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    Clinical Trial Results:
    A Phase 2, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of GS-4774 in Combination With Tenofovir Disoproxil Fumarate (TDF) for the Treatment of Subjects With Chronic Hepatitis B and Who Are Currently Not on Treatment

    Summary
    EudraCT number
    		 2014-001011-39
    Trial protocol
    		 IT  
    Global end of trial date
    30 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 May 2019
    First version publication date
    31 May 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-330-1401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02174276
    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 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were as follows: - To evaluate the safety and tolerability of GS-4774 in subjects with chronic hepatitis B infection (CHB) - To evaluate the efficacy of GS-4774 at Week 24 as measured by mean change in serum HBsAg from Baseline (measured in log10 IU/mL)
    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
    24 Jul 2014
    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
    Romania: 7
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Canada: 46
    Country: Number of subjects enrolled
    Korea, Republic of: 56
    Country: Number of subjects enrolled
    United States: 72
    Worldwide total number of subjects
    195
    EEA total number of subjects
    20
    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)
    192
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America, Europe, New Zealand, and South Korea. The first participant was screened on 24 July 2014. The last study visit occurred on 30 May 2018.

    Pre-assignment
    Screening details
    		 254 participants were screened.

    Period 1
    Period 1 title
    Study Treatment Phase (Weeks 1 to 48)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TDF 48 Weeks
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks during the main study. Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in optional treatment extension phase [OTEP]).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Arm title
    		 TDF + GS-4774 2 YU
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 2 yeast units (YU) administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Investigational medicinal product name
    GS-4774
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

    Arm title
    		 TDF + GS-4774 10 YU
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 10 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Investigational medicinal product name
    GS-4774
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

    Arm title
    		 TDF + GS-4774 40 YU
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 40 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Investigational medicinal product name
    GS-4774
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

    Number of subjects in period 1
    		TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Started
    27
    57
    56
    55
    Completed
    26
    56
    53
    55
    Not completed
    1
    1
    3
    0
         Pregnancy
    -
    -
    1
    -
         Withdrawal by Subject
    -
    1
    2
    -
         Lost to follow-up
    1
    -
    -
    -
    Period 2
    Period 2 title
    OTEP (Weeks 48 to 144)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TDF 48 Weeks
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks during the main study. Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Arm title
    		 TDF + GS-4774 2 YU
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 2 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Investigational medicinal product name
    GS-4774
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

    Arm title
    		 TDF + GS-4774 10 YU
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 10 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Investigational medicinal product name
    GS-4774
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

    Arm title
    		 TDF + GS-4774 40 YU
    Arm description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 40 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    TDF, Viread®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TDF 300 mg tablet administered orally once daily

    Investigational medicinal product name
    GS-4774
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses

    Number of subjects in period 2 [1]
    		TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Started
    26
    54
    51
    52
    Completed
    25
    54
    48
    50
    Not completed
    1
    0
    3
    2
         Withdrew Consent
    1
    -
    1
    2
         Pregnancy
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Seven participants (TDF+GS-4774 2 YU: 2; TDF+GS-4774 10 YU: 2; TDF+GS-4774 40 YU: 3) completing the study treatment phase did not continue in OTEP.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    TDF 48 Weeks
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks during the main study. Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in optional treatment extension phase [OTEP]).

    Reporting group title
    TDF + GS-4774 2 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 2 yeast units (YU) administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 10 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 10 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 40 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 40 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU Total
    Number of subjects
    		 27 57 56 55 195
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44 ± 10.3 46 ± 11.2 44 ± 9.1 43 ± 11.6 -
    Gender categorical
    Units: Subjects
        Female
    		 9 23 23 22 77
        Male
    		 18 34 33 33 118
    Race
    Units: Subjects
        Asian
    		 24 42 44 45 155
        White
    		 1 13 8 6 28
        Black or African American
    		 2 2 2 3 9
        Native Hawaiian or Other Pacific Islander
    		 0 0 2 1 3
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 27 54 56 55 192
        Not Permitted
    		 0 3 0 0 3
    Hepatitis B Envelope Antigen (HBeAg) Status at Baseline
    Units: Subjects
        Positive
    		 10 22 23 21 76
        Negative
    		 17 35 33 34 119
    Baseline Alanine Aminotransferase (ALT) Category
    Upper limit of normal (ULN) for ALT was defined as 19 U/L for women and 30 U/L for men.
    Units: Subjects
        ≤ ULN
    		 6 15 21 12 54
        > ULN
    		 21 42 35 43 141
    Baseline Hepatitis B Surface Antigen (HBsAg)
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 3.8 ± 0.78 3.7 ± 0.82 3.7 ± 0.94 3.7 ± 0.80 -
    Baseline Hepatitis B Virus (HBV) DNA
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 6.0 ± 1.64 5.8 ± 1.99 5.8 ± 1.97 6.0 ± 1.80 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    TDF 48 Weeks
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks during the main study. Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in optional treatment extension phase [OTEP]).

    Reporting group title
    TDF + GS-4774 2 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 2 yeast units (YU) administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 10 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 10 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 40 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 40 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).
    Reporting group title
    TDF 48 Weeks
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks during the main study. Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 2 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 2 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 10 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 10 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 40 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 40 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Primary: Mean Change in Serum HBsAg From Baseline to Week 24

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    End point title
    		 Mean Change in Serum HBsAg From Baseline to Week 24
    End point description
    The change from baseline to Week 24 in HBsAg was analyzed using a mixed effect model for repeated measures (MMRM). The model included treatment groups, ALT levels (> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% confidence intervals (CIs). Participants in the Full Analysis Set (all participants who were randomized and received at least 1 dose of study drug) with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    26
    57
    54
    55
    Units: log10 IU/mL
        least squares mean (confidence interval 95%)
    -0.079 (-0.192 to 0.035)
    -0.096 (-0.174 to -0.018)
    -0.016 (-0.095 to 0.064)
    -0.135 (-0.215 to -0.055)
    Statistical analysis title
    		 TDF 48 Weeks Versus TDF + GS-4774 2 YU
    Statistical analysis description
    The null hypotheses was that the mean change from baseline in serum HBsAg in each of the TDF + GS-4774 groups was equal to the mean change from baseline in serum HBsAg in the TDF only group. Each null hypothesis was tested against the 2-sided alternative hypothesis that the mean change from baseline in serum HBsAg was not equal between each of the respective GS-4774 dose groups and the TDF only group.
    Comparison groups
    TDF 48 Weeks v TDF + GS-4774 2 YU
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.805
    Method
    		 Mixed-Effect Model for Repeated Measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.155
         upper limit
    		 0.12
    Notes
    [1] - Estimated differences in treatment effects between GS-4774 treatment groups and the TDF only group at Week 24 are presented with the 95% CIs and unadjusted P-values.
    Statistical analysis title
    		 TDF 48 Weeks Versus TDF + GS-4774 10 YU
    Statistical analysis description
    The null hypotheses was that the mean change from baseline in serum HBsAg in each of the TDF + GS-4774 groups was equal to the mean change from baseline in serum HBsAg in the TDF only group. Each null hypothesis was tested against the 2-sided alternative hypothesis that the mean change from baseline in serum HBsAg was not equal between each of the respective GS-4774 dose groups and the TDF only group.
    Comparison groups
    TDF 48 Weeks v TDF + GS-4774 10 YU
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.37
    Method
    		 Mixed-Effect Model for Repeated Measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.075
         upper limit
    		 0.202
    Notes
    [2] - Estimated differences in treatment effects between GS-4774 treatment groups and the TDF only group at Week 24 are presented with the 95% CIs and unadjusted P-values.
    Statistical analysis title
    		 TDF 48 Weeks Versus TDF + GS-4774 40 YU
    Statistical analysis description
    The null hypotheses was that the mean change from baseline in serum HBsAg in each of the TDF + GS-4774 groups was equal to the mean change from baseline in serum HBsAg in the TDF only group. Each null hypothesis was tested against the 2-sided alternative hypothesis that the mean change from baseline in serum HBsAg was not equal between each of the respective GS-4774 dose groups and the TDF only group.
    Comparison groups
    TDF 48 Weeks v TDF + GS-4774 40 YU
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.426
    Method
    		 Mixed-Effect Model for Repeated Measures
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.194
         upper limit
    		 0.082
    Notes
    [3] - Estimated differences in treatment effects between GS-4774 treatment groups and the TDF only group at Week 24 are presented with the 95% CIs and unadjusted P-values.

    Secondary: Mean Change in HBsAg From Baseline to Week 12

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    End point title
    		 Mean Change in HBsAg From Baseline to Week 12
    End point description
    The change from baseline to Week 12 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    55
    54
    54
    Units: log10 IU/mL
        least squares mean (confidence interval 95%)
    -0.060 (-0.165 to 0.044)
    -0.061 (-0.133 to 0.011)
    -0.012 (-0.086 to 0.061)
    -0.095 (-0.168 to -0.021)
    No statistical analyses for this end point

    Secondary: Mean Change in HBsAg From Baseline to Week 48

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    End point title
    		 Mean Change in HBsAg From Baseline to Week 48
    End point description
    The change from baseline to Week 48 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    56
    53
    55
    Units: log10 IU/mL
        least squares mean (confidence interval 95%)
    -0.145 (-0.272 to -0.017)
    -0.136 (-0.225 to -0.048)
    -0.086 (-0.176 to 0.004)
    -0.165 (-0.254 to -0.075)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBsAg Loss at Week 24

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    End point title
    		 Percentage of Participants With HBsAg Loss at Week 24
    End point description
    HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    0.0
    0.0
    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 qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24

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    End point title
    		 Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24
    End point description
    HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48

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    End point title
    		 Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48
    End point description
    HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12

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    End point title
    		 Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12
    End point description
    HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
    number (not applicable)
        ≥ 0.5 and < 1.0 log10 IU/mL Decline
    3.7
    3.5
    1.8
    5.5
        ≥ 1.0 and < 2.0 log10 IU/mL Decline
    0.0
    3.5
    0.0
    0.0
        ≥ 2.0 log10 IU/mL Decline
    0.0
    0.0
    0.0
    1.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24

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    End point title
    		 Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24
    End point description
    HBsAg with a ≥ 0.5 or ≥ 1 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
    number (not applicable)
        ≥ 0.5 and < 1.0 log10 IU/mL Decline
    0.0
    1.8
    1.8
    7.3
        ≥ 1.0 and < 2.0 log10 IU/mL Decline
    0.0
    5.3
    0.0
    1.8
        ≥ 2.0 log10 IU/mL Decline
    0.0
    0.0
    0.0
    1.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48

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    End point title
    		 Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48
    End point description
    HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window. Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
    number (not applicable)
        ≥ 0.5 and < 1.0 log10 IU/mL Decline
    11.1
    1.8
    7.1
    7.3
        ≥ 1.0 and < 2.0 log10 IU/mL Decline
    0.0
    5.3
    1.8
    1.8
        ≥ 2.0 log10 IU/mL Decline
    0.0
    0.0
    0.0
    1.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBeAg Loss at Week 24

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    End point title
    		 Percentage of Participants With HBeAg Loss at Week 24
    End point description
    HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    10
    22
    23
    21
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    4.3
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBeAg Loss at Week 48

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    End point title
    		 Percentage of Participants With HBeAg Loss at Week 48
    End point description
    HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    10
    22
    23
    21
    Units: percentage of participants
        number (not applicable)
    0.0
    4.5
    8.7
    9.5
    No statistical analyses for this end point

    Secondary: Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24

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    End point title
    		 Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24
    End point description
    HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window. Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    10
    22
    23
    21
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    4.3
    0.0
    No statistical analyses for this end point

    Secondary: Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48

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    End point title
    		 Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48
    End point description
    HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window. Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    10
    22
    23
    21
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    4.3
    9.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24

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    End point title
    		 Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24
    End point description
    The LLOQ was defined as 20 IU/mL. Participants in the Full Analysis Set with available data were analyzed. The missing equals excluded approach was used.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    26
    56
    53
    55
    Units: percentage of participants
        number (not applicable)
    50.0
    58.9
    58.5
    63.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With HBV DNA < LLOQ at Week 48

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    End point title
    		 Percentage of Participants With HBV DNA < LLOQ at Week 48
    End point description
    The LLOQ was defined as 20 IU/mL. Participants in the Full Analysis Set with available data were analyzed. The missing equals excluded approach was used.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    56
    54
    55
    Units: percentage of participants
        number (not applicable)
    70.4
    69.6
    69.2
    76.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Virologic Breakthrough at Week 24

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    End point title
    		 Percentage of Participants Experiencing Virologic Breakthrough at Week 24
    End point description
    Virologic breakthrough was defined as HBV DNA ≥ 69 IU/mL after having been < 69 IU/mL, or having had ≥ 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
        number (not applicable)
    0.0
    1.8
    1.8
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Virologic Breakthrough at Week 48

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    End point title
    		 Percentage of Participants Experiencing Virologic Breakthrough at Week 48
    End point description
    Virologic breakthrough was defined as HBV DNA ≥ 69 IU/mL after having been < 69 IU/mL, or a ≥ 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    27
    57
    56
    55
    Units: percentage of participants
        number (not applicable)
    3.7
    5.3
    5.4
    0.0
    No statistical analyses for this end point

    Secondary: Number of Participants with Drug-Resistance Mutations at Week 48 or at the Last Visit Available

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    End point title
    		 Number of Participants with Drug-Resistance Mutations at Week 48 or at the Last Visit Available
    End point description
    Resistance surveillance analysis was conducted at Week 48 or Early Discontinuation (with at least 24 weeks of exposure to TDF) for any participants who met inclusion criteria (HBV DNA ≥ 69 IU/mL). Drug-resistant mutation status was assessed using HBV polymerase/ reverse transcriptase (pol/RT) population sequencing. Participants with at least 24 weeks of exposure to TDF and with HBV DNA ≥ 69 IU/mL at Week 48 or Early Discontinuation were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Number of subjects analysed
    5
    12
    13
    8
    Units: participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events: First dose date up to last dose date (maximum exposure: 3 years); All-Cause Mortality: First dose date up to 3 years
    Adverse event reporting additional description
    Safety Analysis Set included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    TDF 48 Weeks
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks during the main study. Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in optional treatment extension phase [OTEP]).

    Reporting group title
    TDF + GS-4774 2 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 2 yeast units (YU) administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 10 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 10 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Reporting group title
    TDF + GS-4774 40 YU
    Reporting group description
    		 Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 40 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP).

    Serious adverse events
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 57 (1.75%)
    1 / 56 (1.79%)
    1 / 55 (1.82%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 55 (1.82%)
         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
    Spinal fracture
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 55 (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
    Uterine polyp
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 57 (1.75%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis tuberculous
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TDF 48 Weeks TDF + GS-4774 2 YU TDF + GS-4774 10 YU TDF + GS-4774 40 YU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 27 (44.44%)
    41 / 57 (71.93%)
    50 / 56 (89.29%)
    53 / 55 (96.36%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    2
    0
    0
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    1
    0
    0
    3
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    2
    0
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 57 (8.77%)
    1 / 56 (1.79%)
    3 / 55 (5.45%)
         occurrences all number
    1
    5
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 27 (7.41%)
    9 / 57 (15.79%)
    17 / 56 (30.36%)
    20 / 55 (36.36%)
         occurrences all number
    2
    15
    37
    35
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    0 / 27 (0.00%)
    16 / 57 (28.07%)
    32 / 56 (57.14%)
    45 / 55 (81.82%)
         occurrences all number
    0
    39
    117
    189
    Injection site erythema
         subjects affected / exposed
    0 / 27 (0.00%)
    14 / 57 (24.56%)
    20 / 56 (35.71%)
    34 / 55 (61.82%)
         occurrences all number
    0
    27
    61
    117
    Fatigue
         subjects affected / exposed
    5 / 27 (18.52%)
    10 / 57 (17.54%)
    21 / 56 (37.50%)
    22 / 55 (40.00%)
         occurrences all number
    8
    15
    50
    45
    Injection site swelling
         subjects affected / exposed
    0 / 27 (0.00%)
    9 / 57 (15.79%)
    11 / 56 (19.64%)
    22 / 55 (40.00%)
         occurrences all number
    0
    11
    28
    72
    Injection site pruritus
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 57 (7.02%)
    18 / 56 (32.14%)
    18 / 55 (32.73%)
         occurrences all number
    0
    6
    29
    44
    Injection site induration
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 57 (7.02%)
    5 / 56 (8.93%)
    18 / 55 (32.73%)
         occurrences all number
    0
    6
    16
    64
    Chills
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 57 (3.51%)
    6 / 56 (10.71%)
    9 / 55 (16.36%)
         occurrences all number
    0
    2
    18
    14
    Pyrexia
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 57 (5.26%)
    1 / 56 (1.79%)
    7 / 55 (12.73%)
         occurrences all number
    2
    3
    1
    9
    Pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 57 (1.75%)
    3 / 56 (5.36%)
    4 / 55 (7.27%)
         occurrences all number
    0
    1
    3
    4
    Influenza like illness
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 57 (5.26%)
    3 / 56 (5.36%)
    1 / 55 (1.82%)
         occurrences all number
    0
    4
    5
    1
    Injection site oedema
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 57 (0.00%)
    2 / 56 (3.57%)
    4 / 55 (7.27%)
         occurrences all number
    0
    0
    6
    12
    Asthenia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 57 (1.75%)
    1 / 56 (1.79%)
    3 / 55 (5.45%)
         occurrences all number
    0
    1
    1
    7
    Injection site reaction
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 57 (0.00%)
    4 / 56 (7.14%)
    0 / 55 (0.00%)
         occurrences all number
    0
    0
    9
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 27 (3.70%)
    6 / 57 (10.53%)
    10 / 56 (17.86%)
    11 / 55 (20.00%)
         occurrences all number
    1
    7
    26
    20
    Diarrhoea
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 57 (5.26%)
    2 / 56 (3.57%)
    2 / 55 (3.64%)
         occurrences all number
    0
    3
    2
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 57 (3.51%)
    3 / 56 (5.36%)
    1 / 55 (1.82%)
         occurrences all number
    0
    2
    3
    1
    Dyspepsia
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 57 (7.02%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 27 (11.11%)
    7 / 57 (12.28%)
    8 / 56 (14.29%)
    8 / 55 (14.55%)
         occurrences all number
    4
    8
    12
    12
    Oropharyngeal pain
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 57 (3.51%)
    3 / 56 (5.36%)
    4 / 55 (7.27%)
         occurrences all number
    2
    2
    4
    4
    Rhinorrhoea
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 57 (3.51%)
    1 / 56 (1.79%)
    1 / 55 (1.82%)
         occurrences all number
    2
    2
    1
    2
    Nasal congestion
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 57 (3.51%)
    0 / 56 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    4
    2
    0
    1
    Productive cough
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    3
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    0
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 57 (1.75%)
    1 / 56 (1.79%)
    4 / 55 (7.27%)
         occurrences all number
    0
    1
    1
    4
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 27 (3.70%)
    6 / 57 (10.53%)
    13 / 56 (23.21%)
    22 / 55 (40.00%)
         occurrences all number
    1
    6
    38
    56
    Back pain
         subjects affected / exposed
    1 / 27 (3.70%)
    6 / 57 (10.53%)
    0 / 56 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    1
    7
    0
    2
    Arthralgia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 57 (1.75%)
    3 / 56 (5.36%)
    3 / 55 (5.45%)
         occurrences all number
    0
    1
    3
    4
    Musculoskeletal pain
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 57 (3.51%)
    1 / 56 (1.79%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    1
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 57 (1.75%)
    2 / 56 (3.57%)
    9 / 55 (16.36%)
         occurrences all number
    2
    1
    3
    10
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 57 (0.00%)
    2 / 56 (3.57%)
    6 / 55 (10.91%)
         occurrences all number
    5
    0
    2
    6
    Influenza
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 57 (0.00%)
    3 / 56 (5.36%)
    5 / 55 (9.09%)
         occurrences all number
    0
    0
    3
    5
    Sinusitis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 57 (3.51%)
    2 / 56 (3.57%)
    3 / 55 (5.45%)
         occurrences all number
    0
    3
    4
    3
    Folliculitis
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    0
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2015
    The main changes were as follows: - An optional treatment extension phase was added: Weeks 48 through 144. - Language for participation in an optional biomarker substudy was clarified to align with the updated protocol template. - The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities version was updated to the version dated 18 June 2012.
    21 Oct 2016
    Changes were made to clarify definition of treatment-emergent for adverse events and laboratory evaluations as well as to update Gilead Study Director and Gilead Medical Monitor contact information and to provide the updated United States (US) Investigational New Drug (IND) (application) number.

    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/30930022
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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