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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Switching from Tenofovir Disoproxil Fumarate (TDF) 300 mg QD to Tenofovir Alafenamide (TAF) 25mg QD in Subjects with Chronic Hepatitis B who are Virologically Suppressed

    Summary
    EudraCT number
    		 2016-003632-20
    Trial protocol
    		 GB   ES   IT  
    Global end of trial date
    30 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2020
    First version publication date
    09 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-320-4018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02979613
    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)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to evaluate the efficacy, safety, and tolerability of switching to tenofovir alafenamide (TAF) versus continuing tenofovir disoproxil fumarate (TDF) in virologically suppressed adults with chronic hepatitis B virus (HBV) 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
    29 Dec 2016
    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
    Korea, Democratic People's Republic of: 138
    Country: Number of subjects enrolled
    United States: 128
    Country: Number of subjects enrolled
    Canada: 89
    Country: Number of subjects enrolled
    Taiwan: 41
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Hong Kong: 28
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    United Kingdom: 14
    Worldwide total number of subjects
    490
    EEA total number of subjects
    66
    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)
    0
    Adults (18-64 years)
    440
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America, Europe, and Asia. The first participant was screened on 29 December 2016. The last study visit occurred on 30 January 2020.

    Pre-assignment
    Screening details
    		 541 participants were screened.

    Period 1
    Period 1 title
    Double-Blind (DB) Phase
    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
    		 TAF 25 mg
    Arm description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TAF 25 mg tablet orally once daily, and placebo to match TDF once daily for up to 53 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the open-label extension (OLE) phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAF
    Investigational medicinal product code
    Other name
    Vemlidy®, GS-7340
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg administered once daily for 53 weeks.

    Investigational medicinal product name
    TDF placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF matched placebo administered once daily for 53 weeks.

    Arm title
    		 TDF 300 mg
    Arm description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TDF 300 mg tablet orally once daily, and placebo to match TAF once daily for up to 50 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TDF
    Investigational medicinal product code
    Other name
    Viread®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg administered once daily for 50 weeks.

    Investigational medicinal product name
    TAF placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAF matched placebo administered once daily for 50 weeks.

    Number of subjects in period 1 [1]
    		TAF 25 mg TDF 300 mg
    Started
    243
    245
    Completed
    235
    237
    Not completed
    8
    8
         Withdrew Consent
    2
    4
         Adverse Event
    2
    -
         Pregnancy
    2
    2
         Protocol Violation
    1
    1
         Lost to follow-up
    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: Two participants who were randomised but did not receive the study drug are not included in the subject disposition table.
    Period 2
    Period 2 title
    Open-Label Extension (OLE) Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TAF 25 mg
    Arm description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TAF 25 mg tablet orally once daily, and placebo to match TDF once daily for up to 53 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAF
    Investigational medicinal product code
    Other name
    Vemlidy®, GS-7340
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg administered once daily for 52 weeks.

    Arm title
    		 TDF 300 mg
    Arm description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TDF 300 mg tablet orally once daily, and placebo to match TAF once daily for up to 50 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    TAF
    Investigational medicinal product code
    Other name
    Vemlidy®, GS-7340
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg administered once daily for 52 weeks.

    Number of subjects in period 2
    		TAF 25 mg TDF 300 mg
    Started
    235
    237
    Completed
    232
    231
    Not completed
    3
    6
         Withdrew Consent
    2
    4
         Adverse Event
    1
    -
         Death
    -
    1
         Investigator's Discretion
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TAF 25 mg
    Reporting group description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TAF 25 mg tablet orally once daily, and placebo to match TDF once daily for up to 53 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the open-label extension (OLE) phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.

    Reporting group title
    TDF 300 mg
    Reporting group description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TDF 300 mg tablet orally once daily, and placebo to match TAF once daily for up to 50 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.

    Reporting group values
    		 TAF 25 mg TDF 300 mg Total
    Number of subjects
    		 243 245 488
    Age categorical
    Units: Subjects
        < 50 Years
    		 107 109 216
        ≥ 50 Years
    		 136 136 272
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.0 ( 10.5 ) 51.0 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 64 79 143
        Male
    		 179 166 345
    Race
    Units: Subjects
        Asian
    		 195 205 400
        Black or African American
    		 9 8 17
        Native Hawaiian or Pacific Islander
    		 0 1 1
        White
    		 38 31 69
        Other
    		 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 0 3
        Not Hispanic or Latino
    		 240 245 485
        Unknown or Not Reported
    		 0 0 0
    ALT Level Based on Central Lab Normal Range
    Measure Description: Central laboratory upper limit of normal (ULN) for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years.
    Units: Subjects
        ≤ ULN
    		 211 226 437
        > ULN to 5xULN
    		 32 19 51
        > 5xULN
    		 0 0 0
    ALT Level Based on 2018 American Association for the Study of Liver Diseases (AASLD) Normal Range
    The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males.
    Units: Subjects
        ≤ ULN
    		 191 192 383
        > ULN to 5xULN
    		 52 53 105
        > 5xULN
    		 0 0 0
    Hepatitis B virus (HBV) DNA Category
    Units: Subjects
        < 20 IU/mL
    		 238 242 480
        20 to < 69 IU/mL
    		 2 3 5
        ≥ 69 IU/mL
    		 3 0 3
    Hepatitis B e Antigen/Antibody (HBeAg/HBeAb) Status
    HBeAb status was imputed as negative if missing.
    Units: Subjects
        Positive/Negative
    		 78 78 156
        Positive/Positive
    		 0 1 1
        Negative/Negative
    		 17 28 45
        Negative/Positive
    		 148 138 286
    Hip Bone Mineral Density (BMD) Status
    Hip Dual-Energy X-Ray Absorptiometry (DXA) Analysis Set included all participants who were randomized into the study, received at least 1 dose of study drug, and had nonmissing baseline hip BMD values.
    Units: Subjects
        Normal (T-score ≥ -1.0)
    		 143 124 267
        Osteopenia (-2.5 ≤ T-score < -1.0)
    		 89 116 205
        Osteoporosis (T-score < -2.5)
    		 9 4 13
        No Data Collected
    		 2 1 3
    Spine BMD Status
    Spine DXA Analysis Set included all participants who were randomized into the study, received at least 1 dose of study drug, and had nonmissing baseline spine BMD values.
    Units: Subjects
        Normal (T-score ≥ -1.0)
    		 125 120 245
        Osteopenia (-2.5 ≤ T-score < -1.0)
    		 90 97 187
        Osteoporosis (T-score < -2.5)
    		 28 28 56
    Alanine Aminotransferase (ALT)
    Units: U/L
        arithmetic mean (standard deviation)
    		 28.0 ( 15.6 ) 26.0 ( 12.0 ) -
    FibroTest® Score
    The FibroTest® score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Participants in the Safety Analysis Set with available data were analyzed (N = 241, 245).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 0.42 ( 0.234 ) 0.41 ( 0.211 ) -
    Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFR-CG)
    Units: mL/min
        arithmetic mean (standard deviation)
    		 95.0 ( 25.58 ) 93.8 ( 25.16 ) -

    End points

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    End points reporting groups
    Reporting group title
    TAF 25 mg
    Reporting group description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TAF 25 mg tablet orally once daily, and placebo to match TDF once daily for up to 53 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the open-label extension (OLE) phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.

    Reporting group title
    TDF 300 mg
    Reporting group description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TDF 300 mg tablet orally once daily, and placebo to match TAF once daily for up to 50 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.
    Reporting group title
    TAF 25 mg
    Reporting group description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TAF 25 mg tablet orally once daily, and placebo to match TDF once daily for up to 53 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.

    Reporting group title
    TDF 300 mg
    Reporting group description
    		 Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TDF 300 mg tablet orally once daily, and placebo to match TAF once daily for up to 50 weeks in the DB phase. Participants who completed DB treatment and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.

    Primary: Percentage of Participants With Hepatitis B Virus (HBV) DNA Levels ≥ 20 IU/mL at Week 48, as Determined by the Modified United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm

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    End point title
    		 Percentage of Participants With Hepatitis B Virus (HBV) DNA Levels ≥ 20 IU/mL at Week 48, as Determined by the Modified United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm
    End point description
    The percentage of participants with HBV DNA ≥ 20 IU/mL at Week 48 was analyzed using the modified US FDA-defined snapshot algorithm, which included participants who: 1. Had the last available on-treatment HBV DNA ≥ 20 IU/mL in the Week 48 analysis window (from Day 295 to Day 378, inclusive), or 2. Did not have on-treatment HBV DNA data available in the Week 48 analysis window and - Discontinued study drug prior to or in the Week 48 analysis window due to lack of efficacy, or - Discontinued study drug prior to or in the Week 48 analysis window due to reason other than lack of efficacy and had the last available on-treatment HBV DNA ≥ 20 IU/mL. The Full Analysis Set included all participants who were randomized into the study and received at least 1 dose of study drug. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    0.4
    0.4
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    The null hypothesis was that the TAF group is at least 4% worse than the TDF group with respect to the percentage of participants with HBV DNA ≥ 20 IU/mL at Week 48. The alternative hypothesis was that the TAF group is less than 4% worse than the TDF group with respect to the percentage of participants with HBV DNA ≥ 20 IU/mL at Week 48.
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in the Percentages
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 2

    Secondary: Percentage of Participants With HBV DNA Levels ≥ 20 IU/mL at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm

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    End point title
    		 Percentage of Participants With HBV DNA Levels ≥ 20 IU/mL at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm
    End point description
    The percentage of participants with HBV DNA ≥ 20 IU/mL at Week 96 was analyzed using the modified US FDA-defined snapshot algorithm, which included participants who: 1. Had the last available on-treatment HBV DNA ≥ 20 IU/mL in the Week 96 analysis window (from Day 589 to Day 840, inclusive), or 2. Did not have on-treatment HBV DNA data available in the Week 96 analysis window and -Discontinued study drug prior to or in the Week 96 analysis window due to lack of efficacy, or -Discontinued study drug prior to or in the Week 96 analysis window due to reason other than lack of efficacy and had the last available on-treatment HBV DNA ≥ 20 IU/mL. Participants in the Full Analysis Set were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    0.4
    0.4
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in the Percentages
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 1.9
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9953 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - P-value for the superiority tests compared the percentage of each HBV DNA outcome was from CMH tests stratified by baseline age groups and baseline HBeAg status strata.

    Secondary: Percentage of Participants With HBV DNA Levels < 20 IU/mL at Week 48

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    End point title
    		 Percentage of Participants With HBV DNA Levels < 20 IU/mL at Week 48
    End point description
    The percentage of participants with HBV DNA < 20 IU/mL at Week 48 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 48 analysis window. Missing=Failure (M = F) approach was used for analysis. Participants in the Full Analysis Set were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    96.3
    96.3
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in the Percentages
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 3.7
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - P-value for the superiority tests compared the percentage of each HBV DNA outcome was from CMH tests stratified by baseline age groups and baseline HBeAg status strata.

    Secondary: Percentage of Participants With HBV DNA Levels < 20 IU/mL (Target Detected/Not Detected) at Week 48

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    End point title
    		 Percentage of Participants With HBV DNA Levels < 20 IU/mL (Target Detected/Not Detected) at Week 48
    End point description
    The percentage of participants with HBV DNA < 20 IU/mL at Week 48 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 48 analysis window. The method of determining percentage of participants with HBV DNA levels <20 IU/mL (target detected/not detected i.e., lower limit of detection) at Week 48, was handled by M = F, and Missing=Excluded (M = E) approaches. Participants in the Full Analysis Set were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
    number (not applicable)
        M = F Approach: < 20 IU/mL Target Not Detected
    63.4
    62.0
        M = F Approach: < 20 IU/mL Target Detected
    32.9
    34.3
        M = E Approach: < 20 IU/mL Target Not Detected
    65.5
    64.1
        M = E Approach: < 20 IU/mL Target Detected
    34.0
    35.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA Levels < 20 IU/mL at Week 96

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    End point title
    		 Percentage of Participants With HBV DNA Levels < 20 IU/mL at Week 96
    End point description
    The percentage of participants with HBV DNA < 20 IU/mL at Week 96 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 96 analysis window. M = F approach was used for analysis. Participants in the Full Analysis Set were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    94.7
    93.9
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in the Percentages
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 5.2
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6863 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - P-value for the superiority tests compared the percentage of each HBV DNA outcome was from CMH tests stratified by baseline age groups and baseline HBeAg status strata.

    Secondary: Percentage of Participants With HBV DNA Levels < 20 IU/mL (Target Detected/Not Detected) at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm

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    End point title
    		 Percentage of Participants With HBV DNA Levels < 20 IU/mL (Target Detected/Not Detected) at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm
    End point description
    The percentage of participants with HBV DNA < 20 IU/mL at Week 96 was analyzed, which included participants who have the last available on-treatment HBV DNA, 20 IU/mL in the Week 96 analysis window. The method of determining percentage of participants with HBV DNA levels <20 IU/mL (target detected/not detected i.e., lower limit of detection) at Week 96, was handled by Missing=Failure (M = F), and Missing=Excluded (M = E) approaches. Participants in the Full Analysis Set were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
    number (not applicable)
        M = F Approach: < 20 IU/mL Target Not Detected
    65.8
    66.1
        M = F Approach: < 20 IU/mL Target Detected
    28.8
    27.8
        M = E Approach: < 20 IU/mL Target Not Detected
    69.3
    70.1
        M = E Approach: < 20 IU/mL Target Detected
    30.3
    29.4
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss at Week 48
    End point description
    HBeAg loss was defined as HBeAg changing from positive at baseline to negative at a postbaseline visit with baseline HBeAb negative or missing. The M = F approach was used for this analysis. The Serologically Evaluable Full Analysis Set for HBeAg loss and seroconversion included all participants who were randomized and received at least 1 dose of study drug and were HBeAg-positive and HBeAb-negative or had a missing value at baseline. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    78
    78
    Units: percentage of participants
        number (not applicable)
    7.7
    6.4
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7258 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 10.1
    Notes
    [4] - P-value was from the CMH test, stratified by baseline age groups (< 50, ≥ 50 years).

    Secondary: Percentage of Participants With HBeAg Seroconversion at Week 48

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    End point title
    		 Percentage of Participants With HBeAg Seroconversion at Week 48
    End point description
    HBeAg seroconversion was defined as HBeAg loss and HBeAb changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis. Participants in the Serologically Evaluable Full Analysis Set for HBeAg loss and seroconversion were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    78
    78
    Units: percentage of participants
        number (not applicable)
    2.6
    0.0
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1348 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 7.7
    Notes
    [5] - P-value was from the CMH test, stratified by baseline age groups (< 50, ≥ 50 years).

    Secondary: Percentage of Participants With HBeAg Loss at Week 96

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    End point title
    		 Percentage of Participants With HBeAg Loss at Week 96
    End point description
    HBeAg loss was defined as HBeAg changing from positive at baseline to negative at a postbaseline visit with baseline HBeAb negative or missing. The M = F approach was used for this analysis. Participants in the Serologically Evaluable Full Analysis Set for HBeAg loss and seroconversion were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    78
    78
    Units: percentage of participants
        number (not applicable)
    17.9
    9.0
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1005 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 20.1
    Notes
    [6] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years).

    Secondary: Percentage of Participants With HBeAg Seroconversion at Week 96

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    End point title
    		 Percentage of Participants With HBeAg Seroconversion at Week 96
    End point description
    HBeAg seroconversion was defined as HBeAg loss and HBeAb changing from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis. Participants in the Serologically Evaluable Full Analysis Set for HBeAg loss and seroconversion were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    78
    78
    Units: percentage of participants
        number (not applicable)
    5.1
    2.6
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4154 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 9.5
    Notes
    [7] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years).

    Secondary: Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48

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    End point title
    		 Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48
    End point description
    HBsAg loss was defined as HBsAg changing from positive at baseline to negative at a postbaseline visit with baseline HBsAb negative or missing. The M = F approach was used for this analysis. The Serologically Evaluable Full Analysis Set for HBsAg loss and seroconversion included all participants who were randomized and received at least 1 dose of study drug and were HBsAg-positive and HBsAb-negative or had a missing value at baseline. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    0.0
    2.0
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0281 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 0.3
    Notes
    [8] - P-value was from the CMH test, stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

    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 HBsAb changes from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis. Participants in the Serologically Evaluable Full Analysis Set for HBsAg loss and seroconversion were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBsAg Loss at Week 96

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    End point title
    		 Percentage of Participants With HBsAg Loss at Week 96
    End point description
    HBsAg loss was defined as HBsAg changing from positive at baseline to negative at a postbaseline visit with baseline HBsAb negative or missing. The M = F approach was used for this analysis. Participants in the Serologically Evaluable Full Analysis Set for HBsAg loss and seroconversion were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    1.6
    2.4
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5373 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 2.1
    Notes
    [9] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

    Secondary: Percentage of Participants With HBsAg Seroconversion at Week 96

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    End point title
    		 Percentage of Participants With HBsAg Seroconversion at Week 96
    End point description
    HBsAg seroconversion was defined as HBsAg loss and HBsAb changes from negative/missing at baseline to positive at a postbaseline visit. The M = F approach was used for this analysis. Participants in the Serologically Evaluable Full Analysis Set for HBsAg loss and seroconversion were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
        number (not applicable)
    0.8
    0.4
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5845 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 2.5
    Notes
    [10] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

    Secondary: Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 48 (by Central Laboratory and the American Association for the Study of Liver Diseases [AASLD] Criteria)

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    End point title
    		 Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 48 (by Central Laboratory and the American Association for the Study of Liver Diseases [AASLD] Criteria)
    End point description
    Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis. Participants in the Full Analysis Set were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
    number (not applicable)
        Central Laboratory Criteria
    89.3
    84.9
        AASLD Criteria
    79.0
    75.1
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    Central Laboratory Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1405 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 10.6
    Notes
    [11] - P-value was from the CMH test, stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    AASLD Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3133 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 11.4
    Notes
    [12] - P-value was from the CMH test, stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

    Secondary: Percentage of Participants With Normalized ALT at Week 48 (by Central Laboratory and AASLD Criteria)

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    End point title
    		 Percentage of Participants With Normalized ALT at Week 48 (by Central Laboratory and AASLD Criteria)
    End point description
    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. Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis. Participants in the Full Analysis Set with Baseline ALT > ULN were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    52
    53
    Units: percentage of participants
    number (not applicable)
        Central Laboratory Criteria (N = 32, 19)
    50.0
    36.8
        AASLD Criteria
    50.0
    26.4
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    Central Laboratory Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3381 [13]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    14.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.4
         upper limit
    		 44.6
    Notes
    [13] - P-value was from the CMH test, stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    AASLD Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0136 [14]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    23.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.3
         upper limit
    		 42.3
    Notes
    [14] - P-value was from the CMH test, stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

    Secondary: Percentage of Participants With Normal ALT at Week 96 (by Central Laboratory and the AASLD Criteria)

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    End point title
    		 Percentage of Participants With Normal ALT at Week 96 (by Central Laboratory and the AASLD Criteria)
    End point description
    Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis. Participants in the Full Analysis Set were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    243
    245
    Units: percentage of participants
    number (not applicable)
        Central Laboratory Criteria
    88.5
    91.4
        AASLD Criteria
    80.7
    86.5
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    Central Laboratory Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2803 [15]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 2.6
    Notes
    [15] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    AASLD Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0788 [16]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    -5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.6
         upper limit
    		 0.7
    Notes
    [16] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

    Secondary: Percentage of Participants With Normalized ALT at Week 96 (by Central Laboratory and AASLD Criteria)

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    End point title
    		 Percentage of Participants With Normalized ALT at Week 96 (by Central Laboratory and AASLD Criteria)
    End point description
    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. Central laboratory ULN for ALT were as follows: ≤ 43 U/L for males aged 18 to < 69 years and ≤ 35 U/L for males aged ≥ 69 years; ≤ 34 U/L for females aged 18 to < 69 years and ≤ 32 U/L for females aged ≥ 69 years. The ULN for ALT using the 2018 AASLD normal range was 25 U/L for females and 35 U/L for males. M = F approach was used for analysis. Participants in the Full Analysis Set with Baseline ALT > ULN were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    52
    53
    Units: percentage of participants
    number (not applicable)
        Central Laboratory Criteria (N = 32, 19)
    56.3
    78.9
        AASLD Criteria
    55.8
    73.6
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    Central Laboratory Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.088 [17]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    -23.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.2
         upper limit
    		 3.4
    Notes
    [17] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    AASLD Criteria
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.051 [18]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in the Percentages
    Point estimate
    -18.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.4
         upper limit
    		 0.2
    Notes
    [18] - P-value was from CMH tests stratified by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

    Secondary: Change From Baseline in FibroTest® Score at Week 48

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    End point title
    		 Change From Baseline in FibroTest® Score at Week 48
    End point description
    The FibroTest score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Change from baseline was calculated as the value at Week 48 minus the value at Baseline. Participants in the Full Analysis Set with available data were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    234
    236
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.02 ( 0.082 )
    -0.01 ( 0.082 )
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    P-value, difference in least squares mean (LSM), and its 95% CI were derived from analysis of variance (ANOVA) model with baseline age groups (< 50, ≥ 50 years), baseline HBeAg status, and treatment group as fixed effects in the model.
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    470
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0186
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0

    Secondary: Change From Baseline in FibroTest® Score at Week 96

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    End point title
    		 Change From Baseline in FibroTest® Score at Week 96
    End point description
    The FibroTest score is used to assess liver fibrosis. Scores range from 0.00 to 1.00, with higher scores indicating a greater degree of fibrosis. Change from baseline was calculated as the value at Week 96 minus the value at Baseline. Participants in the Full Analysis Set with available data were analyzed. Participants were analyzed according to the treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    231
    232
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.03 ( 0.080 )
    -0.03 ( 0.090 )
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    P-value, difference in LSM, and its 95% CI were from ANOVA with baseline age groups (<50, ≥ 50 years), baseline HBeAg status, and treatment group as fixed effects in the model.
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    463
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6956
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.01

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

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    End point title
    		 Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48
    End point description
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%. Participants in the Hip DXA Analysis Set (included all participants who were randomized into the study, received at least 1 dose of study drug, and had non-missing baseline hip BMD values) with available data were analysed. Participants were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    225
    226
    Units: percent change
        arithmetic mean (standard deviation)
    0.659 ( 2.0818 )
    -0.507 ( 1.9051 )
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    P-value, difference in LSM, and its 95% CI were from ANOVA with baseline age groups (<50, ≥ 50 years), baseline HBeAg status, and treatment group as fixed effects in the model.
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    1.167
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.797
         upper limit
    		 1.536

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

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    End point title
    		 Percent Change From Baseline in Hip BMD at Week 96
    End point description
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%. Participants in the Hip DXA Analysis Set with available data were analyzed. Participants were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    227
    224
    Units: percent change
        arithmetic mean (standard deviation)
    1.157 ( 2.8501 )
    0.180 ( 2.6813 )
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    P-value, difference in LSM, and its 95% CI were from ANOVA with baseline age groups (<50, ≥ 50 years), baseline HBeAg status, and treatment group as fixed effects in the model.
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    0.977
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.465
         upper limit
    		 1.49

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

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    End point title
    		 Percent Change From Baseline in Spine BMD at Week 48
    End point description
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%. Participants in the Spine DXA Analysis Set (included all participants who were randomized into the study, received at least 1 dose of study drug, and had non-missing baseline spine BMD values) with available data were analysed. Participants were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    227
    229
    Units: percent change
        arithmetic mean (standard deviation)
    1.743 ( 3.4674 )
    -0.138 ( 3.1072 )
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    P-value, difference in LSM, and its 95% CI were from ANOVA with baseline age groups (<50, ≥ 50 years), baseline HBeAg status, and treatment group as fixed effects in the model.
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    1.881
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.275
         upper limit
    		 2.486

    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
    Percent Change = Change from baseline at a postbaseline visit/baseline * 100%. Participants in the Spine DXA Analysis Set with available data were analyzed. Participants were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    229
    227
    Units: percent change
        arithmetic mean (standard deviation)
    2.330 ( 3.9301 )
    1.726 ( 3.8224 )
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Statistical analysis description
    P-value, difference in LSM, and its 95% CI were from ANOVA with baseline age groups (<50, ≥ 50 years), baseline HBeAg status, and treatment group as fixed effects in the model.
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.097
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    0.604
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 1.317

    Secondary: Change From Baseline in Estimated Glomerular Filtration Rate Calculated Using the Cockcroft-Gault Equation (eGFR-CG) at Week 48

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    End point title
    		 Change From Baseline in Estimated Glomerular Filtration Rate Calculated Using the Cockcroft-Gault Equation (eGFR-CG) at Week 48
    End point description
    Cockcroft-Gault formula is as follows: - For men: Glomerular filtration rate (GFR) = (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL) - For women: GFR = 0.85 * (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL) Change from baseline was calculated as the value at Week 48 minus the value at Baseline. Participants in the Safety Analysis Set (included all randomized participants who received at least 1 dose of study drug) with available data were analyzed. Participants were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 48
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    234
    237
    Units: mL/min
        median (inter-quartile range (Q1-Q3))
    2.240 (-3.957 to 7.704)
    -1.722 (-7.020 to 2.634)
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [19]
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Notes
    [19] - P-values were from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups.

    Secondary: Change From Baseline in eGFR-CG at Week 96

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    End point title
    		 Change From Baseline in eGFR-CG at Week 96
    End point description
    Cockcroft-Gault formula is as follows: - For men: Glomerular filtration rate (GFR) = (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL) - For women: GFR = 0.85 * (140 - age in years) * body weight in kg / 72 * serum creatinine (mg/dL) Change from baseline was calculated as the value at Week 96 minus the value at Baseline. Participants in the Safety Analysis Set with available data were analyzed. Participants were analyzed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 96
    End point values
    		 TAF 25 mg TDF 300 mg
    Number of subjects analysed
    232
    232
    Units: mL/min
        median (inter-quartile range (Q1-Q3))
    1.626 (-4.580 to 6.952)
    0.544 (-5.227 to 7.678)
    Statistical analysis title
    		 TAF 25 mg vs TDF 300 mg
    Comparison groups
    TAF 25 mg v TDF 300 mg
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7535 [20]
    Method
    		 Wilcoxon rank sum test
    Confidence interval
    Notes
    [20] - P-values were from the 2-sided Wilcoxon rank sum test to compare the 2 treatment groups.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause Mortality: First dose date up to 161 weeks (up to approximately 3 years); Adverse Events: First dose date up to the last dose (maximum: 105 weeks) plus 3 days
    Adverse event reporting additional description
    The Safety Analysis Set included all randomized participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    TAF 25 mg
    Reporting group description
    		 Adverse events reported in this group occurred during the DB phase. Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TAF 25 mg tablet orally once daily, and placebo to match TDF once daily for up to 53 weeks in the DB phase.

    Reporting group title
    TDF 300 mg
    Reporting group description
    		 Adverse events reported in this group occurred during the DB phase. Participants who were virologically suppressed and taking TDF 300 mg tablet orally once daily received TDF 300 mg tablet orally once daily, and placebo to match TAF once daily for up to 50 weeks in the DB phase.

    Reporting group title
    OLE TAF 25 mg From TAF 25 mg
    Reporting group description
    		 Adverse events reported in this group occurred during the OLE phase. Participants who completed TAF treatment in the DB phase and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.

    Reporting group title
    OLE TAF 25 mg From TDF 300 mg
    Reporting group description
    		 Adverse events reported in this group occurred during the OLE phase. Participants who completed TDF treatment in the DB phase and were willing to enter in the OLE phase, received TAF 25 mg tablet orally once daily for up to 52 weeks.

    Serious adverse events
    		 TAF 25 mg TDF 300 mg OLE TAF 25 mg From TAF 25 mg OLE TAF 25 mg From TDF 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 243 (4.53%)
    3 / 245 (1.22%)
    8 / 235 (3.40%)
    5 / 237 (2.11%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 243 (0.41%)
    1 / 245 (0.41%)
    2 / 235 (0.85%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Lung squamous cell carcinoma stage II
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    1 / 235 (0.43%)
    0 / 237 (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
    Testicular neoplasm
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    1 / 237 (0.42%)
         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
    Injury, poisoning and procedural complications
    Muscle rupture
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Tendon injury
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Wrist fracture
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Vascular disorders
    Varicose vein
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 245 (0.41%)
    0 / 235 (0.00%)
    0 / 237 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    1 / 237 (0.42%)
         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
    Angina pectoris
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    1 / 237 (0.42%)
         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 arrest
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    1 / 237 (0.42%)
         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 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    1 / 235 (0.43%)
    0 / 237 (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
    Gastrointestinal disorders
    Pancreatic mass
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    1 / 235 (0.43%)
    0 / 237 (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
    Pancreatitis
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Prostatitis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    1 / 235 (0.43%)
    0 / 237 (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
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Homicidal ideation
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Suicidal ideation
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Calculus bladder
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    1 / 235 (0.43%)
    0 / 237 (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
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 243 (0.41%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    0 / 237 (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
    Herpes zoster
         subjects affected / exposed
    0 / 243 (0.00%)
    1 / 245 (0.41%)
    0 / 235 (0.00%)
    0 / 237 (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
    Necrotising fasciitis
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    1 / 235 (0.43%)
    0 / 237 (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
    Pneumonia necrotising
         subjects affected / exposed
    0 / 243 (0.00%)
    0 / 245 (0.00%)
    0 / 235 (0.00%)
    1 / 237 (0.42%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TAF 25 mg TDF 300 mg OLE TAF 25 mg From TAF 25 mg OLE TAF 25 mg From TDF 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 243 (12.76%)
    28 / 245 (11.43%)
    15 / 235 (6.38%)
    15 / 237 (6.33%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 243 (7.41%)
    16 / 245 (6.53%)
    11 / 235 (4.68%)
    12 / 237 (5.06%)
         occurrences all number
    23
    23
    15
    15
    Nasopharyngitis
         subjects affected / exposed
    13 / 243 (5.35%)
    12 / 245 (4.90%)
    4 / 235 (1.70%)
    3 / 237 (1.27%)
         occurrences all number
    16
    14
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    • Tenofovir alafenamide (TAF) had been approved by US Food and Drug administration on 10 November 2016 and is now referred to as Vemlidy®. • Characterization of hepatic status, particularly for subjects with compensated cirrhosis, by Child-Pugh score added to protocol assessments. • Primary endpoint changed from Week 24 to Week 48. Statistical analysis of primary endpoint analysis changed from Week 24 to 48. The primary analysis will be performed when last subject had completed Week 48 or discontinued prematurely. • Approximate number of subjects planned changed from 300 to 460 subjects. • Primary and Secondary efficacy endpoints changed from Week 24 to 48. Secondary safety endpoints changed from Week 24 to Week 48. • Updated the use of anticonvulsants from use with caution to prohibited during the study in order to align with the US prescribing information for Vemlidy. • The non-inferiority margin was changed from 6% to 4%. • The power of primary endpoint and key secondary safety endpoints were updated based on the new non-inferiority margin and new time point had changed from Week 24 to Week 48.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32087795
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