 Blinded Randomized Phase: Tenofovir disoproxil fumarate (TDF) tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo
    Arm description
    		 Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.
    Arm type
    		 Placebo

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

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

    Number of subjects in period 1 [1]
    		Tenofovir Disoproxil Fumarate Placebo
    Started
    60
    29
    Completed
    56
    25
    Not completed
    4
    4
         Withdrew Consent/Assent
    3
    3
         Participant Noncompliance
    1
    1
    Notes
    [1] - 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: 1 participant who was randomized but not treated was not included in the Safety Analysis Set for Period table 1 reported above.
    Period 2
    Period 2 title
    Open-Label Phase (Weeks 49/73-192)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tenofovir Disoproxil Fumarate
    Arm description
    		 Blinded Randomized Phase: Tenofovir disoproxil fumarate (TDF) tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo
    Arm description
    		 Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.
    Arm type
    		 Placebo

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

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

    Number of subjects in period 2
    		Tenofovir Disoproxil Fumarate Placebo
    Started
    56
    25
    Completed
    35
    11
    Not completed
    21
    14
         Withdrew Consent/Assent
    6
    4
         Investigator decision
    2
    1
         Continuing Study
    13
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tenofovir Disoproxil Fumarate
    Reporting group description
    		 Blinded Randomized Phase: Tenofovir disoproxil fumarate (TDF) tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Reporting group title
    Placebo
    Reporting group description
    		 Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Reporting group values
    		 Tenofovir Disoproxil Fumarate Placebo Total
    Number of subjects
    		 60 29 89
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6 ( 2.5 ) 7 ( 3.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 12 39
        Male
    		 33 17 50
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 60 29 89
    Race
    Units: Subjects
        Asian
    		 41 17 58
        Black or African American
    		 4 1 5
        White
    		 15 11 26
    Hepatitis B Virus Surface Antigen (HBsAg)
    Units: Subjects
        Positive
    		 60 29 89
        Negative
    		 0 0 0
    Hepatitis B e antigen (HBeAg)
    Units: Subjects
        Positive
    		 56 29 85
        Negative
    		 4 0 4
    HBeAb
    Units: Subjects
        Positive
    		 4 0 4
        Negative or Missing
    		 56 29 85
    HBV DNA
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 8.089 ( 0.7208 ) 8.133 ( 1.2538 ) -
    Spine Bone Mineral Density
    Units: g/cm^2
        arithmetic mean (standard deviation)
    		 0.586 ( 0.1196 ) 0.626 ( 0.1567 ) -

    End points

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    End points reporting groups
    Reporting group title
    Tenofovir Disoproxil Fumarate
    Reporting group description
    		 Blinded Randomized Phase: Tenofovir disoproxil fumarate (TDF) tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Reporting group title
    Placebo
    Reporting group description
    		 Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.
    Reporting group title
    Tenofovir Disoproxil Fumarate
    Reporting group description
    		 Blinded Randomized Phase: Tenofovir disoproxil fumarate (TDF) tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Reporting group title
    Placebo
    Reporting group description
    		 Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Subject analysis set title
    TDF (Blinded Randomized Phase)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Blinded Randomized Phase: TDF tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3)

    Subject analysis set title
    Placebo (Blinded Randomized Phase)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3)

    Subject analysis set title
    TDF to TDF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Blinded Randomized Phase: TDF tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3).

    Subject analysis set title
    Placebo to TDF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3). Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3).

    Subject analysis set title
    TDF to TDF (Open-Label Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Subject analysis set title
    Placebo to TDF (Open-Label Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Primary: Percentage of Participants With Serum HBV DNA < 400 Copies/mL (69 IU/mL) at Week 48 (Missing = Failure Approach)

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    End point title
    		 Percentage of Participants With Serum HBV DNA < 400 Copies/mL (69 IU/mL) at Week 48 (Missing = Failure Approach)
    End point description
    The Full Analysis Set (FAS) included randomized participants who have received at least 1 dose of study drug. Participants will be analyzed according to the treatment to which they were randomized. The missing equals failure approach was used where all participants with missing data were considered to have failed to achieve the endpoint.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (confidence interval 95%)
    76.7 (64.0 to 86.6)
    6.9 (0.8 to 22.8)
    Statistical analysis title
    		 Statistical Analysis 1 - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - 2-sided Cochran-Mantel-Haenszel test adjusted for age at baseline and region strata
    Statistical analysis title
    		 Statistical Analysis 2 - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - Fisher's exact test without adjusting for strata at baseline

    Primary: Percentage of Participants With Serum HBV DNA < 400 Copies/mL (69 IU/mL) at Week 48 (Missing = Excluded Approach)

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    End point title
    		 Percentage of Participants With Serum HBV DNA < 400 Copies/mL (69 IU/mL) at Week 48 (Missing = Excluded Approach)
    End point description
    Participants in the Full Analysis Set with available data were analyzed. The missing equals failure approach was used where all participants with missing data were excluded.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    55
    26
    Units: percentage of participants
        number (confidence interval 95%)
    83.6 (71.2 to 92.2)
    7.7 (0.9 to 25.1)
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - 2-sided Cochran-Mantel-Haenszel test adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48

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    End point title
    		 Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48
    End point description
    HBeAg seroconversion was defined as HBeAg loss and a change from HBeAb negative or missing at baseline to HBeAb positive. Serologically Evaluable FAS For HBeAg loss/seroconversion: participants who were randomized and had received at least 1 dose of study drug, and with HBeAg positive and HBeAb negative or missing at baseline. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    56
    29
    Units: percentage of participants
        number (not applicable)
    25.0
    24.1
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.935 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - 2-sided Cochran-Mantel-Haenszel test adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 48, Based on the American Association for the Study of Liver Diseases (AASLD) Normal Range

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    End point title
    		 Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 48, Based on the American Association for the Study of Liver Diseases (AASLD) Normal Range
    End point description
    Normal ALT was defined as ≤ 30 U/L for males and females 0−12 years based on the AASLD pediatric normal range. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    51.7
    17.2
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With Normal ALT at Week 192, Based on the AASLD Normal Range

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    End point title
    		 Percentage of Participants With Normal ALT at Week 192, Based on the AASLD Normal Range
    End point description
    Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    71.7
    51.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Normal ALT at Week 48, Based on the Central Lab Normal Range

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    End point title
    		 Percentage of Participants With Normal ALT at Week 48, Based on the Central Lab Normal Range
    End point description
    Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    65.0
    17.2
    Statistical analysis title
    		 Statistical Analysis: TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With Normal ALT at Week 192, Based on the Central Lab Normal Range

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    End point title
    		 Percentage of Participants With Normal ALT at Week 192, Based on the Central Lab Normal Range
    End point description
    Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    80.0
    62.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Normalized ALT at Week 48, Based on the AASLD Normal Range

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    End point title
    		 Percentage of Participants With Normalized ALT at Week 48, Based on the AASLD Normal Range
    End point description
    Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    28
    Units: percentage of participants
        number (not applicable)
    51.7
    17.9
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With Normalized ALT at Week 192, Based on the AASLD Normal Range

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    End point title
    		 Percentage of Participants With Normalized ALT at Week 192, Based on the AASLD Normal Range
    End point description
    Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    28
    Units: percentage of participants
        number (not applicable)
    71.7
    50.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Normalized ALT at Week 48, Based on the Central Lab Normal Range

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    End point title
    		 Percentage of Participants With Normalized ALT at Week 48, Based on the Central Lab Normal Range
    End point description
    Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    58
    27
    Units: percentage of participants
        number (not applicable)
    65.5
    14.8
    Statistical analysis title
    		 Statistical Analysis- TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [8] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With Normalized ALT at Week 192, Based on the Central Lab Normal Range

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    End point title
    		 Percentage of Participants With Normalized ALT at Week 192, Based on the Central Lab Normal Range
    End point description
    Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    58
    27
    Units: percentage of participants
        number (not applicable)
    79.3
    59.3
    No statistical analyses for this end point

    Secondary: Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on AASLD Normal Range) at Week 48

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    End point title
    		 Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on AASLD Normal Range) at Week 48
    End point description
    Normal ALT was defined as ≤ 30 U/L for males and females 0−12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    28
    Units: percentage of participants
        number (not applicable)
    46.7
    7.1
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [9] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on AASLD Normal Range) at Week 192

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    End point title
    		 Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on AASLD Normal Range) at Week 192
    End point description
    Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    28
    Units: percentage of participants
        number (not applicable)
    70.0
    42.9
    No statistical analyses for this end point

    Secondary: Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on Central Lab Normal Range) at Week 48

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    End point title
    		 Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on Central Lab Normal Range) at Week 48
    End point description
    Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    58
    27
    Units: percentage of participants
        number (not applicable)
    53.4
    7.4
    Statistical analysis title
    		 Statistical Analysis- TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [10] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on Central Lab Normal Range) at Week 192

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    End point title
    		 Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on Central Lab Normal Range) at Week 192
    End point description
    Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. Participants in the Full Analysis Set with abnormal ALT values at baseline were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    58
    27
    Units: percentage of participants
        number (not applicable)
    75.9
    55.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA < 169 Copies/mL (29 IU/mL) at Week 48

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    End point title
    		 Percentage of Participants With HBV DNA < 169 Copies/mL (29 IU/mL) at Week 48
    End point description
    Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    71.7
    6.9
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [11] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With HBV DNA < 169 Copies/mL (29 IU/mL) at Week 192

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    End point title
    		 Percentage of Participants With HBV DNA < 169 Copies/mL (29 IU/mL) at Week 192
    End point description
    Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    81.7
    62.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBsAg Loss at Week 48

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    End point title
    		 Percentage of Participants With HBsAg Loss at Week 48
    End point description
    HBsAg Loss was defined as a change from HBsAg positive or missing at baseline to HBsAg negative. Serologically Evaluable Full Analysis Set For HBsAg Loss/Seroconversion; The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    3.3
    3.4
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [12] - 2-sided Cochran-Mantel-Haenszel tests adjusted for age at baseline and region strata

    Secondary: Percentage of Participants With HBsAg Loss at Week 192

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    End point title
    		 Percentage of Participants With HBsAg Loss at Week 192
    End point description
    HBsAg Loss was defined as a change from HBsAg positive or missing at baseline to HBsAg negative. Serologically Evaluable Full Analysis Set For HBsAg Loss/Seroconversion; The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    10.0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBsAg Seroconversion at Week 48

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    End point title
    		 Percentage of Participants With HBsAg Seroconversion at Week 48
    End point description
    HBsAg seroconversion was defined as HBsAg loss and a change from HBsAb negative or missing at baseline to HBsAb positive. Serologically Evaluable Full Analysis Set For HBsAg Loss/Seroconversion; The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBsAg Seroconversion at Week 192

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    End point title
    		 Percentage of Participants With HBsAg Seroconversion at Week 192
    End point description
    HBsAg seroconversion was defined as HBsAg loss and a change from HBsAb negative or missing at baseline to HBsAb positive. Serologically Evaluable Full Analysis Set For HBsAg Loss/Seroconversion; The missing equals failure approach was used where all participants with missing data were considered to have failed to reach the endpoint.
    End point type
    Secondary
    End point timeframe
    Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 48

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    End point title
    		 Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 48
    End point description
    Participants in the Full Analysis Set with serum samples available at baseline and with HBV DNA ≥ 69 IU/mL at Week 48 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    10
    26
    Units: participants
    5
    7
    No statistical analyses for this end point

    Secondary: Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 96

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    End point title
    		 Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 96
    End point description
    Participants in the Full Analysis Set with serum samples available at baseline and with HBV DNA ≥ 69 IU/mL at Week 96 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    5
    12
    Units: participants
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 144

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    End point title
    		 Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 144
    End point description
    Participants in the Full Analysis Set with serum samples available at baseline and with HBV DNA ≥ 69 IU/mL at Week 144 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 144
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    4
    1
    Units: participants
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 192

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    End point title
    		 Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 192
    End point description
    Participants in the Full Analysis Set with serum samples available at baseline and with HBV DNA ≥ 69 IU/mL at Week 192 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    2
    2
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With ≥ 4% Decrease From Baseline in Spine Bone Mineral Density (BMD) at Week 48

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    End point title
    		 Percentage of Participants With ≥ 4% Decrease From Baseline in Spine Bone Mineral Density (BMD) at Week 48
    End point description
    Spine Dual X-Ray Absorptiometry (DXA) Analysis Set: all randomized participants who received at least 1 dose of study drug and had nonmissing baseline spine bone mineral density values.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    18.3
    6.9
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF (Blinded Randomized Phase) v Placebo (Blinded Randomized Phase)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    Method
    Parameter type
    		 Exact Chan-Zhang method
    Point estimate
    11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 25.1
    Notes
    [13] - Comparison of the difference in percentages

    Secondary: Percentage of Participants With ≥ 4% Decrease From Baseline in Spine BMD at Week 192

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    End point title
    		 Percentage of Participants With ≥ 4% Decrease From Baseline in Spine BMD at Week 192
    End point description
    Participants in the Spine DXA Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    60
    29
    Units: percentage of participants
        number (not applicable)
    18.3
    6.9
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    TDF to TDF v Placebo to TDF
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    Method
    Parameter type
    		 Exact Chan-Zhang method
    Point estimate
    11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 25.1
    Notes
    [14] - Comparison of the difference in percentages

    Secondary: Percent Change From Baseline in BMD of Spine at Week 48

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    End point title
    		 Percent Change From Baseline in BMD of Spine at Week 48
    End point description
    Participants in the Spine DXA Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase)
    Number of subjects analysed
    55
    25
    Units: Percent change in spine BMD
        arithmetic mean (standard deviation)
    3.798 ( 5.9118 )
    7.557 ( 4.9790 )
    Statistical analysis title
    		 Statistical Analysis - TDF vs Placebo
    Comparison groups
    Placebo (Blinded Randomized Phase) v TDF (Blinded Randomized Phase)
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007 [15]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [15] - two-sided superiority test

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

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    End point title
    		 Percent Change From Baseline in BMD of Spine at Week 192
    End point description
    Participants in the Spine DXA Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 192
    End point values
    		 TDF to TDF Placebo to TDF
    Number of subjects analysed
    52
    18
    Units: Percent change in spine BMD
        arithmetic mean (standard deviation)
    19.168 ( 12.2805 )
    26.085 ( 14.2586 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date up to the Week 192 Data Cut for Open-Label Phase; Additional adverse event data will be reported after study is completed and final analysis is done.
    Adverse event reporting additional description
    Safety Analysis all randomized participants who have received at least 1 dose of study drug. Participants were analyzed according to the treatment to which they received during the blinded phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    TDF (Blinded Randomized Phase)
    Reporting group description
    		 Blinded Randomized Phase: TDF tablet or oral powder once daily (up to 300 mg depending on weight) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3)

    Reporting group title
    Placebo (Blinded Randomized Phase)
    Reporting group description
    		 Blinded Randomized Phase: Placebo tablet or oral powder once daily for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3)

    Reporting group title
    TDF to TDF (Open-Label Phase)
    Reporting group description
    		 Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Reporting group title
    Placebo to TDF (Open-Label Phase)
    Reporting group description
    		 Open-Label Treatment Phase: After Week 72 (protocol amendment 2) or Week 48 (protocol amendment 3), participants switched to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). Open-Label Extension Phase: After Week 192, participants are offered open-label TDF treatment until it was commercially available in that country for treatment of chronic HBV in individuals of their age and weight.

    Serious adverse events
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase) TDF to TDF (Open-Label Phase) Placebo to TDF (Open-Label Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 60 (16.67%)
    2 / 29 (6.90%)
    8 / 56 (14.29%)
    3 / 25 (12.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 29 (3.45%)
    1 / 56 (1.79%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (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
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (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
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (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
    Hypoxia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (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
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (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
    Renal and urinary disorders
    Pelvi-ureteric obstruction
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (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
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute hepatitis B
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (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
    Adenovirus infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    0 / 25 (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
    Appendicitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    1 / 25 (4.00%)
         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
    Bronchitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    1 / 25 (4.00%)
         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-foot-and-mouth disease
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    1 / 25 (4.00%)
         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
    Influenza
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    0 / 25 (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
    Meningitis viral
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    0 / 25 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    0 / 25 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 29 (3.45%)
    0 / 56 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    		 TDF (Blinded Randomized Phase) Placebo (Blinded Randomized Phase) TDF to TDF (Open-Label Phase) Placebo to TDF (Open-Label Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 60 (63.33%)
    16 / 29 (55.17%)
    21 / 56 (37.50%)
    7 / 25 (28.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 29 (10.34%)
    0 / 56 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 29 (6.90%)
    2 / 56 (3.57%)
    0 / 25 (0.00%)
         occurrences all number
    2
    2
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 60 (15.00%)
    2 / 29 (6.90%)
    4 / 56 (7.14%)
    0 / 25 (0.00%)
         occurrences all number
    9
    3
    7
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 29 (3.45%)
    1 / 56 (1.79%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1
    1
    1
    Vomiting
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 29 (3.45%)
    0 / 56 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    5
    1
    0
    2
    Diarrhoea
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 29 (3.45%)
    0 / 56 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 29 (3.45%)
    0 / 56 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    6
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 29 (6.90%)
    0 / 56 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 60 (15.00%)
    2 / 29 (6.90%)
    12 / 56 (21.43%)
    1 / 25 (4.00%)
         occurrences all number
    29
    12
    51
    27
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 60 (15.00%)
    5 / 29 (17.24%)
    3 / 56 (5.36%)
    3 / 25 (12.00%)
         occurrences all number
    9
    6
    5
    3
    Pharyngitis
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 29 (10.34%)
    2 / 56 (3.57%)
    1 / 25 (4.00%)
         occurrences all number
    4
    4
    2
    1
    Otitis media
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 29 (3.45%)
    1 / 56 (1.79%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1
    1
    1
    Ear infection
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 29 (0.00%)
    1 / 56 (1.79%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Varicella
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 29 (0.00%)
    0 / 56 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2012
    The changes were primarily updates to/clarification of study objectives, eligibility criteria, study procedures, and use of concomitant medications and oral contraception.
    08 Nov 2012
    - Updates to the design and conduct of the PK substudy in response to regulatory authority comments. - Participant dosing diaries, a section defining special situations and instructions for reporting special situations, and criterion and instructions for unblinding an investigator in the event of a medical emergency were also introduced. - Other changes included a change in medical monitor and clarification of study objectives, eligibility criteria, and procedures.
    29 Feb 2016
    Due to difficulty enrolling participants, to limit exposure of participants to Placebo-TDF, and upon agreement of the Food and Drug Administration (FDA) that approximately 90 participants would be sufficient to conduct the study, the primary efficacy endpoint was changed from Week 72 to Week 48. The amendment specified that upon completing 48 weeks of blinded treatment, all participants would switch to open-label TDF for the remainder of the study, and participants who were beyond Week 48 under the previous protocol would switch to open-label TDF at Week 72 (as originally planned). All participants would receive open-label TDF until Week 192 (end of study).
    04 Aug 2016
    - An extension treatment period was added, whereby all participants who completed the study were offered the opportunity to continue receiving open-label TDF until the time that TDF became commercially available for participants of their age and weight in the country of their enrollment. During the extension period, participants were to attend study visits every 12 weeks. Study procedures were updated accordingly. - Clarified the requirements for DXA scans and biochemical bone marker assessments performed at Week 192/end of study or premature discontinuation of study drug and updated the physical description of TDF 300 mg tablets.

    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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